TY  - JOUR
A1  - Lohse, M. J.
A1  - Klotz, Karl-Norbert
A1  - Diekmann, E.
A1  - Friedrich, K.
A1  - Schwabe, U.
T1  - 2',3'-Dideoxy-N\(^6\)-cyclohexyladenosine: an adenosine derivative with antagonist properties at adenosine receptors
N2  - Tbe 2',3'-dideoxy analogue of the potent A\(_1\) receptor agonist, N\(^6\)-cyclohexyladenosine (CHA), was synthesized as a potential antagonist for the A\(_1\) adenosine receptor. In sturlies on adenylate cyclase 2',3'-dideoxy-N\(^6\)-cyclohexyladenosine (ddCHA) did not show agonist properties at A\(_1\) or at A\(_2\) receptors. However, it antagonized the inhibition by R-PIA of adenylate cyclase activity of fat cell membranes via A\(_1\) receptors with a K\(_i\) value of 13 \(\mu\)M. ddCHA competed for the binding of the selective A1 receptor antagonist, [\(^3\) HJ8-cyclopentyl-1,3-dipropylxantbine ([\(^3\)H]DPCPX), to rat brain membranes with a K\(_i\) value of 4.8 \(\mu\)M; GTP did not affect the competition curve. In contrast to the marked stereoselectivity of the A\(_1\) receptor for the cx- and the natural ß-anomer of adenosine, the cx-anomer of ddCHA showed a comparable affinity for the A\(_1\) receptor (K\(_i\) value 13.9 \8\mu\)M). These data indicate that the 2'- and 3'-hydroxy groups of adenosine and its derivatives are required foragonist activity at and high affinity binding to A\(_1\) adenosine receptors and for the distinction between the cx- and ß-forms.
KW  - Toxikologie
KW  - Adenosine receptors
KW  - Adenylate cyclase
KW  - Adenosine receptor antagonists
Y1  - 1988
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-60282
ER  - 
TY  - JOUR
A1  - Cristalli, G.
A1  - Eleuteri, A.
A1  - Vittori, S.
A1  - Volpini, R.
A1  - Lohse, M. J.
A1  - Klotz, Karl-Norbert
T1  - 2-Alkynyl derivatives of adenosine and adenosine-5'-N-ethyluronamides as selective agonists at A\(_2\) adenosine receptors
N2  - 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.
KW  - Toxikologie
Y1  - 1992
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-60412
ER  - 
TY  - JOUR
A1  - Klotz, Karl-Norbert
A1  - Lohse, M. J.
A1  - Schwabe, U.
A1  - Cristalli, G.
A1  - Vittori, S.
A1  - Grifantini, M.
T1  - 2-Chloro-N\(^6\)-[\(^3\)H]cyclopentyladenosine ([\(^3\)H]CCPA) - a high affinity agonist radioligand for A\(_1\) adenosine receptors
N2  - The tritiated analogue of 2-chloro-N6-cyclopentyladenosine (CCPA), an adenosine derivative with subnanomolar affinity and a 10000-fold selectivity for A1 adenosine receptors, has been examined as a new agonist radioligand. [3H]CCP A was prepared with a specifi.c radioactivity of 1.58 TBqjmmol ( 43 Ci/mmol) and bound in a reversible manner to A1 receptors from rat brain membranes with a high affinity K0 -value of 0.2 nmol/1. In the presence of GTP a K0 -value of 13 nmol/1 was determined for the low affinity state for agonist binding. Competition of several adenosine receptor agonists and antagonists for [3H]CCPA binding to rat brain membranes confrrmed binding to an A1 receptor. Solubilized A1 receptors bound [3H]CCPA with similar affinity for the high affinity state. At solubilized receptors a reduced association rate was observed in the presence of MgC12, as has been shown for the agonist [ 3H]N6-phenylisopropyladenosine ([3H]PIA). [3H]CCPA was also used for detection of A1 receptors in rat cardio myocyte membranes, a tissue with a very low receptor density. A K0 -value of 0.4 nmol/1 and a Bmax-value of 16 fmol/ mg protein was determined in these membranes. In human platelet membranes no specific binding of [3H]CCPA was measured at concentrations up to 400 nmoljl, indicating that A2 receptors did not bind [3H]CCPA. Based on the subnanomolar affinity and the high selectivity for A1 receptors [ 3H]CCPA proved to be a useful agonist radioligand for characterization of A 1 adenosine receptors also in tissues with very low receptor density.
KW  - Toxikologie
KW  - Adenosine receptors
KW  - Radioligauds
KW  - agonists
Y1  - 1989
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-60328
ER  - 
TY  - JOUR
A1  - Lohse, M. J.
A1  - Klotz, Karl-Norbert
A1  - Schwabe, U.
A1  - Cristalli, G.
A1  - Vittori, S.
A1  - Grifantini, M.
T1  - 2-Chloro-N\(^6\)-cyclopentyladenosine: a highly selective agonist at A\(_1\) adenosine receptors
N2  - 2-Chloro-N\(^6\)-cyclopentyladenosine (CCPA) was synthesized as a potential high affinity ligand for At adenosine receptors. Binding of [\(^3\)H]PIA to A1 receptors of rat brain membranes was inhibited by CCP A with a Ki-value of 0.4 nM, compared to a Ki-value of 0.8 nM for the parent compound N\(^6\)-cyclopentyladenosine (CPA). Binding of [\(^3\)H]NECA to A\(_2\) receptors of rat striatal membranes was inhibited with a Ki-value of 3900 nM, demonstrating an almost 10,000-fold A\(_1\)-selectivity of CCPA. CCP A inhibited the activity of rat fat cell membrane adenylate cyclase, a model for the A\(_1\) receptor, with an IC\(_{50}\)-value of 33 nM, and it stimulated the adenylate cyclase activity of human platelet membranes with an EC\(_{50}\)-value of 3500 nM. The more than 100-fold A\(_1\)-selectivity compares favourably with a 38-fold selectivity of CPA. Thus, CCPA is an agonist at A\(_1\) adenosine receptors with a 4-fold higher selectivity and 2-fold higher affinity than CPA, and a considerably higher selectivity than the standard At receptor agonist R-N\(^6\) -phenylisopropyladenosine (R-PIA). CCP A represents the agonist with the highest selectivity for A\(_1\) receptors reported so far.
KW  - Toxikologie
KW  - Adenosine receptors
KW  - Adenylate cyclase
Y1  - 1988
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-60279
ER  - 
TY  - JOUR
A1  - Stopper, Helga
A1  - Pechan, R.
A1  - Schiffmann, D.
T1  - 5-azacytidine induces micronuclei in and morphological transformation of Syrian hamster embryo fibroblasts in the absence of unscheduled DNA synthesis
N2  - lt is known that 5-azacytidine (5-AC) induces tumors in several organs of rats and mice. The mechanisms of these effects are still poorly understood although it is known that 5-AC can be incorporated into DNA. Furthermore, it can inhibit DNA methylation. The known data on its clastogenic andjor gene mutation-inducing potential are still controversial. Therefore, we have investigated the kinds of genotoxic effects caused by 5-AC in Syrian hamster embryo (SHE) fibroblasts. Three different endp6ints (micronucleus formation, unscheduled DNA synthesis (UDS) and cell transforrnation) were assayed under similar conditions of metabolism and dose at target in this cell system. 5-AC induces morphological transformation of SHE cells, but not UDS. Therefore, 5-AC does not seem to cause repairable DNA lesions. Furthermore, our studies revealed that 5-AC is a potent inducer of mkronuclei in the SHE system. Immunocytochemical analysis revealed that a certain percentage of these contain kinetochores indicating that 5-AC may induce both clastogenic events and numerical chromosome changes.
