@article{AdamAhrweilerSahaMoelleretal.1993,
  author    = {Adam, W. and Ahrweiler, M. and Saha-M{\"o}ller, C. R. and Sauter, M. and Sch{\"o}nberger, A. and Epe, B. and M{\"u}ller, E. and Schiffmann, D. and Stopper, Helga and Wild, D.},
  title     = {Genotoxicity studies of benzofuran dioxetanes and epoxides with isolated DNA, bacteria and mammalian cells},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-63420},
  year      = {1993},
  abstract  = {1.2-Dioxetanes, very reactive and high energy molecules. are involved as labile intermediates in dioxygenase- activated aerobic metabolism and in physiological processes. Various toxico1ogica1 tests reveal that dioxetanes are indeed genotoxic. In supercoiled DNA of bacteriophage PM2 they induce endonucleasesensitive sites, most of them are FPG protein-sensitive base modifications (8-hydroxyguanine, fonnamidopyrimidines). Pyrimidinedimersand sites ofbase loss (AP sites) which were probed by UV endonuclease and exonuclease 111 are minor lesions in this system. While the alky1-substituted dioxetanes do not show any significant mutagenic activity in different Salmonella typhimurium strains, heteroarene dioxetanes such as benzofuran and furocoumarin dioxetanes are strongly mutagenic in S. typhimurium strain TA I 00. DNA adducts formed with an intermediary alkyJating agent appear to be responsible for the mutagenic activity of benzofuran dioxetane. We assume that the benzofuran epoxides, generated in situ from benzofuran dioxetanes by deoxygenation are the ultimate mutagens of the latter. since benzofuran epoxides are highly mutagenic in the S. typhimurium strain TAIOO and they form DNA adducts. as detected by the 212Ppostlabelling technique. Our results imply that the type of D NA darnage promoted by dioxetanes is dependent on the structural feature of dioxetanes. Furthermore, the direct photochemical DNA darnage by energy transfer. i.e., pyrimidine dimers, plays a minor role in the genotoxicity of dioxetanes. Instead, photooxidation dominates in isolated DNA. while radical darnage and alkylation prevail in the cellular system.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{AlldrickLutz1989,
  author    = {Alldrick, A. J. and Lutz, Werner K.},
  title     = {Covalent binding of [2-\(^{14}\)C]2-amino-3,8-dimethylimidazo[4,5-f]-quinoxaline (MeIQx) to mouse DNA in vivo},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-60832},
  year      = {1989},
  abstract  = {Fernale BALB/c mice were administered intragastrically with equimolar amounts of either [2-\(^{14}\)C]2-amino-3,8-dimethyi[ 4,5-J]qulnoxaline (MeiQx) or 2-acetylamino[9-\(^{14}\)C]fluorene (2AAF). DNA was isolated from tissues of mice killed either 6 or 24 h after administration. Analysis of liver DNA nucleotide digests by HPLC analysis revealed that all of the radioactivity was attributable to adduct formation. Tbe specific activities of DNA samples were converted to covalent bindlog indices (CBI, J.LIDOI adduct per mol DNA nucleotides/mmol chemical app6ed per kg animal body weight). CBI values of 25 and 9 were detennined for 2AAF and MeiQx in tbe llvers of mice killed 6 h after dosing. The values were in general agreement with the moderate carcinogenic potency of these compounds. The specific activities of DNA preparations obtained from the lddneys, spleens, stomachs, small intestines and large intestlnes of mice treated witb MeiQx and killed 6 h after doslng were S- to 35-times less tban those obtained witb the llver. DNA isolated from tbe lungs (a target organ for MeiQx tumorigenicity) of MeiQx-treated mice was not radiolabeUed at tbe limit of detection (CBI <0.3). With tbe exception of tbe gastrolntestinal tract, the specific activities of DNA samples isolated from mice killed 6 h after administration were higher than those from mice killed after 24 h.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{BaertschLutzSchlatter1991,
  author    = {Baertsch, A. and Lutz, Werner K. and Schlatter, C.},
  title     = {Effect of inhalation exposure regimen on DNA binding potency of 1,2-dichloroethane in the rat},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-60743},
  year      = {1991},
  abstract  = {1 ,2-Dichloroethane (DCE) was reported to be carcinogenic in rats in a long-tenn bioassay using gavage in com oil (24 and 48 mg/kg/day), but not by inhalation (up to 150-250 ppm, 7 h/day, 5 days/week). The daily dose metabolized was similar in the two experiments. In order to address this discrepancy, the genotoxicity of DCE was investigated in vivo under different exposure conditions. Fernale F-344 rats (183-188 g) were exposed to [1,2-14C]DCE in a closed inhalation chamber to either a low, constant concentration (0.3 mg/l = 80 ppm for 4 h) or to a peak concentration (up to 18 mg/1 = 4400 ppm) for a few minutes. After 12 h in the chamber, the dose metabolized under the two conditions was 34 mg/kg and 140 mg/k:g. DNA was isolated from liver and lung and was purified to constant specific radioactivity. DNA was enzymaticaBy hydrolyzed to the 3' -nucleotides which were separated by reverse phase HPLC. Most radioactivity eluted without detectable or with little optical density' indicating that the major part of the DNA radioactivity was due to covalent binding of the test compound. The Ievel of DNA adducts was expressed in the dose-nonnalized units ofthe Covalent Binding Index, CBI = f.Lmol adduct per mol DNA nucleotide/ mmol DCE per kg body wt. In liver DNA, the different exposure regimens resulted in markedly different CBI values of 1.8 and 69, for "constant-low" and ''peak" DCE exposure Ievels. In the Jung, the respective values were 0.9 and 31. It is concluded that the DNA darnage by DCE depends upon the concentration-time profile and that the carcinogenic potency determined in the gavage study should not be used for low-Ievel inhalation exposure.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{BommakantiBokochTolleyetal.1992,
  author    = {Bommakanti, R. and Bokoch, G. M. and Tolley, J. O. and Schreiber, R. E. and Siemsen, D. W. and Klotz, Karl-Norbert and Jesaitis, A. J.},
  title     = {Reconstitution of a physical complex between the N-formyl chemotactic peptide receptor and G protein: Inhibition by pertussis toxin-catalyzed ADP ribosylation},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-60406},
  year      = {1992},
  abstract  = {Photoaffinity-labeled N-formyl chemotactic peptide receptors from human neutrophils solubilized in octyl glucoside exhibit two forms upon sucrose density gradient sedimentation, with apparent Sedimentation coefficients of approximately 4 and 7 S. Tbe 7 S form can be converted to the 4 S form by guanosine 5' -0- (3-thiotriphosphate) (GTP-yS) with an EC\&o of -20 nM, suggesting that the 7 S form may represent a physical complex of the receptor with endogenous G protein (Jesaitis, A. J., Tolley, J. 0., Bokoch, G. M., and Allen, R. A. (1989) J. Cell Biol. 109, 2783-2790). To probe the nature of the 7 S form, we reconstituted the 7 S form from the 4 S form by adding purified G protein. The 4 S form, obtained by solubilizing GTP-yS-treated neutrophil plasma membranes, was incubated with purified (>95\%) G. protein from bovine brain (containing both G\(_{ia1}\) and G\(_{ia2}\)) or with neutrophil G protein (G\(_a\)), and formation of the 7 S complex was analyzed on sucrose density gradients. The EC\(_{50}\) of 7 S complex formation induced by the two G proteins was 70 \(\pm\) 25 and 170 \(\pm\) 40 DM for G\(_a\) and G\(_1\), respectively. No complexation was measurable when bovine transducin (G\(_t\)) was used up to 30 times the EC\(_{50\) for G\(_a\). The EC\(_{50}\) for G\(_t\) was the same for receptors, obtained from formyl peptide-stimulated or unstimulated cells. The addition of 10 \(\mu\)M GTP-yS to the reconstituted 7 S complex caused a complete reversion of the receptor to the 4 S form, and anti-G\(_1\) peptide antisera immunosedimented the 7 S form. ADP-ribosylation of Gt prevented formation of the 7 S form even at 20 times the concentration of unribosylated G. normally used to attain 50\% conversion to the 7 S form. These observations suggest that the 7 S species is a pbysical complex containing N-formyl chemotactic peptide receptor and G protein.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{BommakantiKlotzDratzetal.1993,
  author    = {Bommakanti, R. K. and Klotz, Karl-Norbert and Dratz, E. A. and Jesaitis, A. J.},
  title     = {A carboxyl-terminal tail peptide of neutrophil chemotactic receptor disrupts its physical complex with G protein},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-60456},
  year      = {1993},
  abstract  = {No abstract available},
  subject      = {Toxikologie},
  language  = {en}
}
@article{BussCaviezelLutz1990,
  author    = {Buss, P. and Caviezel, M. and Lutz, Werner K.},
  title     = {Linear dose-response relationship for DNA adducts in rat liver from chronic exposure to aflatoxin B1},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-60779},
  year      = {1990},
  abstract  = {Male F-344 rats were given eH]aßatoxin B1 (AFB1) in the drinking water at three exposure Ievels (0.02, 0.6, 20 J,Lgll, resulting in average dose Ievels of 2.2, 73, 2110 nglkg per day). After 4, 6 and 8 weeks, DNA was ~ted frorn the livers and analyzed for aßatoxin-DNA adducts. Tbe Ievel of DNA adducts did not increase significantly after 4 weeks, indicating that a steady-state for adduct formation and removal had nearly been reached. At 8 weeks, the adduct Ievels were 0.91, 32 and 850 nucleotide-aßatoxin adducts per to' nucleotides, i.e. clearly proportional to the dose. At the high dose Ievel, a near SO\% tumor incidence would be expected in a 2-year bioassay with F -344 rats while the low dose used is within the range of estlmated human dietary exposures to aßatoxin in W estem countries. The proportionality seen between exposure and steady-state DNA adduct Ievel is discussed with respect to a linear extrapolation of the tumor risk to low dose.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{BoeschFriederichLutzetal.1987,
  author    = {B{\"o}sch, R. and Friederich, U. and Lutz, Werner K. and Brocker, E. and Bachmann, M. and Schlatter, C.},
  title     = {Investigations on DNA binding in rat liver and in Salmonella and on mutagenicity in the Ames test by emodin, a natural anthraquinone},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-60913},
  year      = {1987},