KW  - Toxikologie
KW  - 5-Azacytidine
KW  - Micronuclei
KW  - Kinetochores
KW  - Unscheduled DNA synthesis
KW  - Cell transformation
Y1  - 1992
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-63443
ER  - 
TY  - JOUR
A1  - Grunicke, H.
A1  - Pyerin, W.
A1  - Eisenbrand, G.
A1  - Havemann, K.
A1  - Rabes, H. M.
A1  - Molling, K.
A1  - Schwab, M.
A1  - Lutz, Werner K.
A1  - Wahrendorf, J.
A1  - Schirrmacher, V.
T1  - 7th International Symposium of the Division of Experimental Cancer Research (AEK) of the German Cancer Society : [Meeting report]
N2  - No abstract available
KW  - Toxikologie
Y1  - 1994
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-60651
ER  - 
TY  - JOUR
A1  - Lohse, M. J.
A1  - Klotz, Karl-Norbert
A1  - Lindenborn Fotinos, J.
A1  - Reddington, M.
A1  - Schwabe, U.
A1  - Olsson, R. A.
T1  - 8-Cyclopentyl-1,3-dipropylxanthine (DPCPX) - a selective high affinity antagonist radioligand for A\(_1\) adenosine receptors
N2  - The properties of 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) as an antagonist ligand for A\(_1\) adenosirre receptors were examined and conipared with other radioligands for this receptor. DPCPX competitively antagonized both the inhibition of adenylate cyclase activity via A\(_1\) adenosirre receptors and the stimulationvia A\(_2\) adenosirre receptors. The K\(_i\)-values of this antagonism were 0.45 nM at the A\(_1\) receptor of rat fat cells, and 330 nM at the A\(_2\) receptor of human platelets, giving a more than 700-fold A\(_1\)-selectivity. A similar A\(_1\)-selectivity was determined in radioligand binding studies. Even at high concentrations, DPCPX did not significantly inhibit the soluble cAMPphosphodiesterase activity of human platelets. [\(^3\)H]DPCPX (105 Ci/mmol) bound in a saturable manner with high affinity to A\(_1\) receptors in membranes of bovine brain and heart, and rat brain and fat cells (K\(_D\) -values 50-190 pM). Its nonspecific binding was about 1% of total at K\(_D\) , except in bovine myocardial membranes (about 10%). Binding studies with bovine myocardial membranes allowed the analysis of both the high and low agonist affinity states of this receptor in a tissue with low receptor density. The binding properties of [\(^3\)H]DPCPX appear superior to those of other agonist and antagonist radioligands for the A\(_1\) receptor.
KW  - Toxikologie
KW  - Adenosine receptors
KW  - Adenylate cyclase
KW  - Phosphodiesterase
KW  - Xanthines
KW  - Radioligands
Y1  - 1987
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-60246
ER  - 
TY  - JOUR
A1  - Bommakanti, R. K.
A1  - Klotz, Karl-Norbert
A1  - Dratz, E. A.
A1  - Jesaitis, A. J.
T1  - A carboxyl-terminal tail peptide of neutrophil chemotactic receptor disrupts its physical complex with G protein
N2  - No abstract available
KW  - Toxikologie
Y1  - 1993
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-60456
ER  - 
TY  - JOUR
A1  - Lutz, Werner K.
A1  - Schlatter, C.
T1  - A closed inhalation system for pharmacokinetic and metabolism studies of volatile compounds with small laboratory animals
N2  - In the inhalation system described an animal can be kept in the same atmosphere of a 2-liter desiccator for up to 24 h. The expired carbon dioxide is adsorbed with soda lime and the resulting reduced pressure is balanced by a supply of oxygen also used for the inflow of the chemical to be investigated. Urine and faeces can be collected ~eparately and the system allows a periodical control of the concentration of the chemical by sampling the air with needle and syringe.
KW  - Toxikologie
Y1  - 1978
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-80145
ER  - 
TY  - JOUR
A1  - Holler, E.
A1  - Fischer, H.
A1  - Weber, C.
A1  - Stopper, Helga
A1  - Steger, H.
A1  - Simek, H.
T1  - A DNA polymerase with unusual properties from the slime mold Physarum polycephalum
N2  - 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.
KW  - Toxikologie
Y1  - 1987
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-63501
ER  - 
TY  - JOUR
A1  - Cristalli, G.
A1  - Franchetti, P.
A1  - Grifantini, M.
A1  - Vittori, S.
A1  - Klotz, Karl-Norbert
A1  - Lohse, M. J.
T1  - Adenosine receptor agonists: Synthesis and biological evaluation of 1-deaza analogues of adenosine
N2  - 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.
KW  - Toxikologie
Y1  - 1988
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-60262
ER  - 
TY  - JOUR
A1  - Lohse, M. J.
A1  - Böser, S.
A1  - Klotz, Karl-Norbert
A1  - Schwabe, U.
T1  - Affinities of barbiturates for the GABA-receptor complex and A\(_1\) adenosine receptors: A possible explanation of their excitatory effects
N2  - The effects of barbiturates on the GABA·receptor complex and the A\(_1\) adenosine receptor were studied. At the GABA-receptor complex the barbiturates inhibited the binding of [\(^{35}\)S]t-butylbicyclophosphorothionate [\(^{35}\)S]TBPT) and enhanced the binding of [\(^3\)H]diazepam. Kinetic and saturation experiments showed that both effects were allosteric. Whereas all barbiturates caused complete inhibition of [\(^{35}\)S]TBPT binding, they showed varying degrees of maximal enhancement of [\(^3\)H]diazepam binding; (±)methohexital was idenafied as the most efficacious compound for this enhancement. At the A\(_1\) adenosine receptor all barbiturates inhibited the binding of [\(^3\)H]N\(^6\)-phenylisopropyladenosine (\(^3\)H]PIA) in a competitive manner. The comparison of the effects on [\(^3\)H]diazepam and [\(^3\)H]PIA binding showed that excitatory barbiturates interact preferentially with the A\(_1\) adenosine receptor, and sedative/anaesthetic barbiturates with the GABA-receptor complex. It is speculated that the interaction with these two receptors might be the basis of the excitatory versus sedative/ anaesthetic properties of barbiturates.
KW  - Toxikologie
KW  - GABA-receptor complex
KW  - Adenosine receptors
KW  - Barbiturates
Y1  - 1987
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-60250
ER  - 
TY  - JOUR
A1  - Lutz, Werner K.
A1  - Wipf, H. K.
A1  - Simon, W.