  abstract  = {Emodin (1,6,8-trihydroxy-3-methylanthraquinone), an important aglycone found in natural anthraquinone glycosides frequently used in Iaxative drugs, was mutagenic in the Salmonellajmammalian microsome assay (Ames test) with a specificity for strain TA1537. The mutagenic activity was activationdependent with an optimal amount of S9 from Aroclor 1254-treated male Sprague-Dawley rats of 20\% in the S9 mix (v jv) for 10 p.g emodin per plate. Heat inactivation of the S9 for 30 min at 60 ° C prevented mutagenicity. The addition of the cytochrome P-448 inhibitor 7,8-benzoflavone (18.5 nmoles per plate) reduced the mutagenic activity of 5.0 p.g emodin per plate to about one third, whereas the P-450 inhibitor metyrapone (up to 1850 nmoles per plate) was without effect. To test whether a metabolite" binds covalently to Salmonella DNA, [10-\(^{14}\)C]emodin was radiosynthesized, large batches of bacteria were incubated with [10-\(^{14}\)C]emodin and DNA was isolated. [G- \(^{3}\)H]Aflatoxin B1 (AFB1) was used as a positive control mutagen known to act via DNA binding. DNA obtained after aflatoxin treatment could be purified to constant specific activity. With emodin, the specific activity of DNA did not remain constant after repeated precipitations so that it is unlikely that the mutagenicity of emodin is due to covalent interaction of a metabolite with DNA. The antioxidants vitamin C and E or glutathione did not reduce the mutagenicity. Emodin was also negative with strain TA102. Thus, oxygen radicals are probably not involved. When emodin was incubated with S9 alone for up to 50 h before heat-inactivation of the enzymes and addition of bacteria, the mutagenic activity did not decrease. It is concluded that the mutagenicity of emodin is due to a chemically stable, oxidized metabolite forming physico-chemical associations with DNA, possibly of the intercalative type. In order to check whether an intact mammalian organism might be able to activate emodin to a DNA-binding metabolite, radiolabelled emodin was administered by oral gavage to male SD rats and liver DNA was isolated after 72 h. Very little radioactivity was associated with the DNA. Considering that DNA radioactivity could also be due to sources other than covalent interactions, an upper limit for the · covalent binding index, CBI = (p.moles chemical bound per moles DNA nucleotides)/(mmoles chemical administered per kg body weight) of 0.5 is deduced. This is 104 times below the CBI of AFB1. The demonstration of a lack of covalent interaction with DNA bothin Salmonellaandin rat liver is discussed in terms of a reduced hazard posed by emodin as a mutagenic drug in use in humans.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{BuesserLutz1987,
  author    = {B{\"u}sser, M. T. and Lutz, Werner K.},
  title     = {Stimulation of DNA synthesis in rat and mouse liver by various tumor promoters},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-60908},
  year      = {1987},
  abstract  = {In order to investigate whether the Stimulation of liver DNA synthesis might be used to detect one class of hepatic tumor promoters, the incorporation of orally administered radiolabelled thymidine into liver DNA was detennined in rats and mice 24 h after a single oral gavage of test compounds at various dose Ievels. Three DNA-binding hepatocarcinogens, aflatoxin B1; benzidine and carbon tetrachloride, did not stimulate but rather inhibited DNA synthesis (not for CCla). Four hepatic tumor promoters, clofibrate, DDT, phenobarbital and thioacetamide, gave rise to a Stimulation in a dosedependent manner. Single oral doses between 0.02 and 0.3 mmol/kg were required to double the level of thymidine incorporation into liver DNA (= doubling dose, DD). Differentes between species or sex as obsprved in long-term carcinogenicity studies were reflected by a different stimulation of liver DNA synthesis. In agreement with the bioassay data, aldrin was positive only in male mice (DD = 0.007 mmol/kg) but not in male rats or female mice. 2,3, 7,8-TCDD was positive in male mice (DD = 10\(^{-6}\) mmol/kg) andin female rats (DD = 2 x 10\(^{-6}\) mmol/kg) but not in male rats. The assay was also able to distinguish between structural isomers with different carcinogenicities. [alpha]Hexachlorocyclohexane stimulated Iiver DNA synthesis with a doubling dose of about 0.2 mmol/kg in male rats whereas the [gamma]isomer was ineffective even at l mmol/kg. So far, only one result was inconsistent with carcinogenicity bioassay data. The different carcinogenicity of di(2-ethylhexyl)adipate (negative in rats) and di(2-ethylhe.xyl)phthalate (positive) was not detectable. 8oth plasticizers were positive in.this short-term system with DD's of 0. 7 mmol/kg for DEHA and 0.5 mmol/kg for DEHP. The proposed assay is discussed as an attempt to devise short-term assays for carcinogens not detected by the routine genotoxicity test systems.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{CantoreggiDietrichLutz1993,
  author    = {Cantoreggi, S. and Dietrich, D. R. and Lutz, Werner K.},
  title     = {Induction of cell proliferation in the forestomach of F344 rats following subchronic administration of styrene 7,8-oxide and butylated hydroxyanisole},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-60669},
  year      = {1993},
  abstract  = {The question addressed was whether Stimulation of cell proliferation could be responsible for tumor induction in the torestornach by styrene 7,8-oxide (SO). Male F344 rats were treated for 4 weeks with 0, 137,275, and 550 mglkg SO by p.o. gavage 3 times/week. Positive controls received 0, 0.5, I, and 2\% butylated hydroxyanisole (BHA) in the diet for 4 weeks. Twenty-four h before termination of the experlment, the rats were implanted s.c. with an osmotic minipump deliverlog S-bromo-2'-deoxyuri· dine (BrdU). Cell proliferation in the forestomach was assessed by immunohistochemistry for BrdU incorporated into DNA. Cell number/mm section length and fraction of replicating cells (labeling Index) were determined in 3 domains of the forestomach, the saccus caecus, the midregion, and the prefundic region. With the exception of the prefundic reglon of the low-dose SO group, a significant increase of the labeling index was found in all regions both with SO and BHA. Rats treated with BHA showed, in addition, a dose-dependent increase in number and size of hyperplastic lesions. This was most pronounced in the prefundic region where carcinomas were reported to be localized. In this region, the number of dividing cells/mm section length was increased up to 17-fold. With SO, only marginal morphological changes were occasionally observed, despite the fact that the respective long-term treatment bad been reported to result in a higher carcinoma incidence than treatment with BHA. It ls concluded that the rate of replicating cells alone, numerically expressed by the labeling Index, is an lnsufficient tool for interpretlog the role of cell division in carcinogenesis. It is postulated that SO and BHA induce forestomach tumors via different mechanisms. While hyperplasia in the prefundic region most likely dominates the carcinogenicity of BHA, a mechanism combining marginal genotoxicity with strong promotion by increased cell proliferation appears to be involved in the tumorigenic action of SO.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{CantoreggiLutz1993,
  author    = {Cantoreggi, S. and Lutz, Werner K.},
  title     = {Covalent binding of styrene to DNA in rat and mouse},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-60693},
  year      = {1993},
  abstract  = {No abstract available},
  subject      = {Toxikologie},
  language  = {en}
}
@article{CantoreggiLutz1992,
  author    = {Cantoreggi, S. and Lutz, Werner K.},
  title     = {Investigation of the covalent binding of styrene-7,8-oxide to DNA in rat and mouse},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-60721},
  year      = {1992},
  abstract  = {Styrene-7,8-oxide (SO), the main intennediate metabolite of styrene, induces hyperkeratosis and tumors in the forestomach of rats and mice upon chronic administration by gavage. The aim of this study was to investigate wbether DNA binding could be responsible for the carcinogenic effect observed. [7-\(^3\)H]SO was administered by oral gavage in com oll to male CD rats at two dose levels (1.65 or 240 mg/kg). After 4 or 24 h, forestomach, glandular stomach and Uver were exclsed, DNA was isolated and its radioactivity detennined. At the 4 h time polnt, the DNA radioactivity was below the Iimit of detection in the torestornach and the liver. Expressed in the units of the covalent bindlng Index, CBI = (pmol adduct/mol DNA nucleotide)/(mmol cbemical administeredlkg body wt), the DNA-binding potency was below 2.6 and 2.0 respectively. In the glandular stomach at 4 b, and in most 24 b samples, DNA was slightly radiolabeled. Enzymatic degradation of the DNA and separation by HPLC ofthe normal nucleotides sbowed that the DNA rad.ioactivity represented biosynthetic incorporation of radlolabel into newly synthesized DNA. The Iimit of detection of DNA adducts in the glandular stomach was 1.0. In a second experlment, [7-\(^3\)H]SO was administered by i.p. injection to male 86C3Fl rnice. Liver DNA was analyzed after 2 h. No radloactivity was detectable at a Iimit of detection of CBI < 0.6. In agreement with the relatively long half-life of SO in animals, the cbemical reactivity of SO appears to be too low to result in a detectable production of DNA adducts in an in vivo situation. Upon comparison with the DNA-binding of other carcinogens, a purely genotoxic mechanism of tumorigenJc action of SO is unlikely. The observed tumorigenic potency in the forestomach could be the result of strong tumor promotion by high-dose cytotoxicity foUowed by regenerative hyperplasia.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{CaviezelLutzMininietal.1984,
  author    = {Caviezel, M. and Lutz, Werner K. and Minini, U. and Schlatter, C.},
  title     = {Interaction of estrone and estradiol with DNA and protein of liver and kidney in rat and hamster in vivo and in vitro},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-60995},
  year      = {1984},
  abstract  = {(6,7-\(^3\)H] Estrone (E) and [6,7-\(^3\)H]estradiol-17ß (E\(_2\)) have been synthesized by reduction of 6-dehydroestrone and 6-dehydroestradiol with tritium gas. Tritiated E and E\(_2\) were administered by oral gavage to female rats and to male and female hamsters on a dose level of about 300 \(\mu\)g/kg (54 mCi/kg). After 8 h, the liver was excised from the rats; liver and kidneys were taken from the hamsters. DNA was purified either directly from an organ homogenate or via chromatin. The radioactivity in the DNA was expressed in the units of the Covalent Binding Index, CBI = (\(\mu\)mol chemical bound per mol Similar considerations can be made for the liver where any true covalent DNA binding must be below a Ievel of 0.01. It is concluded that an observable tumor induction by estrone or estradiol is unlikely to be due to DNA binding. DNA-P)/(mmol chemical administered per kg b.w.). Rat liver DNA isolated via chromatin exhibited the very low values of 0.08 and 0.09 for E and E\(_2\) respectively. The respective figures in hamster liver were 0.08 and 0.11 in females and 0.21 and 0.18 in the males. DNA isolated from the kidney revealed a detectable radioactivity only in the female, with values of 0.03 and 0.05 for E and E\(_2\) respectively. The values for male hamster kidney were < 0.01 for both hormones. The minute radioactivity detectable in the DNA samples does not represent covalent binding to DNA, however, as indicated by' two sets of control experiments. (A) Analysis by HPLC of the nucleosides prepared by enzyme digest of liver DNA isolated directly or via chromatin did not reveal any consistent peak which could have been attributed to a nucleoside-steroid adduct. (B) All DNA radioactivity could be due to protein contaminations, because the specific activity of chromatin protein was determined to be more than 3 ,000 tim es high er than of DNA. The high affinity of the hormone to protein was also demonstrated by in vitro incubations, where it could be shown that the specific activity of DNA and protein was essentially proportional to the concentration of radiolabelled hormone in the organ homogenate, regardless of whether the animal was treated or whether the hormone was added in vitro to the homogenate. Carcinogens acting by covalent DNA binding can be classified according to potency on the basis of the Covalent Binding Index. Values of 10\(^3\)-10\(^4\) have been found for potent, 10\(^2\) for moderate, and 1-10 for weak carcinogens. Since estrone is moderately carcinogenic for the kidney of the male hamster, a CBI of about 100 would be expected. The actually measured Iimit of detection of 0.01 places covalent DNA binding among the highly unlikely mechanisms of action.},
  subject      = {Toxikologie},
  language  = {en}
}
@phdthesis{Colnot2001,
  author    = {Colnot, Thomas},
  title     = {Beurteilung von Phyto- und Xeno{\"o}strogenen am Beispiel ausgew{\"a}hlter Substanzen},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-1180438},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2001},
  abstract  = {Bei Daidzein und Bisphenol A handelt es sich um zwei Vertreter einer Klasse von Stoffen, die als „Umwelthormone" (engl. endocrine disrupter) bezeichnet werden. Aus der Gruppe der Phyto{\"o}strogene wurde Daidzein als wichtiger Vertreter, der in hohen Konzentrationen in vielen Nutzpflanzen und Nahrungsmitteln vorkommt, ausgew{\"a}hlt. Sojaprodukte, die den gr{\"o}ßten Beitrag einer menschlichen Exposition gegen Daidzein liefern, werden in zunehmendem Maße auch in westlichen L{\"a}ndern konsumiert. Bisphenol A wurde als Vertreter der Xeno{\"o}strogene gew{\"a}hlt, da es - was Weltjahresproduktion und Verwendung angeht - die wohl wichtigste Substanz dieser Gruppe darstellt. Im ersten Teil der Arbeit wurde die Biotransformation und Toxikokinetik der beiden Verbindungen nach oraler Gabe in der Ratte aufgekl{\"a}rt. Dabei konnte gezeigt werden, daß die orale Bioverf{\"u}gbarkeit beider Substanzen in der Ratte sehr gering war. Maximal zehn Prozent der jeweils applizierten Dosis konnten im Urin der Tiere wiedergefunden werden. Als Hauptmetabolit wurden sowohl von Daidzein als auch von Bisphenol A das jeweilige Glucuronid-Konjugat gebildet. Bei Daidzein {\"u}berwog in der m{\"a}nnlichen Ratte zus{\"a}tzlich das Sulfat-Konjugat. Der Anteil an freier, d.h. unkonjugierter Verbindung betrug im Urin der Tiere zwischen 1 und 3 Prozent der Dosis. Außer den Phase II-Konjugaten, die aufgrund ihrer mangelnden {\"o}strogenen Wirksamkeit zu einer Detoxifizierung der beiden Verbindungen f{\"u}hrte, konnten nach Gabe von Bisphenol A in der Ratte keine weiteren Metabolite identifiziert werden. Nach Exposition mit Daidzein konnten in den Faeces der Tiere in geringem Umfang die beiden reduktiven Metabolite Equol und O-DMA gefunden werden. Diese wurden wahrscheinlich im Magen-Darm-Trakt durch die Bakterien der Darmflora gebildet. Sowohl Daidzein als auch Bisphenol A wurden bei der Ratte nur unvollst{\"a}ndig aus dem Magen-Darm-Trakt resorbiert; der Großteil der gegebenen Dosis wurde als unver{\"a}nderte Substanz in den Faeces wiedergefunden. Bei Bisphenol A wurde die Ausscheidung zudem durch einen ausgepr{\"a}gten enterohepatischen Kreislauf verz{\"o}gert. Im zweiten Teil der Arbeit wurden zun{\"a}chst empfindliche GC/MS- und HPLC-Methoden zur Quantifizierung der Verbindungen in humanen Plasma- und Urinproben entwickelt. Danach wurden freiwillige Probanden oral mit jeweils 5 mg Daidzein bzw. d16-Bisphenol A exponiert, um Daten zur Biotransformation und Toxikokinetik der beiden Substanzen im Mensch zu erhalten. Wegen des deutlich meßbaren Hintergrundes an Bisphenol A, das in allen Kontrollproben nachweisbar war, wurde f{\"u}r die Humanstudie die deuterierte Verbindung gegeben, f{\"u}r die kein st{\"o}render Hintergrund meßbar war. Die Bioverf{\"u}gbarkeit der Gesamt-Substanz (freie Verbindung + Konjugate) im Menschen war in beiden F{\"a}llen deutlich h{\"o}her als in der Ratte. Von Daidzein wurden 40 Prozent (Ratte 10 Prozent), von Bisphenol A > 95 Prozent (Ratte 13 Prozent) der applizierten Dosis im Urin der Probanden wiedergefunden. Dabei zeigte sich ein sehr effizienter Phase II-Metabolismus; weniger als 1 Prozent der Glucuronid-Konjugatkonzentrationen wurden als unver{\"a}nderte Substanz gefunden. Das Glucuronid stellte in beiden F{\"a}llen den einzigen nachweisbaren Metaboliten dar. Die Elimination von Daidzein und Bisphenol A verlief in den beiden Studien sehr schnell nach einer Kinetik erster Ordnung. Im Gegensatz zu der Ratte konnten auch bei Bisphenol A keine Auff{\"a}lligkeiten in den Ausscheidungskurven beobachtet werden, Hinweise auf einen enterohepatischen Kreislauf im Menschen wurden nicht gefunden. Im Falle von Bisphenol A wurde fast die komplette applizierte Dosis (> 95 Prozent) in Form des Glucuronides im Urin wiedergefunden. Anhand der erhobenen Daten wurde anschließend eine Beurteilung des Risikos f{\"u}r den Menschen abgegeben.},
  subject      = {Phyto{\"o}strogen},
  language  = {de}
}
@article{CristalliEleuteriVittorietal.1992,
  author    = {Cristalli, G. and Eleuteri, A. and Vittori, S. and Volpini, R. and Lohse, M. J. and Klotz, Karl-Norbert},
  title     = {2-Alkynyl derivatives of adenosine and adenosine-5'-N-ethyluronamides as selective agonists at A\(_2\) adenosine receptors},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-60412},
  year      = {1992},
  abstract  = {In the search for more selective A2-receptor agonists and on the basis that appropriate substitution at C2 is known to impart selectivity for A\(_2\) receptors, 2-alkynyladenosines 2a-d were resynthesized and evaluated in radioligand binding, adenylate cycla.se, and platelet aggregation studies. Binding of [\(^3\)H]NECA to A\(_2\) receptors of rat striatal membranes was inhibited by compounds 2a-d with K\(_i\) values ranging from 2.8 to 16.4 nM. 2-Alkynyladenosines also exhibited high-affmity binding at solubilized A\(_2\) receptors from human platelet membranes. Competition of 2-alkynyladenosines 2a-d for the antagonist radioligand [\(^3\)H]DPCPX and for the agonist [\(^3\)H]CCPA gave K\(_i\) values in the nanomolar range, and the compounds showed moderate A\(_2\) selectivity. In order to improve this selectivity, the correaponding 2-alkynyl derivatives of adenosine-5'-N-ethyluronamide 8a-d were synthesized and tested. A\(_1\) expected, the 5'-N-ethyluronamide derivatives retained the A\(_2\) affinity whereas the A\(_1\) affinity was attenuated, resulting in an up to 10-fold increase in A\(_2\) selectivity. A similar patternwas observed in adenylate cyclase assays andin platelet aggregation studies. A 30- to 45-fold selectivity for platelet A\(_2\) receptors compared to A\(_1\) receptors was found for compounds 8a-c in adenylate cyclase studies.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{CristalliFranchettiGrifantinietal.1988,
  author    = {Cristalli, G. and Franchetti, P. and Grifantini, M. and Vittori, S. and Klotz, Karl-Norbert and Lohse, M. J.},
  title     = {Adenosine receptor agonists: Synthesis and biological evaluation of 1-deaza analogues of adenosine},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-60262},
  year      = {1988},
  abstract  = {In a search for more selective A\(_1\) adenosine receptor agonists, N\(^6\)-[(R)-(-)-1-methyl-2-phenethyl]-1-deazaadenosine (1-deaza-R-PIA, 3a), N\(^6\)-cyclopentyl-1-deazaadenosine (1-deazaCPA, 3b), N\(^6\)-cyclohexyl-l-deazaadenosine (1-deazaCHA, Sc), and the corresponding 2-chloro derivatives 2a-c were synthesized from 5,7-dichloro-3-ß-D-ribofuranosyl-3Himidazo[ 4,5-b]pyridine (1). On the other band, N-ethyl-1'-deoxy-1'-(1-deaza-6-amino-9H-purin-9-yl)-ß-D-ribofuranuronamide (1-deazaNECA, 10) was prepared from 7-nitro-3-ß-D-ribofuranosyl-3H-imidazo[4,5-b]pyridine (4), in an attempt to find a more selective A\(_2\) agonist. The activity of all deaza analogues at adenosine receptors has been determined in adenylate cyclase andin radioligand binding studies. 1-DeazaNECA (10) proved tobe a nonselective agonist at both subtypes of the adenosine receptor. It is about 10-fold less active than NECA but clearly more active than the parent compound 1-deazaadenosine as an inhibitor of platelet aggregation and as a stimulator of cyclic AMP accumulation. The N\(^6\)-substituted 1-deazaadenosines largely retain the A\(_1\) agonist activity of their parent compounds, but lose some of their A\(_2\) agonist activity. This results in A\(_1\)-selective compounds, of which N\(^6\)cyclopentyl- 2-chloro-1-deazaadenosine (1-deaza-2-Cl-CPA, 2b) was identified as the most selective agonist at A\(_1\) adenosine receptors so far known. The activity of all 1-deaza analogues confirms that the presence of the nitrogen atom at position 1 of the purine ring is not critical for A\(_1\) receptor mediated adenosine actions.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{DaenikenFriederichLutzetal.1981,
  author    = {D{\"a}niken, A. von and Friederich, U. and Lutz, Werner K. and Schlatter, C.},
  title     = {Tests for mutagenicity in Salmonella and covalent binding to DNA and protein in the rat of the riot control agent o-chlorobenzylidene malononitrile (CS)},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-61073},
  year      = {1981},
  abstract  = {The aim of this study was to determine whether o-chlorobenzylidene malononitrile ( CS) exhibits any genotoxic activity towards Salmonella or mammalian DNA in vivo. CS was synthesized with a [\(^{14}\)C]-label at the benzylic carbon atom. It was administered i. p. at a dose level of 13 mg/kg (1 mCi/kg) to young adult male rats. Liverand kidney DNA was isolated after 8, 25, and 75 h. The radioactivity was at (liver, 8 and 75 h) or below (all other samples) the limit of detection of 3 dpm. Therefore, a possible binding of CS to DNA is at least 10\(^5\) times lower than that of the strong hepatocarcinogen aflatoxin B1, and 4,000 times lower than that of vinyl chloride. In contrast to this lack of DNA binding, but in agreement with the chemical reactivity of CS, a binding to nuclear proteins could be detected with specific activities ranging between 50 and 121 dpm/mg for liver and between 3 and 41 dpm/mg for kidney. Protein binding could well be responsible for its pronounced cytotoxic effects. Cs was also tested in the Ames Salmonella/microsome assay. Strains TA 1535, TA 1537, TA 1538, TA 98, and TA 100 were used with or without pre-incubation. Only with strain TA 100 and only without pre-incubation, a doubling of the number of revertants was detectable at the highest dose Ievels used, 1,000 and 2,000 !lg CS per plate. With pre-incubation of TA 100 with CS, a slight increase of the number of revertants was seen at 100 and 500 !lg per plate, and a subsequent fall below control values at 1,000 J.tg. A check for the number of surviving bacteria revealed a strong bacteriotoxicity of the higher doses of es so that the calculated mutation frequencies, i.e., the oumber of revertants per number of surviving bacteria, increased with doses up to 500 !J.g. This toxicity could be counteracted in part by the addition of increasing amounts of rat liver microsomes. In the view of these results, and taking into account the rare and low exposure of man, it is concluded that CS will not create a risk for the induction of point mutations or of carcinogenic processes mediated by DNA binding.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{DaenikenLutzJaeckhetal.1984,