T1  - Alkalikationen-Spezifität und Träger-Eigenschaftender Antibiotica Nigerfein und Monensin
T1  - Alkali-cation specificity and carrier qualities of the antibiotics nigericin and monensin
N2  - It is shown by means of IR. spectroscopic methodsthat nigericin and monensin bave a cyclic conformation similar to that of their silver salts. Camplex fonnation constants with sodium and potassium ions follow the selectivity order determined by EMF. measurements on liquid membranes: nigericin: K\(^+\) >Rb\(^+\)> Na\(^+\)> Cs\(^+\) >Li\(^+\); monensin: Na\(^+\)> K\(^+\) >Li\(^+\)> Rb\(^+\)> Cs\(^+\). Transport experiments show that nigericin and monensin facilitate the diffusion of potassium ions across model membranes, although in electrolytic transport experiments the permeability is not affected.
KW  - Toxikologie
Y1  - 1970
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-61233
ER  - 
TY  - JOUR
A1  - Stopper, Helga
A1  - Körber, C.
A1  - Spencer, D. L.
A1  - Kirchner, S.
A1  - Caspary, W.J.
A1  - Schiffmann, D.
T1  - An investigation of micronucleus and mutation induction by oxazepam in mammalian cells
N2  - Tbe benzodiazepines are a class of d.rugs that are widely used in the treatment of various psychiatric disorders. One member of um ~' oxazepam, is also a common metabolite of sevmd other benzod.iazepines. Since the evidence for the genetic toxicity and carcinogenic properties of these compounds is incol:lsb1ent, we investigated the oxazepam-induced fonnation of micronuclei in Syrian Hamster embryo fibroblast (SHE) cells, human amniotic fluid fibroblast-like (AFFL) cells and LS178Y mouse cells. A dose-dependent increase in micronucleus fractions was found in all tbree ceU llnes. The time course of micronucleus induction in L5178Y cells showed a maximum at 5 h after treatment, suggesting that the micronuclei were fonned in the first mitosis after treatment. Kinetochore staining (CREST -antiserum) revealed the presence of kinetochores in -SO% of the micronuclei in aU tbree ceU types. ThJs resu1t was further confinned by in situ bybridization in LS178Y cells and indicates tbe presence of wbole Chromosomes or centric fragments as weU as acentric fragments in the oxazepam-induced micronuclei. The LS178Y cells did not show a mutagenic response to oxazepam at any of the doses or expression times used.
KW  - Toxikologie
Y1  - 1993
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-63404
ER  - 
TY  - JOUR
A1  - Shephard, S. E.
A1  - Schlatter, C.
A1  - Lutz, Werner K.
T1  - Assessment of the risk of formation of carcinogenic N-nitroso compounds from dietary precursors in the stomach
N2  - A literature review has shown that the daily intakes of various N -nitroso-precursor classes in a typical European diet span five orders of magnitude. Amides in the form of protein, and guanidines in the form of creatine and creatinine, are the nitrosatable groups found most abundantly in the diet, approaching Ievels of 100 g/day and 1 gjday, respectively. Approximately 100 mg of primary amines and amino acids are consumed daily, whereas aryl amines, secondary amines and ureas appear to lie in the 1-10 mg range. The ease of nitrosation of each precursor was estimated, the reactivities being found to span seven orders of magnitude, with ureas at the top and amines at the bottom of the scale. From this infonnation and an assessment of the carcinogenicity of the resulting N-nitroso derivatives, the potential health risk due to gastric in vivo nitrosation was calculated. The combined effects of these risk variables were analysed using a simple mathematical model: Risk = [daily intake of precursor] x [gastric concentration of nitrite]\(^n\) x [nitrosatability rate constant} x [carcinogenicity of derivative]. The risk estimates for the various dietary components spanned nine orders of magnitude. Dietary ureas and aromatic amines combined with a high nitrite burden could pose as great a risk as the intake of preformed dimethylnitrosamine in the diet. In contrast, the risk posed by the in vivo nitrosation of primary and secondary amines is probably negligib1y small. The risk contribution by amides (including protein), guanidines and primary amino acids is intermediate between these two extremes. Thus three priorities for future work are a comprehensive study of the sources and Ievels of arylamines and ureas in the diet, determination of the carcinogenic potencies of key nitrosated products to replace the necessarily vague categories used so far, and the development of short-term in situ tests for studying the alkylating power or genotoxicity of N-nitroso compounds too unstable for inclusion in long-term studies.
KW  - Toxikologie
Y1  - 1987
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-60925
ER  - 
TY  - JOUR
A1  - Lohse, M. J.
A1  - Klotz, Karl-Norbert
A1  - Jakobs, K. H.
A1  - Schwabe, U.
T1  - Barbiturates are selective antagonists at A\(_1\) adenosine receptors
N2  - Barbiturates in pharmacologically relevant . concentrations inhibit binding of (R)-\(N^6\)-phenylisopropyl[\(^3\)H]adenosine ([\(^3\)H]PIA) to solubilized A\(_1\) adenosine receptors in a concentration-dependent, stereospecific, and competitive manner. K\(_i\) values are similar to those obtained for membrane-bound receptors and are 31 \(\mu\)M for ( ± )-5-(1 ,3-dimethyl)-5-ethylbarbituric acid [( ± )DMBB] and 89 \(\mu\)M for ( ± )-pentobarbital. Kinetic experiments demoostrate that barbiturates compete directly for the binding site of the receptor. The inhibition of rat striatal adenylate cyclase by unlabelled (R)-\(N^6\)-phenylisopropyladenosine [(R)-PIA] is antagonized by barbiturates in the same concentrations that inhibit radioligand binding. The Stimulation of adenylate cyclase via A\(_2\) adenosine receptors in membranes from NIE 115 neuroblastoma cells is antagonized only by 10-30 times higher concentrations of barbiturates. lt is concluded that barbiturates are selective antagonists at the A1 receptor subtype. In analogy to the excitatory effects of methylxanthines it is suggested that A\(_1\) adenosine receptor antagonism may convey excitatory properties to barbiturates. Key Words: Adenosine receptors-Barbiturates - Adenylate cyclase-Receptor solubilization-[3H]PIA binding-N1E 115 cells. Lohse M. J. et al. Barbiturates are selective antagonists at A1 adenosine receptors.