  author    = {D{\"a}niken, A. von and Lutz, Werner K. and J{\"a}ckh, R. and Schlatter, C.},
  title     = {Investigation of the potential for binding of Di(2-ethylhexyl) phthalate (DEHP) and Di(2-ethylhexyl) adipate (DEHA) to liver DNA in vivo},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-61004},
  year      = {1984},
  abstract  = {Investigation of the Potential for Binding of Di(2-ethylhexyl) Phthalate (DEHP) and Di(2- ethylhexyl) Adipate (DEHA) to Liver DNA in Vivo. VON D{\"A}NIKEN, A., LUTZ, W. K., J{\"A}CKH, R., AND ScHLATTER, C. (1984). Toxico/. App/. Pharmaco/. 73, 373-387. It was the aim oftbis investigation to determine whether covalent binding of di(2-ethylhexyl) phthalate (DEHP) to rat liver DNA and of di(2-ethylhexyl) adipate (DEHA) to mouse liver DNA could be a mechanism of action contributing to the observed induction of liver tumors after lifetime feeding of the respective rodent species with high doses of DEHP and DEHA. For this purpose, DEHP and DEHA radiolabeled in different parts of the molecule were administered orally to female rats and mice, respectively, with or witbout pretreatment for 4 weeks with 1\% unlabeled compound in the diet. Liver DNA was isolated after 16 hr and analyzed for radioactivity. The data were converted to a covalent binding index, CBI = (micromoles of substance bound per mole of DNA nucleotides)/(millimoles of substance applied per kilogram body weight), in order to allow a quantitative comparison also with other carcinogens and noncarcinogens. Administration of [\(^{14}\)H]carboxylate-labeled DEHP to rats resulted in no measurable DNA radioactivity. The Iimit of detection, CBI < 0.02 was about 100 times below the CBI of compounds where an observable tumor-inducing potential could be due to genotoxicity. With [\(^{14}\)C]- and [\(^{3}\)H]DEHP labeled in the alcohol moiety, radioactivity was clearly measurable in rat liver DNA. HPLC analysis of enzyme-degraded or acid-hydrolyzed DNA revealed that the natural nucleosides or purine bases were radiolabeled whereas no radioactivity was detectable in those fractions where tbe carcinogenmodified nucleoside or base adducts are expected. The respective Iimits of detection were at 0.07 and 0.04 CBI units for the \(^{14}\)C and \(^{3}\)H Iabels, respectively. The experiments with [\(^{14}\)C]- and [\(^{3}\)H]DEHA, labeled in the alcobol moiety and administered to mice, revealed aminute radioactivity of <50 dpm/mg liver DNA, too little to allow a nucleoside analysis to determine that fraction of the radioactivity which bad been incorporated via biosynthesis. Expressed in the CBI units, values of 0.05 to 0.15 for \(^{14}\)C and 0.01 to 0.12 for \(^{3}\)H resulted. Determination of the level· of \(^{14}\)C02 expiration revealed a linear correlation with the speciftc activity of DNA. Experiments with 2-ethyl[ 1-\(^{14}\)C]hexanol perfonned with both rats and mice allowed the conclusion tbat most if not all DEHA radioactivity in mouse liver DNA was due to biosynthetic incorporation. A maximum possible true DNA binding by DEHA must be below CBI 0.01. Pretreatment of the animals witb unlabeled compound bad no effect on the DNA radioactivities in either species. The present negative data, in conjunction witb other negative short-term tests for mutagenicity, strongly indicate that covalent interaction with DNA is highly unlikely to be the mode of tumorigenic action of DEHP and DEHA in rodents.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{DaenikenLutzSchlatter1981,
  author    = {D{\"a}niken, A. von and Lutz, Werner K. and Schlatter, C.},
  title     = {Lack of covalent binding to rat liver DNA of the hypolipidemic drugs clofibrate and fenofibrate},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-61087},
  year      = {1981},
  abstract  = {\(^{14}\)C-Labelled clofibric acid and fenofibric acid were administered p.o. to 200 g male and female rats. After 10 h, liver nuclear DNA and protein were isolated and the radioactivity was determined. Binding to protein was clearly measurable whereas no binding to DNA could be detected from any drug. A comparison of the Iimit of detection of such DNA binding with well-known chemical carcinogens revealed that the known hepatocarcinogenicity of clofibrate cannot be based upon an initiating, DNA damaging, mode of action but must be due to other, nongenotoxic, mechanisms such as peroxisome proliferation, hepatomegaly, or cytotoxicity due to protein binding. The risk assessment in man and the interpretation of the carcinogenicity data for rodents are discussed.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{EpeHarttigStopperetal.1990,
  author    = {Epe, B. and Harttig, U. and Stopper, Helga and Metzler, M.},
  title     = {Covalent binding of reactive estrogen metabolites to microtubular protein as a possible mechanism of aneuploidy induction and neoplastic cell transformation},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-63478},
  year      = {1990},
  abstract  = {Neoplastic cell transfonnation induced by estrogens and some other carcinogen\& such as benzene appears to involve the induction of mitotic aneuploidy rather than DNA damage and point mutations. As metabolic activation may also play an important roJe in the mechanism of carcinogenesis of these nongenotoxic compounds, we have studied the Interaction of reactive quinone metabolites of various estrogens and of benzene with the major microtubular protein, tubulin, in a cell-free system. Covalent binding of the radioactively labeled metabolites to the a- and 13-subunit of tubulin was found to depend on the structure of the metabolite. When the adducted tubulins were tested in vitro for their ability to polymerize to microtubules, Inhibition of microtubule assembly was obsened in every case, although to varying extents. It is proposed that the fonnation of covalent tubulin adducts may impair the formation of mitotic spindies and thus contribute to chromosomal nondisjunction and aneuploidy induction.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{FischerBelandLutz1993,
  author    = {Fischer, W. H. and Beland, P. E. and Lutz, Werner K.},
  title     = {DNA adducts, cell proliferation and papilloma latency time in mouse skin after repeated dermal application of DMBA and TPA},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-60673},
  year      = {1993},
  abstract  = {'lbe mouse skin tumor model was used to investigate whether the Ievel of DNA 8dducts and/or the rate of cell division in the epidermis are indicators of the risk of cancer formation for an individual in an outbred animal popul8tion. A high risk was considered to be reftected by 8 short latency period for the 8ppearance of 8 papilloma. Fernale NMRI mice were treated twice weekly with 2.5 nmol 7 ,12-dimethylbenz[a]antbracene (DMBA) and 3 nmoi12-0-tetradecanoylphorbol-13- 8cetate (TPA) and the appearance of papillomas was registered. The first papilloma 8ppeared after 7.5 weeks. After 17 weeks, when 12 of 14 mice bad 8t least one papilloma, an osmotic minipump deliverlog 5-bromo-2'deoxyuridine (BrdU) was implanted into eacb mouse for 24 h. The mice were killed after 24 h ~d the epidermis was analyzed for D:MBA-nucleotide 8dducts by 32p.postlabeling, for the cell number per unit skin length, and for the labeling index for DNA synthesls. Unexpectedly, D:MBA-nucleotide 8dduct Ievels were highest in those anima1s wbich showed the Iongest latency periods. Adduct Ievels were negatively correlated with the 18beling index, indicating that dilution of adducts by cell division was a predominant factor in determining average adduct concentrations. Individual tumor-latency time was not corTelated with either cell ntunber or labeling index. This could be due to the fact that the measurements only provided 8veraged data and gave no infonnation on the specific situation in clones of premalignant cells. Under the conditions of tbis assay, therefore, neither DNA adduct Ievels nor information on the average kinetics of cell division bad a predidive value for the individual amcer risk withln a group of outbred animals receiving the same treatment},
  subject      = {Toxikologie},
  language  = {en}
}
@article{FischerLutz1994,
  author    = {Fischer, W. H. and Lutz, Werner K.},
  title     = {Short communication : Mouse skin papilloma formation by chronic dermal application of 7,12-dimethylbenz[a]anthracene is not reduced by diet restriction},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-60644},
  year      = {1994},
  abstract  = {No abstract available},
  subject      = {Toxikologie},
  language  = {en}
}
@article{FoertschHuppMaetal.2011,
  author    = {F{\"o}rtsch, Christina and Hupp, Sabrina and Ma, Jiangtao and Mitchell, Timothy J. and Maier, Elke and Benz, Roland and Iliev, Asparouh I.},
  title     = {Changes in Astrocyte Shape Induced by Sublytic Concentrations of the Cholesterol-Dependent Cytolysin Pneumolysin Still Require Pore-Forming Capacity},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-69084},
  year      = {2011},
  abstract  = {Streptococcus pneumoniae is a common pathogen that causes various infections, such as sepsis and meningitis. A major pathogenic factor of S. pneumoniae is the cholesterol-dependent cytolysin, pneumolysin. It produces cell lysis at high concentrations and apoptosis at lower concentrations. We have shown that sublytic amounts of pneumolysin induce small GTPase-dependent actin cytoskeleton reorganization and microtubule stabilization in human neuroblastoma cells that are manifested by cell retraction and changes in cell shape. In this study, we utilized a live imaging approach to analyze the role of pneumolysin's pore-forming capacity in the actin-dependent cell shape changes in primary astrocytes. After the initial challenge with the wild-type toxin, a permeabilized cell population was rapidly established within 20-40 minutes. After the initial rapid permeabilization, the size of the permeabilized population remained unchanged and reached a plateau. Thus, we analyzed the non-permeabilized (non-lytic) population, which demonstrated retraction and shape changes that were inhibited by actin depolymerization. Despite the non-lytic nature of pneumolysin treatment, the toxin's lytic capacity remained critical for the initiation of cell shape changes. The non-lytic pneumolysin mutants W433F-pneumolysin and delta6-pneumolysin, which bind the cell membrane with affinities similar to that of the wild-type toxin, were not able to induce shape changes. The initiation of cell shape changes and cell retraction by the wild-type toxin were independent of calcium and sodium influx and membrane depolarization, which are known to occur following cellular challenge and suggested to result from the ion channel-like properties of the pneumolysin pores. Excluding the major pore-related phenomena as the initiation mechanism of cell shape changes, the existence of a more complex relationship between the pore-forming capacity of pneumolysin and the actin cytoskeleton reorganization is suggested.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{GimplGerstbergerMaussetal.1990,
  author    = {Gimpl, G. and Gerstberger, R. and Mauss, U. and Klotz, Karl-Norbert and Lang, R. E.},
  title     = {Solubilization and characterization of active neuropeptide-Y receptors from rabbit kidney},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-60375},
  year      = {1990},
  abstract  = {Active neuropeptide Y receptors were solubilized from rabbit kidney membranes using the zwitterionic detergent 3-[ (3-cholamidopropy l)dimethylammonio ]- 1-propanesulfonic acid (CHAPS). In membrane fragmentsandsoluble extracts neuropeptide Y bindingwas time dependent, saturable, reversible, and of high affinity. Scatchard analysis of equilibrium binding data indicated a single class of binding sites with respective Kn and Bmax values of 0.09 nM and 530 fmol/mg of protein for the membrane-bound receptors and 0.10 nM and 1585 fmol/mg of protein for the soluble receptors. Neuropeptide Y bindingwas specifically inhibited by the nonhydrolyzable GTP analog guanosine 5' -0- (3-thiotripbosphate) in a concentration-dependent manner, with IC\(_{50}\) values of 28 and 0.14 \(\mu\)M for membrane- bound and soluble receptors, respectively, suggesting that neuropeptide Y receptors are functionally coupled to GTP-binding regulatory proteins. CrossHoking studies were performed with the heterobifunctional N-hydroxysuccinimidyl-4-azidobenzoate and the monofunctional neuropeptide Y derivative, azidobenzoyl and led to the identification of a 100 kDa peptide that should represent the covalently labeled neuropeptide Y receptor.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{GonzalesCaleroCuberoKlotz1992,
  author    = {Gonzales-Calero, G. and Cubero, A. and Klotz, Karl-Norbert},
  title     = {G protein coupled A\(_1\) adenosine receptors in coated vesicles of mammalian brain. Characterization by radioligand binding and photoaffinity labeling},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-60435},
  year      = {1992},
  abstract  = {A\(_1\) adenosine receptors in coated vesicles have been characterized by radioligand binding and photoaflinity labelling. Saturation experiments with the antagonist 8-cyclopentyl-1 ,3-[\(^3\)H]dipropyl-xanthine ([\(^3\)H]DPCPX) gave a Kdvalue of 0.7 nM and a Bmax value of 82± 13 fmol/mg protein. For the highly A\(_1\)-selective agonist 2-chloro-N\(^6\)-[\(^3\)H]cyclopentyladenosine ([\(^3\)H]CCPA) a Kd value of 1.7 nM and a Bmax value of 72 ± 29 fmol/mg protein was estimated. Competition of agonists for [\(^3\)H]DPCPX binding gave a pharmacological profile with R-N\(^6\)-phenylisopropyladenosine (R-PIA) > CCPA > S-PIA > 5'-N-ethylcarboxamidoadenosine (NECA), which is identical to brain membranes. The competition curves were best fitted according to a two-site model, suggesting the existence of two affinity states. GTP shifted the competition curve for CCP A to the right and only one affinity state similar to the low affinity state in the absence of GTP was detected. The photoreactive agonist 2-azido-N\(^6\)- \(^{125}\)I-p-hydroxyphenylisopropyladenosine ([\(^{125}\)I]AHPIA) specifically labelled a single protein with an apparent molecular weight of 35,000 in coated vesicles, which is identical to A\(_1\) receptors labelled in brain membranes. Therefore, coated vesicles contain A\(_1\) adenosine receptors with similar binding characteristics as membrane-bound receptors, including GTP-sensitive high-affinity agonist binding. Photoaffinity labelling data suggest that A\(_1\) receptors in these vesicles are not a processed receptor fonn. These results confirm that A\(_1\) receptors in coated vesicles are coupled to a G-protein, and it appears that the A\(_1\) receptor systems in coated vesicles andin plasma membranes are identical.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{GrilliLutzParodi1987,
  author    = {Grilli, S. and Lutz, Werner K. and Parodi, S.},
  title     = {Possible implications from results of animal studies in human risk estimations for benzene: nonlinear dose-response relationship due to saturation of metabolism},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-60936},
  year      = {1987},
  abstract  = {To date, all risk assessment studies on benzene have been based almost exclusively on epiderniological data. Wehave attempted a more integrated and quantitative evaluation of carcinogenic risk for hurnans, trying to utilize, in addition to the epidemiological data, all data available, specifically data on metabolism, genotoxicity, and carcinogenicity in small rodents. An integrated evaluation of the globality of the available data seems to suggest a progressive saturation of metabolic capacity both for man and rodents between 10 and 100 ppm. The most susceptible target cells seem tobe different in humans (predominant induction of myelogenous leukemia) and small rodents (induction of a wide variety of tumors). Nevertheless, both epidemiological and experimental carcinogenicity data tend to indicate a flattening ofthe response for the highest dosages, again suggesting a general Saturation of mechanisms of metabolic activation, extended to different target tissues. From a quantitative point of view, the data suggest a carcinogenic potency at 10 ppm two to three times higher than that computable by a linear extrapolation from data in the 100 ppm range. These observations are in accord with the recent proposal of the European Economic Community of reducing benzene time-weighted average occupationallevels from 10 to 5 ppm.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{GrossRuzickaRestorffetal.1990,
  author    = {Gross, E. and Ruzicka, T. and Restorff, B. von and Stolz, W. and Klotz, Karl-Norbert},
  title     = {High-affinity binding and lack of growth-promoting activity of 12(S)-hydroxyeicosatetraenoic acid (12(S)-HETE) in a human epidermal cell line},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-60358},
  year      = {1990},
  abstract  = {No abstract available},
  subject      = {Toxikologie},
  language  = {en}
}
@article{GrunickePyerinEisenbrandetal.1994,
  author    = {Grunicke, H. and Pyerin, W. and Eisenbrand, G. and Havemann, K. and Rabes, H. M. and Molling, K. and Schwab, M. and Lutz, Werner K. and Wahrendorf, J. and Schirrmacher, V.},
  title     = {7th International Symposium of the Division of Experimental Cancer Research (AEK) of the German Cancer Society : [Meeting report]},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-60651},
  year      = {1994},
  abstract  = {No abstract available},
  subject      = {Toxikologie},
  language  = {en}
}
@article{GunzShephardLutz1993,
  author    = {Gunz, D. and Shephard, S. E. and Lutz, Werner K.},
  title     = {Can nongenotoxic carcinogens be detected with the lacI transgenic mouse mutation assay?},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-60707},
  year      = {1993},
  abstract  = {No abstract available},
  subject      = {Toxikologie},
  language  = {en}
}
@article{HegiUlrichSagelsdorffetal.1990,
  author    = {Hegi, M. E. and Ulrich, D. and Sagelsdorff, P. and Richter, C. and Lutz, Werner K.},
  title     = {No measurable increase in thymidine glycol or 8-hydroxydeoxyguanosine in liver DNA of rats treated with nafenopin or choline-devoid low-methionine diet},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-60790},
  year      = {1990},
  abstract  = {Male rats were treated for 2 months with 1000 ppm nafenopin in the diet or for 4 or 7 days with a choline-devoid low-methionine diet. DNA was isolated from the livers and analyzed for the presence of cis-thymidine glycol-3'-phosphate (cis-dTGp) by 32P-postlabeling and for the Ievel of 8-hydroxy-deoxyguanosine (8-0H-dG) by electrochemical detection (ECD). In no DNA sample was the Ievel of cis-dTGp above the Iimit of detection of 1 modified thymidine per 106 nucleotides. With 8-0H-dG, a background Ievel of this modification of 20 8-0H-dG per 106 nucleosides was found in liver DNA of control rats, which was not affected by either treatment. It is postulated for thymidine glycol that a potential increase was below the Iimit of detection or was rapidly repaired in vivo and that the steady-state Ievel of endogenous 8-hydroxydeoxyguanosine appears not tobe influenced by the treatments chosen.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{HegiSagelsdorffLutz1989,
  author    = {Hegi, M.E. and Sagelsdorff, P. and Lutz, Werner K.},
  title     = {Detection by \(^{32}\)P-postlabeling of thymidine glycol in gamma-irradiated DNA},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-60863},
  year      = {1989},
  abstract  = {No abstract available},
  subject      = {Toxikologie},
  language  = {en}
}
@article{HintzscheJastrowKleineOstmannetal.2012,
  author    = {Hintzsche, Henning and Jastrow, Christian and Kleine-Ostmann, Thomas and K{\"a}rst, Uwe and Schrader, Thorsten and Stopper, Helga},
  title     = {Terahertz electromagnetic fields (0.106 THz) do not induce manifest genomic damage in vitro},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-76268},
  year      = {2012},
  abstract  = {Terahertz electromagnetic fields are non-ionizing electromagnetic fields in the frequency range from 0.1 to 10 THz. Potential applications of these electromagnetic fields include the whole body scanners, which currently apply millimeter waves just below the terahertz range, but future scanners will use higher frequencies in the terahertz range. These and other applications will bring along human exposure to these fields. Up to now, only a limited number of investigations on biological effects of terahertz electromagnetic fields have been performed. Therefore, research is strongly needed to enable reliable risk assessment. Cells were exposed for 2 h, 8 h, and 24 h with different power intensities ranging from 0.04 mW/cm2 to 2 mW/cm2, representing levels below, at, and above current safety limits. Genomic damage on the chromosomal level was measured as micronucleus formation. DNA strand breaks and alkali-labile sites were quantified with the comet assay. No DNA strand breaks or alkali-labile sites were observed as a consequence of exposure to terahertz electromagnetic fields in the comet assay. The fields did not cause chromosomal damage in the form of micronucleus induction.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{HollerFischerWeberetal.1987,
  author    = {Holler, E. and Fischer, H. and Weber, C. and Stopper, Helga and Steger, H. and Simek, H.},
  title     = {A DNA polymerase with unusual properties from the slime mold Physarum polycephalum},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-63501},
  year      = {1987},