KW  - Toxikologie
KW  - adenosine receptors
KW  - barbiturates
KW  - adenylate cyclase
KW  - receptor solubilization
KW  - N1E 115 cells
KW  - [3H]PIA binding
Y1  - 1985
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-60187
ER  - 
TY  - THES
A1  - Colnot, Thomas
T1  - Beurteilung von Phyto- und Xenoöstrogenen am Beispiel ausgewählter Substanzen
T1  - Assessment of Phyto- and Xenoestrogens for Selected Substances
N2  - 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 Phytoöstrogene wurde Daidzein als wichtiger Vertreter, der in hohen Konzentrationen in vielen Nutzpflanzen und Nahrungsmitteln vorkommt, ausgewählt. Sojaprodukte, die den größten Beitrag einer menschlichen Exposition gegen Daidzein liefern, werden in zunehmendem Maße auch in westlichen Ländern konsumiert. Bisphenol A wurde als Vertreter der Xenoöstrogene gewählt, 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 aufgeklärt. Dabei konnte gezeigt werden, daß die orale Bioverfügbarkeit 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 überwog in der männlichen Ratte zusätzlich 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 östrogenen Wirksamkeit zu einer Detoxifizierung der beiden Verbindungen führte, 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 unvollständig aus dem Magen-Darm-Trakt resorbiert; der Großteil der gegebenen Dosis wurde als unveränderte Substanz in den Faeces wiedergefunden. Bei Bisphenol A wurde die Ausscheidung zudem durch einen ausgeprägten enterohepatischen Kreislauf verzögert. Im zweiten Teil der Arbeit wurden zunächst 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 für die Humanstudie die deuterierte Verbindung gegeben, für die kein störender Hintergrund meßbar war. Die Bioverfügbarkeit der Gesamt-Substanz (freie Verbindung + Konjugate) im Menschen war in beiden Fällen deutlich höher 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 unveränderte Substanz gefunden. Das Glucuronid stellte in beiden Fällen 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 Auffälligkeiten 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 für den Menschen abgegeben.
N2  - Daidzein and bisphenol a are two representatives of a class of substances known as endocrine disrupters. A common mark of these compounds is their affinity to at least one of two estrogen receptors in vitro. This leads to speculation on how such compounds may interfere with hormonal regulation in animals and humans. As an important representative of the group of phytoestrogens daidzein has been chosen. Daidzein occurs in high concentrations in plants like soy, thus contributing to a human exposure via food. Bisphenol a has been chosen for this thesis because it probably is the most important industrial chemical suspected of endocrine activity, considering worldwide annual production numbers. Biotransformation and kinetics of the two model substances, daidzein and bisphenol a, have been elucidated. The results showed that oral bioavailability of the two chemicals has been very low. Less than ten percent of the dose given could be recovered from urine of animals. The major metabolite in biotransformation of both daidzein and bisphenol a proved to be the glucuronide of the respective compound. Additionally, after application of daidzein to rats, daidzein sulfate could be identified specifically in male animals only. The percentage of unconjugated parent compound in both studies has been shown to be between one and three percent of the dose given. No further metabolites could be found after oral administration of bpa to rats; after oral administration of daidzein to rats, equol and o-dma could be identified as minor metabolites in feces of animals. In both studies, the major part of the administered dose could be recovered as unchanged parent compound from feces. In the case of BPA, elimination was slowed by the occurence of enterohepatic circulation. This explains why the elimination of BPA and its conjugates was slow and did not follow a first-order kinetics. Furthermore, sensitive analytical methods (HPLC and GC/MS) were developed to allow quantification of low amounts of the two model compounds in human plasma und urine samples. To obtain information on the biotransformation and toxicokinetics in humans, volunteers were given 5 mg of either daidzein or d16-bisphenol a. Because of a rather high background for bisphenol a in control samples, deuterated bisphenol a had been chosen for the human study. Bioavailability of total substance (i.e. unconjugated + conjugated compound) in humans was markedly higher than in rats. After controlled exposure to daidzein 40 per cent (as compared to 10 per cent in rats) could be recovered from urine, in the case of d16-bpa more than 95 per cent (as compared to 13 per cent in rats) could be recovered. Less than 1 per cent of the concentration of the conjugated compound could be found as unchanged parent compound. In both cases, the glucuronide has been identified as sole metabolite in human volunteers. Elimination of both substances was quick and followed a first order kinetics. In the case of d16-bisphenol a, all of the given dose could be recovered from urine. With the data gathered, an assessment of the risk posed by these chemicals to humans was given.
KW  - Phytoöstrogen
KW  - Bisphenol A
KW  - Biotransformation
KW  - Toxikologie
KW  - Biotransformation
KW  - Toxikokinetik
KW  - Phytoöstrogene
KW  - Xenoöstrogene
KW  - Daidzein
KW  - Bisphenol A
KW  - Metabolismus
KW  - biotransformation
KW  - toxicokinetics
KW  - phytoestrogens
KW  - xenoestrogens
KW  - daidzein
KW  - bisphenol A
KW  - metabolism
Y1  - 2001
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-1180438
ER  - 
TY  - JOUR
A1  - Gunz, D.
A1  - Shephard, S. E.
A1  - Lutz, Werner K.
T1  - Can nongenotoxic carcinogens be detected with the lacI transgenic mouse mutation assay?
N2  - No abstract available
KW  - Toxikologie
Y1  - 1993
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-60707
ER  - 
TY  - JOUR
A1  - van Calker, D.
A1  - Steber, R.
A1  - Klotz, Karl-Norbert
A1  - Greil, W.
T1  - Carbamazepine distinguishes between adenosine receptors that mediate different second messenger responses
N2  - The mechanism of the therapeutic and prophylactic effects of carbamazepine (CBZ) in affective psychoses is unknown but may in part be related to the potent competitive interaction of CBZ with adenosine-binding sites in the brain. The antioonvulsant and sedative properties of CBZ are reminiscent of the effects evoked by adenosine-agonists and contrast sharply with the opposite aclions of adenosine-antagonists like caffeine. However. indirect evidence suggests an antagonist- rather than an agonist-like activity of CBZ at adenosi11e-receptors. We have used various model systems, in which adenosine receptor subtypes mediate different second messenger-responses, to investigate this apparent paradox. CBZ was found to antagonize the A\(_1\) receptor-mediated inhibition of cydic AMP accumulation in cultured astroblasts and in GH3-cells. Furthermore, CBZ also inhibits the adenosine-induced increase in the level of cyclic AMP in cultured astroblasts, which is mediated by low-affinity A\(_{2b}\)-receptors. ln contrast, CBZ does not block the inhibition elicited by adenosine-agonists of the agonist-induced increased formation of inositolphosphates in human neutrophils, which is mediated by high-affinity A\(_{2a}\)-receptors. The specific antagonism by CBZ of A\(_1\)- but not of high-affinity A\(_{2a}\)-receptors was further supported by binding experiments using rat brain membranes. These results suggest tbat the paradox of CBZ's antagonistic effects at adenosine-receptors might be at least partially reconciled by a selective antagonistic action of CBZ at A\(_1\)recertors but not at high-affinity A\(_{2a}\)-receptors.
KW  - Toxikologie
Y1  - 1991
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-60392
ER  - 
TY  - JOUR
A1  - Stopper, Helga
A1  - Metzler, M.
T1  - Carcinogenic oestrogens induce respiration deficiency mutation in yeast
N2  - In addition to hormonal activity, genetic darnage has been proposed as an important factor in oestrogen-mediated carcinogenesis. However, as short-term tests for oestrogens usually fail to show DNA mutations, lesions other than dassie nuclear DNA mutation have to be considered. Oestrogeninduced mitochondrial darnage was studied in the yeast Saccharomyces cerevisiae. Stilbene-type, but not steroidal, oestrogens were found to induce respiration-dcficient petite mutation. The effect was inversely correlated with cytotoxicity and required aromatic hydroxyl groups at the stilbene molecule. It only occurred under growth conditions and apparently was not due to the A TPase inhibitory qualities of stilbene oestrogens. Other studies have shown that petite mutation clones, which can be induced by a variety of substances, contain altered mitochondrial DNA. The mechanism of petite mutation induction might be important in tumorigenesis by also acting on nuclear DNA or facilitating carcinogenesis by disturbance of mitochondrial function.