  abstract  = {Two forms of a DNA polymerase have been purified from microplasmodia of Physarum polycephalum by poly(ethyleneimine) precipitation and chromatography on DEAE-Sephacel, phosphocellulose, heparin Sepharose, hydroxyapatite, DNA-agarose, blue-Sepharose. They were separated from DNA polymerase cx on phosphocellulose and from each other on heparin-Sepharose. Form HS1 enzymewas 30-40\% pure and form HS2 enzyme 60\% with regard toprotein contents of the preparations. Form HS2 enzymewas generated from form HS1 enzyme on prolonged standing of enzyme preparations. The DNA polymerases were obtained as complexes of a 60-kDa protein associated with either a 135-kDa (HS1) or a 110-kDa (HS2) DNA-polymerizing polypeptidein a 1:1 molar stoichiometry. The biochemical function of the 60-kDa protein remained unknown. The complexes tended to dissociate during gradient centrifugation and during partition chromatography as weil as during polyacrylamide gradient gel electrophoresis under nondenaturing conditions at high dilutions of samples. Both forms existed in plasmodia extracts, their proportions depending on several factors including those which promoted proteolysis. The DNA polymerases resembled eucaryotic DNA polymerase ß by several criteria and were functionally indistinguishable from each other. It is suggested that lower eucaryotes contain repair DNA polymerases, which are similar to those of eubacteria on a molecular mass basis.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{HuberLutz1984,
  author    = {Huber, K. W. and Lutz, Werner K.},
  title     = {Methylation of DNA in stomach and small intestine of rats after oral administration of methylamine and nitrite},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-60984},
  year      = {1984},
  abstract  = {Young adult male Sprague-Dawley rats were given 30 \(\mu\)mol/kg body weight [\(^{14}\)C]methylamine hydrochloride and 700 \(\mu\)mol/ kg body weight sodium nilrite by oral gavage. DNA isolated from the stomach and from the first 15 cm of the smaß intestine was methylated, containing 7-methylguanine (7mG) at a level of one 7mG molecule per 5x10\8^6\) and lx10\(^7\) nucleotides, respectively. No 7mG was found fn the liver at a limit of detection of one 7mG molecule per 2xl0\(^8\) nucleotides. ln a second experiment, the excised stomachs were incubated with deoxyribonuclease before the isolation of the DNA in order to degrade DNA in the Iumen and in the uppermost lining cells. This treatment resulted in a 30\% decrease in the yield of DNA and a 90\% reduction in the level of 7mG formation. The results show that nitrosation of a primary alkylamine yields a precursor of an alkylating agent which has a long enough lifetime to diffuse towards and react with intracellular DNA. A correlation of DNA methylation in the stomach with the corresponding tumor formation by the methylating carcinogen N-methyi-N'-nitro-N-nitroso-guanidine was used to estimate the roJe of DNA damage resulting from endogenous nitrosation of dietary methylamine in man. It was concluded that the risk resulting from this single amine must be negligible bot that a similar evaluation of other primary amines is required before the over-aU role of primary amine nitrosation in the etiology of human gastric cancer can be assessed.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{HuberLutz1984,
  author    = {Huber, K. W. and Lutz, Werner K.},
  title     = {Methylation of DNA by incubation with methylamine and nitrite},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-61011},
  year      = {1984},
  abstract  = {DNA was incubated in septum-closed reaction vials with [\(^{14}\)C]methylamine and nitrite. The DNA was purified, hydrolysed with hydrochloric acid, and the purines were analysed by h.p.l.c. 7-Methylguanine was detectable as a result of DN A methylation in experiments perfonned in 100 mM acetate at pH 4. Using different concentrations of amine and nitrite a first order reaction for total amine and a second order for total nilrite could be shown. A study on the pH dependence using 100 mM malonate buffer, pH 2.0-6.0, revealed a maximum rate at pH 3.5, with steep slopes above and below this pH value, in agreement with a mathematical analysis of the reaction equations. The data show that the alkylating agent fonned spontaneously by nitrosation and deamination of a primary amine has a long enough lifetime to react with DNA in vitro. Using the reactioil orders established here, an extrapolation to lower concentrations found in the stomach can now be perfonned. Future in vivo experiments on the methylation of gastro-intestinal DNA then would show to what extent DNA in a cell is protected from alkylation.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{JaggiLutzLuethyetal.1980,
  author    = {Jaggi, W. and Lutz, Werner K. and L{\"u}thy, J. and Zweifel, U. and Schlatter, C.},
  title     = {In vivo covalent binding of aflatoxin metabolites isolated from animal tissue to rat-liver DNA},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-61101},
  year      = {1980},
  abstract  = {Ring-labelled [\(^{14}\)C)aflatoxin B\(_1\) (AFB\(_1\)), prepared by biosynthesis. or generally labelled [\(^3\)H]AFB\(_1\) was administered by oral gavage to young adult male rats. After 6 hr. the liver was removed and two fractions were isolated, namely macromolecules, which contamed about 3 \% of the initial dose of AFB\(_1\) radioactivity. and water-soluble, low-molecular aftatoxin conjugates containing about0·2\% of the administered radioactivity. These two fractions were administered orally to other rats in order to determine the potential of radioactive aftatoxin residues for covalent binding to DNA. Such binding can be used as an indicator for carcinogenic potency. Liver DNA was isolated 9-12 hr after admmistration of the aflatoxin derivatives and in no case was any radioactivity detected on the DNA. It can be deduced on the basis of the limit of detection of radioactivity on the DNA, that macromolecule bound AFB\(_1\) derivatives are at least 4000 times less active than AFB\(_1\) with respect to covalent binding to rat-liver DNA. and that the water-soluble conjugates are at least 100 times less potent than AFB, itself. It is concluded that the carcinogenic risk for humans who consume liver or meat. containing such aflatoxin residues is negligible when compared with the risk from intake of aftatoxins in other food items.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{JaggiLutzSchlatter1979,
  author    = {Jaggi, W. and Lutz, Werner K. and Schlatter, C.},
  title     = {Comparative studies on the covalent binding of the carcinogen benzo(a)pyrene to DNA in various model systems},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-61131},
  year      = {1979},
  abstract  = {The covalent binding of tritiated benzo(a)pyrene (BP) to DNA has been determined in rat liver in vivo, in rat liver perfused in situ, after incubation of BP with liver single cells, with liver homogenate, with liver microsomes and DNA, with fibroblasts from a rat granulorna pouch, and with · 2 cell lines. Li ver single cells were found to be a valuable compromise between the rnost sensitive system (microsomal incubation of BP with DNA) and the biologically most relevant system (in vivo ).},
  subject      = {Toxikologie},
  language  = {en}
}
@article{JaggiLutzSchlatter1978,
  author    = {Jaggi, W. and Lutz, Werner K. and Schlatter, C.},
  title     = {Covalent binding of ethinylestradiol and estrone to rat liver DNA in vivo},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-61162},
  year      = {1978},
  abstract  = {Thecovalent bindingof [6,7-\(^3\)H]ethinylestradiol (EE)and [6,7-\(^3\)H]estrone (E) to liver DNA of 200 g female ratswas measured 8 h after the administration of 80 \(\mu\)g (9.2 mCi) estrogen by gavage. The binding is 1.5 for EE and 1.1 for E, expressedas binding to DNA/dose, in units of \(\mu\)mol hormonefmol DNA phosphate/mmole honnone/kg body wt. It is in the same order of magnitude as for benzene and about 10 000 tim es below the binding of typical liver carcinogens, such as aflatoxin B\(_1\) or N,N-dimethylnitrosamine.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{JauchLutz1983,
  author    = {Jauch, A. and Lutz, Werner K.},
  title     = {In vivo assay for somatic point mutations induced by genotoxic carcinogens: incorporation of [\(^{35}\)S]methionine into a rat liver cytochrome b\(_5\) normally lacking sulphur-containing amino acids},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-61047},
  year      = {1983},
  abstract  = {The trypsin fragments of rat liver microsomal cytochron1e b\(_5\) (Tb\(_5\)) lack both methionine (met) and cysteine (cys), i.e., the sulphur-containing antino acids. Tb\(_5\) should therefore contain no 358-radioactivity after isolation from animals treated wHh [\(^{35}\)S]met or [\(^{36}\)S]cys. If, however, the nucleic acids coding for this polypeptide have been damaged by a genotoxic carcinogen, a miscoding could result in an incorporation of met or cys into the polypeptide so that Tb\(_8\) could now be \(^{36}\)S-radiolabelled. Two experiments are descrihed. the first one where a toxic regimen of N -nitrosomorpholine (NNM) to rats resulted in a significant increase of \(^{35}\)S-radioactivity in the Tbs of liver microsomes, and a second experiment with a non-toxic regimen of N,N diethylnitrosamine (DENA), where no increase was observable.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{JauchLutz1986,
  author    = {Jauch, A. and Lutz, Werner K.},
  title     = {Metallothionein protein variants generated in rat liver as a result of DNA and RNA ethylations by the carcinogen diethylnitrosamine},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-60946},
  year      = {1986},
  abstract  = {Metallothionein (MT) is a protein which contains 20 cysteine residues but no aromatic amino acids. It was tested whether treatment of male rats with the hepatocarcinogen diethylnitrosamine (DENA) could ethylate nucleic acids in such a way that protein variants containing measurable amounts of aromatic amino acid residues could be isolated from the livers of treated animals. To give a low Iimit of detection, the "wrong" amino acid precursors were administered in radiolabelled form at high Ievels of activity (7 mCi/kg each of [\(^3\)H]tyrosine and [\(^3\)H]phenylalanine). 11 \(\mu\)Ci/kg [\(^{14}\)C]cysteine was given as an intemal marker for MT biosynthesis. 6 h after amino acid administration, metallothionein (MT) was isolated from the liver and extensively purified. Afteracid hydrolysis and collection of Cys, Tyr, and Phe from an HPLC analysis of the amino acids, the \(^3\)H/\(^{14}\)C ratio was determined. The carcinogen-treated rats exhibited a significantly higher ratio than the vehicle-treated animals. This type of in vivo assay might find interesting applications in the investigation of nucleic acid alkylations as promutagenic lesions.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{JesaitisEricksonKlotzetal.1993,
  author    = {Jesaitis, A. J. and Erickson, R. W. and Klotz, Karl-Norbert and Bommakanti, R. K. and Siemsen, D. W.},
  title     = {Functional molecular complexes of human N-formyl peptide chemoattractant receptors and actin},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-60445},
  year      = {1993},
  abstract  = {When human neutrophils become desensitized to formyl peptide chemoattractants, the receptors (FPR) for these peptides are converted to a high affinity, GTP-insensitive form that is associated with the Triton X-1 00- insoluble membrane skeleton from surface membrane domains. These domains are actin and fodrin-rich, but G protein-depfeted suggesting that FPR shuttling between G protein-enriched and depleted domains may control signal transduction. Todetermine the molecular basis for FPR interaction with the membrane skeleton, neutrophil subcellular fractions were screened for molecules that could bind photoaffinity-radioiodinated FPR solubilized in Triton X-1 00. These receptors showed a propensity to bind to a 41- to43-kDa proteinband on nitrocelluloseoverlays of SOS-PAGE-separated cytosol and plasma membrane fractions of neutrophils. This binding, as weil as FPR binding to purified neutrophil actin, was inhibited 50\% by 0.6 \(\mu\)M free neutrophil cytosolic actin. Addition of greater than 1 \(\mu\)M G-actin to crude or lectin-purified Triton X-1 00 extracts of FPR from neutrophil membranes increased the sedimentationrate of a significant fraction of FPR two to three fold as measured by velocity sedimentation in Triton X-1 00-containing linear sucrose density gradients. Addition of anti-actin antibodies to FPR extracts caused a concentration-dependent immunoprecipitation of at least 65\% of the FPR. More than 40\% of the immunoprecipitated FPR was specifically retained on protein A affinity matrices. Membrane actin was stabilized to alkaline washing when membranes were photoaffinity labeled. Conversely, when purified neutrophil cytosolic actinwas added to membranes or their digitonin extracts, after prior depletion of actin by an alkaline membrane wash, photoaffinity labeling of FPR was increased two- to fourfold with an EC\(_{50}\) of approximately 0.1 \(\mu\)M actin. We conclude that FPR from human neutrophils may interact with actin in membranes to form Triton X-1 00-stable physical complexes. These complexes can accept additional G-actin monomers to form higher order molecular complexes. Formation of FPR-actin complexes in the neutrophil may play a role in the regulation of chemoattractantinduced activation or actin polymerization.},
  subject      = {Toxikologie},
  language  = {en}
}
@phdthesis{Kalb2005,
  author    = {Kalb, Stefanie},
  title     = {Wilhelm Neumann (1898 - 1965) - Leben und Werk unter besonderer Ber{\"u}cksichtigung seiner Rolle in der Kampfstoff-Forschung},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-16124},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2005},
  abstract  = {Gegenstand der vorliegenden Untersuchung ist das Leben und Werk des deutschen Pharmakologen und Toxikologen Wilhelm Neumann (11. Februar 1898 - 15. April 1965). Wesentliche Erkenntnisse hierzu konnten aus Aktenbest{\"a}nden des Bundesarchivs der Bundesrepublik Deutschland in Berlin-Lichterfelde, Freiburg im Breisgau, und Koblenz, des Dekanatsarchiv der Medizinischen Fakult{\"a}t der Bayerischen Julius-Maximilians-Universit{\"a}t W{\"u}rzburg, des Archivs der „Deutschen Gesellschaft f{\"u}r experimentelle und klinische Pharmakologie und Toxikologie" in Mainz, des Scheringianums, dem Archiv der Schering AG in Berlin, des Staatsarchivs W{\"u}rzburg und des Universit{\"a}tsarchivs der Bayerischen Julius-Maximilians-Universit{\"a}t W{\"u}rzburg gewonnen werden. Von 1919 bis 1923 studierte Wilhelm Neumann in Berlin Chemie und promovierte in der chemischen Abteilung des Preußischen Instituts f{\"u}r Infektionskrankheiten „Robert Koch" zum Dr. phil. Im Jahr 1924 trat er eine Stelle als Privatassistent am Pharmakologischen Institut der Universit{\"a}t W{\"u}rzburg unter der Leitung Ferdinand Flurys an. Parallel zu seiner Arbeit am Pharmakologischen Institut studierte er von 1929 bis 1934 an der Universit{\"a}t W{\"u}rzburg Humanmedizin und promovierte zum Dr. med. 1937 folgte seine Habilitation und die Ernennung zum Dozenten. Weitere Stationen seiner wissenschaftlichen Laufbahn am Pharmakologischen Institut waren die Ernennungen zum planm{\"a}ßigen Assistenten 1939, zum Konservator 1941 und zum außerplanm{\"a}ßigen Professor 1942. Im Jahr 1937 nahm Wilhelm Neumann als Arzt der Reserve seine milit{\"a}rische Karriere im Sanit{\"a}tsdienst der Wehrmacht auf. W{\"a}hrend des Zweiten Weltkrieges war er als „beratender Arzt" und als Wissenschaftler f{\"u}r die Wehrmacht t{\"a}tig. Neumanns politischer Werdegang begann im Juli 1933 mit seinem Beitritt zur Veteranenorganisation Stahlhelm. Im Februar 1934 wurde er Mitglied der SA, und ab dem 1. Mai 1937 geh{\"o}rte er der NSDAP an. Nach Ende des Zweiten Weltkrieges wurde Neumann im Zuge des Entnazifizierungsprozesses 1946 aus dem Staatsdienst entlassen. Das 1947 ergangene Spruchkammerurteil reihte ihn in die Gruppe der „Mitl{\"a}ufer" ein. Infolgedessen konnte er 1948 wieder von der Universit{\"a}t W{\"u}rzburg eingestellt werden. Im Jahr 1949 wurde er dort zum ordentlichen Professor f{\"u}r Pharmakologie und Toxikologie berufen. Von 1954 bis 1955 {\"u}bte er das Amt des Dekans der Medizinischen Fakult{\"a}t der Universit{\"a}t W{\"u}rzburg aus. Am Pharmakologischen Institut der Universit{\"a}t W{\"u}rzburg untersuchte Neumann zun{\"a}chst die Chemie und Pharmakologie der herzwirksamen Glykoside. Ihm gelang auf diesem Gebiet die Reindarstellung eines neuen Wirkstoffs, der 1935 von der Firma Schering im Herzinsuffizienztherapeutikum Folinerin auf den Markt gebracht wurde. Auf toxikologischem Gebiet arbeitete er von 1925 bis 1945 mit Ferdinand Flury an gewerbetoxikologischen Projekten und in der chemischen Kampfstoff-Forschung. Als ordentlicher Professor widmete sich Wilhelm Neumann dann neben eigenen toxikologischen Arbeiten der F{\"o}rderung der Toxikologie als Fachrichtung. Zu Beginn der 1950er Jahre befasste er sich mit tierischen Giften und erforschte die Toxikologie der Reizgase und der Luftverschmutzung. Von 1955 bis 1965 war Wilhelm Neumann Vorsitzender der DFG-Kommission zur Pr{\"u}fung gesundheitssch{\"a}dlicher Arbeitsstoffe.},
  language  = {de}
}
@article{KirchnerStopperPappetal.1993,
  author    = {Kirchner, S. and Stopper, Helga and Papp, T. and Eckert, I. and Yoo, H. J. and Vig, B. K. and Schiffmann, D.},
  title     = {Cytogenetic changes in primary, immortalized and malignant mammalian cells},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-63439},
  year      = {1993},
  abstract  = {Some chromosomes in transformed rat cells and somatic cell hybrids fail to display the presence of kinetochore proteins as detected by antikinetochore antibodies. Suchchromosomes (K- Chromosomes) may constitute a novel mechanism for the genesis of aneuploidy. Wehave analyzed primary~ immortalized and malignant marnmalian cells for the presence of kinetochore proteins and micronuclei. Our resuJts suggest a correlation of the K- chromosome and micronucleus frequency with the variability in chromosome number. Upon in situ hybridization with the minor satellite and alpha satellite sequences some Kchromosomes showed a signal. This indicates that the observed lack of kinetocbores is not necessarily due to a lack of centromeric DNA. We conclude that dislocated K- chromosomes may become incorporated into micronuclei which are prone to loss. Such events would be associated with the generation of aneuploidy.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{KlotzCristalliGrifantinietal.1985,
  author    = {Klotz, Karl-Norbert and Cristalli, G. and Grifantini, M. and Vittori, S. and Lohse, M. J.},
  title     = {Photoaffinity labeling of A\(_1\) adenosine receptors},
  series = {The journal of biological chemistry},
  volume    = {27},
  journal   = {The journal of biological chemistry},
  number    = {260},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-60198},
  year      = {1985},
  abstract  = {The ligand-binding subunit of the A\(_1\)-adenosine receptor has been identified by photoaffinity labeling. A photolabile derivative of R- \(N^6\)-phenylisopropyladenosine, R-2-azido-\(N^6\)-p-hydroxyphenylisopropyladenosine (R-AHPIA), has been synthesized as a covalent specific Iigand for A\(_1\)-adenosine receptors. In adenylate cyclase studies with membranes of rat fat cells and human platelets, R·AHPIA has adenosine receptor agonist activity with a more than 60-fold selectivity for the A\(_1\)-subtype. It competes for [\(^3\)H].\(N^6\)- phenylisopropyladenosine binding to Arreceptors of rat brain membranes with a Ki value of 1.6 nM. After UV irradiation, R-AHPIA binds irreversibly to the receptor, as indicated by a loss of [\(^3\)H)\(N^6\)-phenylisopropyladenosine binding afterextensive washing; the K; value for this photoinactivation is 1.3 nM. The p-hydroxyphenyl substituent of R-AHPIA can be directly radioiodinated to give a photoaffinity Iabel of high specific radioactivity (\(^{125}\)I-AHPIA). This compound has a KD value of about 1.5 nM as assessed from saturation and kinetic experiments. Adenosine analogues compete for \(^{125}\)I-AHPIA binding to rat brain membranes with an order of potency characteristic for A\(_1\)-adenosine receptors. Dissociation curves following UV irradiation at equilibrium demonstrate 30-40\% irreversible specific binding. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis indicates that the probe is photoincorporated into a single peptide of M\(_r\) = 35,000. Labeling of this peptide can be blocked specifically and stereoselectively by adenosine receptor agonists and antagonists in a manner which is typical for the A\(_1\)-subtype. The results indicate that \(^{125}\)I-AHPIA identifies the ligand-binding subunit of the A\(_1\)-adenosine receptor, which is a peptide with M\(_r\) = 35,000.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{KlotzJesaitis1994,
  author    = {Klotz, Karl-Norbert and Jesaitis, A. J.},
  title     = {Neutrophil chemoattractant receptors and the membrane skeleton},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-60471},
  year      = {1994},
  abstract  = {Signal transduction via receptors for N-formylmethionyl peptide chemoattractants (FPR) on human neutrophils is a highly regulated process which involves participation of cytoskeletal elements. Evidence exists suggesting that the cytoskeleton and/or the membrane skeleton controls the distributJon of FPR in the plane of the plasma membrane, thus controlling the accessibility of FPR to different proteins in functionally distinct domains. In desensitized cells, FPR are restricted todomains which are depleted of G proteins but enriched in cytoskeletal proteins such as actin and fodrin. Thus, the G protein signal transduction partners of FPR become inaccessible to the agonist-occupied receptor, preventing cell activation. The mechanism of interaction of FPR with the membrane skeleton is poorly understood but evidence is accumulating that suggests a direct binding of FPR (and other receptors) to cytoskeletal proteins such as actin.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{KlotzJesaitis1994,
  author    = {Klotz, Karl-Norbert and Jesaitis, A. J.},
  title     = {Physical coupling of N-formyl peptide chemoattractant receptors to G protein is not affected by desensitization},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-60483},
  year      = {1994},