KW  - Toxikologie
Y1  - 1991
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-63466
ER  - 
TY  - JOUR
A1  - Stopper, Helga
A1  - Kirchner, S.
A1  - Schiffmann, D.
A1  - Poot, M.
T1  - Cell cycle disturbance in relation to micronucleus formation induced by the carcinogenic estrogen diethylstilbestrol
N2  - In addition to its tumor-promoting activity in honnone-receptive tissue, the carcinogenic estrogen diethylstilbestrol (DES) has been found to induce cell transformation, aneuploidy and micronucleus formation in mammalian cells. The majority of these micronuclei contained whole chromosomes and were fonned during mitosis. Here a possible relationship between a disturbance in cell cycle progression and micronucleus fonnation is investigated by exposing Syrian hamster embryo (SHE) cells to DES. Continuous bromodeoxyuridine labeling followed by bivariate Hoechst 33258/ethidium bromide flow cytometry was employed for analysis of cell cycle transit and related to the time course of micronucleus formation. Treatment of SHE cells with DES resulted in delayed and impaired cell activation (exit from the GO/G 1 phase), impaired S-phase transit and, mainly, G2-phase traverse. Cells forming micronuclei, on the other hand, were predominantly in G2 phase during DES treatment. These results suggest that impairment of Sand G2 transit may involve a process ultimately leading to micronucleus formation.
KW  - Toxikologie
KW  - Flow cytometry
KW  - Micronucleus formation
KW  - Diethylstilbestrol
KW  - Hoechst 33258 dye
KW  - Bromodeoxyuridine labeling
KW  - continuous
Y1  - 1994
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-82250
ER  - 
TY  - JOUR
A1  - Stopper, Helga
A1  - Körber, C.
A1  - Schiffmann, D.
A1  - Caspary, W. J.
T1  - Cell-cycle dependent micronucleus formation and mitotic disturbances induced by 5-azacytidine in mammalian cells
N2  - 5-Azacytidine was originally developed to treat human myelogenous leukemia. However, interest in this compound has expanded because of reports of its ability to affect cell differentiation and to alter eukaryotic gene expression. In an ongoing attempt to understand the biochemical effects of this compound, we examined the effects of 5-azacytidine on mitosis and on micronucleus formation in mammalian cells. In L5178Y mouse cells, 5-azacytidine induced micronuclei at concentrations at which we and others have already reported its mutagenicity at the tk locus. Using CREST staining and C-banding studies, we showed that the induced micronuclei contained mostly chromosomal fragments although some may have contained whole chromosomes. By incorporating BrdU into the DNA of SHE cells, we determined that micronuclei were induced only when the compound was added while the cells were in S phase. Microscopically visible effects due to 5-azacytidine treatment were not observed until anaphase of the mitosis following treatment or thereafter. 5-Azacytidine did not induce micronuclei via interference with formation of the metaphase chromosome arrangement in mitosis, a common mechanism leading to aneuploidy. SupravitalUV microscopy revealed that chromatid bridges were observed in anaphase and, in some cases, were sustained into interphase. In the first mitosis after 5-azacytidine treatment we observed that many cells were unable to perform anaphase separation. All of these observations indicate that 5-azacytidine is predominantly a clastogen through its incorporation into DNA.
KW  - Toxikologie
KW  - Micronuclei
KW  - L5178Y cells
KW  - 5-Azacytidine
KW  - Berenil
KW  - DES
KW  - Ethionine
KW  - Mitosis
Y1  - 1993
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-63411
ER  - 
TY  - JOUR
A1  - Förtsch, Christina
A1  - Hupp, Sabrina
A1  - Ma, Jiangtao
A1  - Mitchell, Timothy J.
A1  - Maier, Elke
A1  - Benz, Roland
A1  - Iliev, Asparouh I.
T1  - Changes in Astrocyte Shape Induced by Sublytic Concentrations of the Cholesterol-Dependent Cytolysin Pneumolysin Still Require Pore-Forming Capacity
N2  - 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.
KW  - Toxikologie
KW  - pneumolysin
KW  - pore formation
KW  - cytoskeleton
Y1  - 2011
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-69084
ER  - 
TY  - JOUR
A1  - Koch, R.
A1  - Deger, A.
A1  - Klotz, Karl-Norbert
A1  - Schenzle, D.
A1  - Krämer, H.
A1  - Kelm, S.
A1  - Müller, G.
A1  - Rapp, R.
A1  - Weber, U.
T1  - Characterization of solubilized insulin receptors from rat liver microsomes. Existence of two receptor species with  different binding properties
N2  - Insulin receptors were solubilized from rat liver microsomes by the nonionic detergent Triton X-100. After gel filtration of the extract on Sepharose CL-6B, two insulin-binding species (peak I and peak li) were obtained. The structure and binding properties of both peaks were characterized. Gel filtration yielded Stokes radii of 9.2 nm (peak I) and 8.0 nm (peak Il). Both peaks were glycoproteins. At 4°C peak 1 showed optimal insulin binding at pH 8.0 and high ionic strength. In contrast, peak li bad its binding optimum at pH 7.0 and low ionic strength, where peak I bindingwas minimal. For peak I the change in insulin binding under different conditions of pH and ionic strength was due to a change in receptor affinity only. For peak 11 an additional change in receptor number was found. Both peaks yielded non-linear Scatchard plots under most of the buffer conditions examined. At their binding optima at 4 oc the high affinity dissociation constants were 0.50 nM (peak I) and 0.55 nM (peak II). Sodium dodecyl sulfatejpolyacrylamide gel electrophoresis of peak I revealed five receptor bands with Mr 400000, 365000, 320000, 290000, and 245000 under non-reducing conditions. For peak II two major receptor bands with M\(_r\) 210000 and 115000 were found. The peak II receptor bands were also obtained aftermild reduction of peak I. After complete reduction both peaks showed one major receptor band with M\(_r\) 130000. The reductive generation of the peak II receptor together with molecular mass estimations suggest that the peak I receptor is the disulfide-linked dimer of the peak II receptor. Thus, Triton extracts from rat liver microsomes contain two receptor species, which are related, but differ considerably in their size and insulin-binding properties.
KW  - Toxikologie
Y1  - 1986
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-60215
ER  - 
TY  - JOUR
A1  - Tawfik-Schlieper, H.
A1  - Klotz, Karl-Norbert
A1  - Kreye, V. A. W.
A1  - Schwabe, U.