  abstract  = {Desensitization of N-formyl peptide chemoattractant receptors (FPR) in human neutrophils results in association of these receptors to the membrane skeleton. This is thought to be the critical event in the lateral segregation of receptors and guanyl nucleotide-binding proteins (G proteins) within the plane of the plasma membrane resulting in an interruption of the signaling cascade. In this study we probed the interaction of FPR with G protein in human neutrophils that were desensitized to various degrees. Human neutrophils were desensitized using the photoreactive agonist N-formyl-met-leu-phelys- N\(^\epsilon\)-[\(^{125}\)I]2(p-azidosalicylamido )ethyl-1 ,3 '-dithiopropionate (/MLFK-[\(^{125}\)I]ASD). The interaction if FPR with G protein was studied via a reconstitution assay and subsequent analysis of FPR-G protein complexes in sucrose density gradients. FPR-G protein complexes were reconstituted with solubilized FPR from partially and fully desensitized neutrophils with increasing concentrations of Gi purified from bovine brain. The respective EC\(_{50}\) values for reconstitution were similar to that determined for FPR from unstimulated neutrophils (Bommakanti RK et al., J Bio[ Chem 267: 757~7581, 1992). We conclude, therefore, that the affinity of the interaction of FPR with G protein is not affected by desensitization, consistent with the model of lateral segregation of FPR and G protein as a mechanism of desensitization.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{KlotzJesaitis1994,
  author    = {Klotz, Karl-Norbert and Jesaitis, A. J.},
  title     = {The interaction of N-formyl peptide chemoattractant receptors with the membrane skeleton is energy-dependent},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-60499},
  year      = {1994},
  abstract  = {Desensitization of N-fonnyl peptide chemoattractant receptors (FPR) in human neutrophils is thought to be achieved by lateral segregation of receptors and G proteins within the plane of the plasma membrane resulting in an interruption of the signalling cascade. Direct coupling of FPR to membrane skeletal actin appears to be the basis of this process~ however, the molecular mechanism is unknown. In this study we investigated the effect of energy depletion on formation of FPR-membrane skeleton complexes. In addition the effect of the protein kinase C inhibitor stauroporine and the phosphatase inhibitor okadaic acid on coupling of FPR to the membrane skeletonwas studied. Human neutrophils were desensitized using the photoreactive agonist N-formy1-met-leu-phe-1ys-N'[\(^{125}\)I]2(p-azidosalicylamido)ethyl-1,3'-dithiopropionate (fMLFK-[\(^{125}\)I]ASD) after ATP depletion with NaF or after incubation with the respective inhibitors. The interaction of FPR with the membrane skeleton was studied by Sedimentation of the membrane skeleton-associated receptors in sucrose density gradients. Energy depletion of the cells markedly inhibited the formation of FPR-membrane skeleton complexes. This does not appear tobe related to inhibition of protein phosphorylation due to ATP depletion because inhibition of protein kinases and phosphatases bad no significant effect on coupling of FPR to the membrane skeleton. We conclude, therefore, that coupling of FPR to the membrane skeleton is an energy,dependent process which does not appear to require modification of the receptor protein by phosphorylation.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{KlotzKeilZimmeretal.1990,
  author    = {Klotz, Karl-Norbert and Keil, R. and Zimmer, F. J. and Schwabe, U.},
  title     = {Guanine nucleotide effects on 8-cyclopentyl-1,3-[\(^3\)H]dipropylxanthine binding to membrane-bound and solubilized A\(_1\) adenosine receptors of rat brain},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-60369},
  year      = {1990},
  abstract  = {The effects of guanine nucleotides on binding of 8-cyclopentyl-1,3-[\(^3\)H]dipropylxanthine [\(^3\)H]DPCPX), a highly selective A\(_1\) adenosine receptor antagonist, have been investigated in rat brain membranes and solubilized A\(_1\) receptors. GTP, which induces uncoupling of receptors from guanine nucleotide binding proteins, increased binding of [\(^3\)H]DPCPX in a concentration-dependent manner. The rank order of potency for different guanine nucleotides for increasing [\(^3\)H]DPCPX bindingwas the same as for guanine nuc1eotide-induced inhibition of agonist binding. Therefore, a role for a guanine nucleotide binding protein, e.g., G\(_i\), in the regulation of antagonist binding is suggested. This was confirmed by inactivation ofGi by N-ethylmaleimide (NEM) treatment of membranes, which resulted in an increase in [\(^3\)H]DPCPX binding similar to that seen with addition of GTP. Kinetic and equilibrium binding studies showed that the GTP- or NEM-induced increase in antagonist binding was not caused by an affinity change of A\(-1\) receptors for [\(^3\)H]DPCPX but by an increased Bmu value. Guanine nucleotides had similar effects on membrane-bound and solubilized receptors, with the effects in the solubilized system being more pronounced. In the absence of GTP, when rnost receptors are in a high-affinity state for agonists, only a few receptors are labeled by [\(^3\)H]DPCPX. It is suggested that [\(^3\)H]DPCPX binding is inhibited when receptors are coupled to G\(_i\). Therefore, uncoupling of A\(_1\) receptors from G\(_i\) by guanine nucleotides or by inactivation of G\(_i\) with NEM results in an increased antagonist binding. Key Words: Adenosine receptors-8 -Cyclopentyl-1,3-eH]dipropylxanthine-Antagenist binding-Guanine nucleotide effects. Klotz K.-N. et al. Guanine nucleotide etfects on 8-cyclopentyl-1 ,3-eH]dipropylxanthine binding to membrane-bound and solubilized A1 adenosine receptors of rat brain. J. Neurochem. 54, 1988-1994 (1990).},
  subject      = {Toxikologie},
  language  = {en}
}
@article{KlotzKrotecGripentrogetal.1994,
  author    = {Klotz, Karl-Norbert and Krotec, K. L. and Gripentrog, J. and Jesaitis, A. J.},
  title     = {Regulatory interaction of N-formyl peptide chemoattractant receptors with the membrane skeleton in human neutrophils},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-60466},
  year      = {1994},
  abstract  = {The cytoskeleton and/or membrane skeleton has been implicated in the regulation of N-formyl peptide receptors. The coupling of these chemotactic receptors to the membrane skeleton was investigated in plasma membranes from unstimulated and desensitized human neutrophils using the photoreactive agonist N-formyl-met-leu-phelys-N\(^6\)-[\(^{125}\)I]2(p-azidosalicylamido)ethyl-1,3'-dithiopropionate (fMLFK-[\(^{125}\)I]ASD). When membranes of unstimulated cells were solubilized in Triton-X 100, a detergent that does not disrupt actin filaments, only 50\% of the photoaffinity-labeled receptors were solubilized sedimenting in sucrose density gradients at a rate consistent with previous reports. The remainder were found in the pellet fraction along with the membrane skeletal actin. Solubilization of the membranes in the presence of p-chloromercuriphenylsulfonic acid, elevated concentrations of KCI, or deoxyribonuclease I released receptors in parallel with actin. When membranes from neutrophils, desensitized by incubation with fMLFK-e 251]ASD at 15°C, were solubilized, nearly all receptors were recovered in the pellet fraction. lncubation of cells with the Iigand at 4°C inhibited desensitization partially and prevented the conversion of a significant fraction of receptors to the form associated with the membrane skeletal pellet. ln these separations the photoaffinity-labeled receptors not sedimenting to the pellet cosedimented with actin. Approximately 25\% of these receptors could be immunosedimented with antiactin antibodies suggesting that N-formyl peptide receptors may interact directly with actin. These results are consistent with a regulatory role for the interaction of chemotactic N-formyl peptide receptors with actin of the membrane skeleton.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{KlotzLohse1986,
  author    = {Klotz, Karl-Norbert and Lohse, M. J.},
  title     = {The glycoprotein nature of A\(_1\) adenosine receptors},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-60231},
  year      = {1986},
  abstract  = {A\(_1\) adenosine receptors from different tissues and species we~e photoaffinity labelled and then the carbohydrate content was examined by both enzymatic and chemical treatment. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of the labelled membrane receptors shows that neuraminidase treatment alters the electrophoretic mobility of the receptor band indica ting the presence of terminal neurandnie acids. Neuraminidase digestion does not influence the binding characteristics of the receptor. The totally deglycosylated receptor protein obtained by chemical treatment has an apparent molecular weight Of 32,000.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{KlotzLohseSchwabe1988,
  author    = {Klotz, Karl-Norbert and Lohse, M. J. and Schwabe, U.},
  title     = {Chemical modification of A\(_1\) adenosine receptors in rat brain membranes - evidence for histidine in different domains of the ligand binding site},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-60295},
  year      = {1988},
  abstract  = {Chemical modification of amino acid residues was used to probe the ligand recognition site of A\(_1\) adenosine receptors from rat brain membranes. The effect of treatment with group·specific reagents on agonist and antagonist radioligand binding was investigated. The histidine-specific reagent diethylpyrocarbonate (DEP) induced a loss of binding of the agonist R-N\(^6\)-[\(^3\)H]phenylisopropyladenosine ([\(^3\)H]PIA), which could be prevented in part by agonists, but not by antagonists. DEP treatment induced also a loss of binding of the antagonist [\(^3\)H]8- cyclopentyl-1 ,3-dipropylxanthine ([\(^3\)H]DPCPX). Antagonists protected A\(_1\) receptors from this inactivation while agonists did not. This result provided evidence for the existence of at least 2 different histidine residues involved in ligand binding. Consistent with a modification of the binding site, DEP did not alter the affinity of [\(^3\)H]DPCPX, but reduced receptor number. From the selective protection of [\(^3\)H] PIA and [\(^3\)H]DPCPX binding from inactivation, it is concluded that agonists and antagonists oocupy different domains at the binding site. Sulfhydryl modifying reagents did not influence antagonist binding, but inhibited agonist binding. This effect is explained by modification of tbe inhibitory guanine nucleotide binding protein. Pyridoxal 5-phosphate inactivated both [\(^3\)H]PIA and [\(^3\)H]DPCPX binding, but the receptors could not be protected from inactivation by ligands. Therefore, no amino group seems to be located at the Iigand binding site. In addition, it was shown that no further amino acids witb polar side chains are present. The absence of bydrophilic amino acids frout the recognition site of the receptor apart from histidine suggests an explanation for the lack of hydrophilic ligands with high affinity for A\(_1\) receptors.},
  subject      = {Toxikologie},
  language  = {en}
}