T1  - Characterization of the K\(^+\)-channel-coupled adenosine receptor in guinea pig atria
N2  - In the present work we studied the pharmacological profile of adenosine receptors in guinea pig atria by investigating the effect of different adenosine analogues on 86Rb + -efflux from isolated left atria and on binding of the antagonist radioligand 8-cyclopentyl-1 ,3-[\(^3\)H]dipropylxanthine ([\(^3\)H]DPCPX) to atrial membrane preparations. The rate of \8^{86}\)Rb\(^+\) -effiux was increased twofold by the maximally effective concentrations of adenosine receptor agonists. The EC50-values for 2-chloro-N\(^6\)-cyclopentyladenosine (CCPA), R-N\(^6\)-phenylisopropyladenosine (R-PIA), 5'-Nethylcarboxamidoadenosine (NECA), and S-N\(^6\)-phenylisopropyladenosine (S-PIA) were 0.10, 0.14, 0.24 and 12.9 \(\mu\)M, respectively. DPCPX shifted the R-PIA concentration-response curve to the right in a concentration-dependent manner with a K\(_B\)-value of 8.1 nM, indicating competitive antagonism. [\(^3\)H]DPCPX showed a saturable binding to atrial membranes with a Bmax·value of 227 fmol/mg protein and a K\(_D\)-value of 1.3 nM. Competition experiments showed a similar potency for the three agonists CCPA, R-PIA and NECA. S-PIA is 200 times less potent than R-PIA. Our results suggest that the K\(^+\) channel-coupled adenosine receptor in guinea pig atria is of an A\(_1\) subtype.
KW  - Toxikologie
KW  - A1 Adenosine receptors
KW  - K + -channels
KW  - Atria
KW  - Radioligand binding - 86Rb + -efflux
Y1  - 1989
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-60333
ER  - 
TY  - JOUR
A1  - Klotz, Karl-Norbert
A1  - Lohse, M. J.
A1  - Schwabe, U.
T1  - Characterization of the solubilized A\(_1\) adenosine receptor from rat brain membranes
N2  - A\(_1\) adenosine receptors from rat brain membranes were solubilized with the zwitterionic detergent 3-[3-( cholamidopropyl)dimethylammonio]-1-propanesulfonate. The solubilized receptors retained all the characteristics of membrane-bound A\(_1\) adenosine receptors. A high and a low agonist affinity state for the radiolabelled agonist (R)-\(N^6\)-[\(^3\)H]phenylisopropyladenosine([\(^3\)H]PJA) with K\(_D\) values of 0.3 and 12 nM, respectively, were detected. High-affinity agonist binding was regulated by guanine nucleotides. In addition agonist binding was still modulated by divalent cations. The solubilized A\(_1\) adenosine receptors could be labelled not only with the agonist [\(^3\)H]PIA but also with the antagonist I ,3-diethyi-8-[\(^3\)H]phenylxanthine. Guanine nucleotides did not affect antagonist binding as reported for membrane-bound receptors. These results suggest that the solubilized receptors are still coupled to the guanine nucleotide binding protein N; and that all regulatory functions are retained on solubilization. Key Words: A1 adenosine receptors - Solubilization- Rat brain membranes. Klotz K.-N. et al. Characterization of the solubilized A1 adenosine receptor from rat brain membranes. J. Neurochem. 46, 1528-1534 (1986).
KW  - Toxikologie
KW  - A1 adenosine receptors
KW  - solubilization
KW  - rat brain membranes
Y1  - 1986
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-60222
ER  - 
TY  - JOUR
A1  - Lutz, Werner K.
A1  - Schlatter, J.
T1  - Chemical carcinogens and overnutrition in diet-related  cancer [commentary]
N2  - The intake of known dietary carclnogens was compiled and the cancer risk was estlmated on the basis of carcinogenic potencies in animals as derived from the Carcinogenic Potency Database by Gold and co-workers. The total cancer risk was compared with the number of cancer cases attributed by epidemiologists to dietary factors (one-third of all cancer cases, i.e. -80 000 per one million Jives). Except for alcohol, the known dietary carcinogens could not account for more than a few bundred cancer cases. Tbis was seen both with tbe DNA-reactive carcinogens (beterocyclic aromatic amines, polycyclic aromatic hydrocarbons, N-nitroso compounds, estragole, aflatoxin B., ethyl carbamate, to name the most important factors) as wen as with those carclnogens wbich have not been shown to react with DNA (e.g. caffelc acid and the carcinogeruc metals arsenic and cadmium). Residues and contaminants turned out to be negligible. Among the various pmsibilities to explain the discrepancy we investigated the roJe of ovemutritlon. Dietary restriction in animals is weil known for its strong reducing effect on spontaneous tumor formation. These data can be used to derive a carcinogenic potency for excess macronutrients: tbe tumor incidence seen with the restrlcted animals is taken as a control value and the increased tumor incidence in the animals fed ad libitum is attributed to the additional feed iotake. For excess standard diet in rats, a carcinogenic potency TD50 of 16 glkg/day was deduced from a recent study. Ovemutrition in Switzerland, estimated to be 5.5 kcallkg/day, was converted to excess food (1.9 g/kg/day) and tbe cancer incidence was calculated. The result, 60 000 cancer cases per one million Jives, is provocatively close to the number of cases not explained by the known dietary chemical carcinogens. Mechanistic studies will be required to test our hypothesis and investigate the role of different types of macronutrients in ovemutrition.
KW  - Toxikologie
Y1  - 1992
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-60712
ER  - 
TY  - JOUR
A1  - Klotz, Karl-Norbert
A1  - Lohse, M. J.
A1  - Schwabe, U.
T1  - Chemical modification of A\(_1\) adenosine receptors in rat brain membranes - evidence for histidine in different domains of the ligand binding site
N2  - 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.
KW  - Toxikologie
Y1  - 1988
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-60295
ER  - 
TY  - JOUR
A1  - Stopper, Helga
A1  - Kühnel, A.
A1  - Podschun, B.
T1  - Combination of the chemotherapeutic agent 5-fluorouracil with an inhibitor of its catabolism results in increased micronucleus induction
N2  - The rate limiting step in 5-fluorouracil catabolism is catalyzed by the enzyme dihydropyrimidine dehydrogenase. Since degradation of 5-fluorouracil decreases its efficacy in chemotherapy, the inhibition of its catabolism is a promising tool. We investigated the formation of micronuclei in vitro in mouse L5178Y cells. 5-fluorouracil induced an increase in micronucleus frequency, which could significantly be enhanced by the concurrent application of 2,6-dihydroxypyridine, an inhibitor of dihydropyrimidine dehydrogenase. The 5-fluorouracil concentration necessary to reach maximal genotoxic effects could be reduced to half in the presence of inhibitor. 2,6-Dihydroxypyridine alone and the naturally occuring enzyme substrate uracil did not induce micronucleus formation. Combined application of the chemotherapeutic agent 5-fluorouracil and an inhibitor of its could reduce side-effects by lowering the effective dose of the active drug. With this study we provide further support for the usefulness of this concept.
KW  - Toxikologie
Y1  - 1994
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-63383
ER  - 
TY  - JOUR
A1  - Jaggi, W.
A1  - Lutz, Werner K.
A1  - Schlatter, C.
T1  - Comparative studies on the covalent binding of the carcinogen benzo(a)pyrene to DNA in various model systems
N2  - 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 ).
KW  - Toxikologie
Y1  - 1979
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-61131
ER  - 
TY  - JOUR
A1  - Klotz, Karl-Norbert
A1  - Vogt, H.
A1  - Tawfik-Schlieper, H.
T1  - Comparison of A\(_1\) adenosine receptors in brain from different species by radioligand binding and photoaffinity labelling
N2  - Radioligand binding to A\(_1\) adenosine receptors at brain membranes from seven species was investigated. The antagonist 8-cyclopentyl-1 ,3-[\(^3\)H]dipropylxanthine ([\(^3\)H]DPCPX) bound with affinities between 0.17 nM in sheep brain and 2.1 nM in guinea pig brain. Competition of several antagonists for [\(^3\)H]DPCPX binding showed that the most potent compounds were DPCPX with K\(_i\) values of 0.05 nM in bovine brain and 1.1 nM in guinea pig brain and xanthine amine congener (XAC) with K\(_i\) values of 0.03 nM in bovine brain and 5.5 nM in guinea pig brain. The differences in affinity of the agonist radio Iigand 2-chloro-N\(^6\) -[\(^3\)H]cyclopen tyladenosine ([\(^3\)H]CCP A) were less pronounced, rauging from a K\(_D\) value of 0.12 nM (hamster brain) to 0.42 nM (guinea pig brain). Agonist competition for [\(^3\)H]DPCPX binding of photoaffinity labelling, however, exhibited marked species differences. N-Ethylcarboxamidoadenosine (NECA) and S-N\(^6\)-phenylisopropyladenosine (S-PIA) showed 20 to 25-fold different K\(_D\) values in different species. NECA had a particularly high affinity in guinea pig brain and was only two-fold less potent than R-PIA. Thus, the difference from the "classical" A\(_1\) receptor profile (R-PIA > -NECA > S-PIA) is not sufficient to speculate that A\(_1\) receptor subtypes may exist that are coupled to different effector systems. Our data show that these difference can easily be explained by species differences.
KW  - Toxikologie
KW  - A1 adenosine receptors
KW  - Species differences
KW  - Radioligand binding
KW  - Photoaffinity labelling
Y1  - 1991
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-60388
ER  - 
TY  - JOUR
A1  - Alldrick, A. J.
A1  - Lutz, Werner K.
T1  - Covalent binding of [2-\(^{14}\)C]2-amino-3,8-dimethylimidazo[4,5-f]-quinoxaline (MeIQx) to mouse DNA in vivo
N2  - 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.
KW  - Toxikologie
Y1  - 1989
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-60832
ER  - 
TY  - JOUR
A1  - Marinovich, M.
A1  - Lutz, Werner K.
T1  - Covalent binding of aflatoxin B\(_1\) to liver DNA in rats pretreated with ethanol
JF  - Experientia
N2  - Male Fischer F-344 rats were given ethanol in the drinking water and/or by single oral administration. Following this, the animals received p.o. 100 ng/kg of the hepatocarcinogen eHJaflatoxin BI (AFBI)' 24 h later, the level of DNA-bound AFBI was determined in the liver and was found not to be affected by any type of ethanol pretreatment. A cocarcinogenic effect of ethanol in the liver is therefore unlikely to be due to an effect on the metabolic activation and inactivation processes governing the formation of DNA-binding AFBI metabolites.
KW  - Toxikologie
KW  - Carcinogenesis
KW  - DNA
KW  - covalent binding
KW  - aflatoxin
KW  - ethanol
Y1  - 1985
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-55237
VL  - 41
IS  - 10
SP  - 1338
EP  - 1340
ER  - 
TY  - JOUR
A1  - Lutz, Werner K.
A1  - Jaggi, W.
A1  - Schlatter, C.
T1  - Covalent binding of diethylstilbestrol to DNA in rat and hamster liver and kidney [Short Communication]
N2  - No abstract available
KW  - Toxikologie
KW  - Carcinogenesis
KW  - Covalent binding index - Diethylstilbestrol
KW  - DNA binching
KW  - Estrogen
KW  - Hormone
Y1  - 1982
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-61066
ER  - 
TY  - JOUR
A1  - Jaggi, W.
A1  - Lutz, Werner K.
A1  - Schlatter, C.
T1  - Covalent binding of ethinylestradiol and estrone to rat liver DNA in vivo
N2  - 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.
KW  - Toxikologie
Y1  - 1978
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-61162
ER  - 
TY  - JOUR
A1  - Epe, B.
A1  - Harttig, U.
A1  - Stopper, Helga
A1  - Metzler, M.
T1  - Covalent binding of reactive estrogen metabolites to microtubular protein as a possible mechanism of aneuploidy induction and neoplastic cell transformation
N2  - 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.
KW  - Toxikologie
Y1  - 1990
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-63478
ER  - 
TY  - JOUR
A1  - Cantoreggi, S.
A1  - Lutz, Werner K.
T1  - Covalent binding of styrene to DNA in rat and mouse
N2  - No abstract available
KW  - Toxikologie
Y1  - 1993
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-60693
ER  - 
TY  - JOUR
A1  - Lutz, Werner K.
A1  - Winkler, F. K.
A1  - Dunitz, J. D.
T1  - Crystal structure of the antibiotic monensin similarities and differences betweeen free acid and metal complex
N2  - The structure of monensin, C36H620 11 , has been deterrnined by X-ray analysis of its crystalline monohydrate (orthorhombic, a = 15.15, b = 23.61, c = 10.65 A, Z = 4, space group P212121). Phases were assigned by direct methods, malring use of the 'tangent formula'. Although the conformation of the free acid resembles that of the silver salt in being cyclic, there are differences in the hydrogen bonding pattern. These featurcs are discussed in relation to the cornplexation of metal ions by m.onensin.
KW  - Toxikologie
Y1  - 1971
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-61228
ER  - 
TY  - JOUR
A1  - Kirchner, S.
A1  - Stopper, Helga
A1  - Papp, T.
A1  - Eckert, I.
A1  - Yoo, H. J.
A1  - Vig, B. K.
A1  - Schiffmann, D.
T1  - Cytogenetic changes in primary, immortalized and malignant mammalian cells
N2  - 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.
KW  - Toxikologie
KW  - Micronuclei
KW  - Kinetochore
KW  - Chromosome distribution
Y1  - 1993
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-63439
ER  - 
TY  - JOUR
A1  - Hegi, M.E.
A1  - Sagelsdorff, P.
A1  - Lutz, Werner K.
T1  - Detection by \(^{32}\)P-postlabeling of thymidine glycol in gamma-irradiated DNA
N2  - No abstract available
KW  - Toxikologie
Y1  - 1989
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-60863
ER  - 
TY  - JOUR
A1  - Fischer, W. H.
A1  - Beland, P. E.
A1  - Lutz, Werner K.
T1  - DNA adducts, cell proliferation and papilloma latency time in mouse skin after repeated dermal application of DMBA and TPA
N2  - '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
KW  - Toxikologie
Y1  - 1993
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-60673
ER  - 
TY  - JOUR
A1  - Sagelsdorff, P.
A1  - Lutz, Werner K.
A1  - Schlatter, C.
T1  - DNA methylation in rat liver by daminozide, 1,1-dimethylhydrazine, and dimethylnitrosamine
N2  - DNA Methylation in Rat Li ver by Daminozide, 1, 1-Dimethylhydrazine, and Dimethylnitrosamine. SAGELSDORFF, P., LUTZ, W. K., AND ScHLAITER C. (1988). Fundam. Appl. Toxico/. 11, 723-730. [methyP4C]Daminozide (succinic acid 2',2'-dimethylhydrazide; 37 mgjkg), l,l( 14C]dimethylhydrazine (UDMH; 19 mgtkg), and (14C]dimethylnitrosamine (DMNA; 0.1 mg/ kg) were administered by oral gavage to male Sprague-Dawley rats. After 24 hr, the animals were killed and DNA was purified from the livers to constant specific radioactivity. After enzymatic degradation of the DNA to the 3'-deoxynucleotides the Ievel of DNA methylation was determined by HPLC analysis. Radiolabeled 7-methylguanine (7mG) was identified by cochromatography with unlabeled 7mG added as standard after acidic depurination of DNA and HPLC analysis ofpurines and apurinic acid. All three compounds were found to methylate DNA. The relative potencies were 1:47:4900 for daminozide:UDMH:DMNA. With [methyPH]UDMH, the formation of7mG was investigated as a function of dose administered, at 20, 2, and 0.2 mgj kg. The methylation ofDNA was strictly proportional to the dose. The data were used to compare the Ievel of DNA alkylation derived from residues of daminozide and UDMH in treated apple with the genotoxicity of the intake of N-nitroso compounds in Germany and Japan. It is estimated that these residues could Iead to a DNA methylation in the Ii ver of about 6% of an average exposure to DMNA
KW  - Toxikologie
Y1  - 1988
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-60875
ER  - 
TY  - JOUR
A1  - Ohgaki, H.
A1  - Ludeke, B. I.
A1  - Meier, I.
A1  - Kleihues, P.
A1  - Lutz, Werner K.
A1  - Schlatter, C.
T1  - DNA methylation in the digestive tract of F344 rats during chronic exposure to N-methyl-N-nitrosourea
N2  - The formation of \(O^6\)-methyldeoxyguanosine (\(O^6\)-MedGuo) was determined by an immuno-slot-blot assay in DNA of various tissues of F344 rats exposed to N-methyl-N-nitrosourea (MNU) in the drinking waterat 400 ppm for 2 weeks. Although the pyloric region of the glandular stomach is a target organ under these experimental conditions, the extent of DNA methylation was highest in the forestomach (185 \(\mu\)mol \(O^6\)-MedGuojmol guanine). Fundus (91 J.!moljmol guanine) and pylorus (105 J.!moljmol guanine) of the glandular stomach, oesophagus (124 \(\mu\)mol/mol guanine) and duodenum (109 )lmoljmol guanine) showed lower Ievels of \(O^6\) - MedGuo but differed little between each other. Thus, no correlation was observed between target organ specificity and the extent of DNA methylation. This is in contrast to the gastric carcinogen, N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), which preferentially alkylates DNA of the pylorus, the main site of induction of gastric carcinomas by this chemical. In contrast to MNU, the nonenzymic decomposition of MNNG is accelerated by thiol compounds (reduced glutathione, L-cysteine), which are present at much higher concentrations in the glandular stomach than in the forestomach and oesophagus. During chronic exposure to MNNG (80 ppm), mucosal cells immunoreactive to 0 6-MedGuo are limited to the luminal surface [Kobori et al. (1988) Carcinogenesis 9:2271-2274]. Although MNU (400 ppm) produced similar Ievels of \(O^6\)-MedGuo in the pylorus, no cells containing methylpurines were detectable by immunohistochemistry, suggesting a more uniform methylation of mucosal cells by MNU than by MNNG. After a single oral dose of MNU (90 mg/kg) cells containing methylpurines were unequivocally identified using antibodies to \(O^6\)-MedGuo and the imidazole-ring-opened product of 7-methyldeoxyguanosine. In the gastric fundus, their distribution was similar to those methylated by exposure to MNNG, whereas the pyloric region contained immunoreactive cells also in the deeper mucosallayers. After a 2-week MNU treatment, the rate of cell proliferation, as determined by bromodeoxyuridine immunoreactivity, was only slightly enhanced in the oesophagus andin the fundus, but markedly in the forestomach and the pyloric region of the glandular stomach. lt is concluded that the overall extent of DNA methylation, the distribution of alkylated cells within the mucosa and the proliferative response all contribute to the organ-specific carcinogenicity of MNU.
KW  - Toxikologie
KW  - Gastric carcinogenesis
KW  - N-methyl-N-nitrosourea
KW  - DNA methylation
Y1  - 1991
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-60759
ER  - 
TY  - JOUR
A1  - Lutz, Werner K.
T1  - Dose-response relationship and low dose extrapolation in chemical carcinogenesis [commentary]
N2  - Data supporting various dose-respome relationships in chemical carcinogenesis are summarized. General principles are derived to explain the relationships between exposure dose, JI>NA adduct Ievel, induction of genetic changes, and tumor incidence. Some mechanistic aspects of epigenetic carcinogens (stimulation of ceU division and maldlfl'erentlation) are analyzed in a similar way. In a bomogeneous pnpulation, non-linearities are frequent. They are due to pbenomena of induction or saturation of enzymatic activities and to the multi-step nature of carcinog~: if a carcinogen acce1erates more than one step, the SUperposition of the dose- response curves for the indJvidual steps can result in an exponential relationship. A fourth power of the dose was the maximum seen in animals (fonnaldehyde). At the lowest dose Ievels, a proportionality between dose and tumor induction is postulated independent of the mechanism of action if the carcinogen aceeierotes the endogenous proass responsible for spootaneous tumor formation. Low-dose thresholds are expected only for situations where the carcinogen acts in a way that has no endogenous counterpart. Epidemiologfcal studies in humans show linear dose- response curves in all but two investigations. The difference from the strongly nonlinear slopes ·seen in animal studies could be due to the heterogeneity of the human population: if the individual sensitivity to a carcinogen is governed by a large number of genetic and Iife-style factors, the non-linea.rities will tend to cancel each other out and the dose- response curve becomes 'quasi-linear'.
KW  - Toxikologie
Y1  - 1990
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-60789
ER  - 
TY  - JOUR
A1  - Lutz, Werner K.
T1  - Dose-response relationship for chemical carcinogenesis by genotoxic agents
N2  - No abstract available
KW  - Toxikologie
Y1  - 1991
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-60766
ER  - 
TY  - JOUR
A1  - Lutz, Werner K.
T1  - Dosis-Wirkungs-Beziehungen in der chemischen Kanzerogenese
T1  - Dose-response relations in chemical carcinogenesis
N2  - Ich habe versucht darzulegen, daß mechanistische Überlegungen zur Extrapolation der Dosis-WirkungsBeziehung herangezogen werden können. Ein nichtlinearer Verlauf ist nicht nur bei den epigenetischen Kanzerogenen wahrscheinlich, sondern auch bei den DNA-bindenden. Echte Schwellen sind aber nur in solchen Fällen zu erwarten, wo kein endogenes Korrelat besteht. Immerhin können auch steile Nichtlinearitäten zu einer drastischen Risikoreduktion führen, so daß die Anstrengungen dahin gehen sollten, die Steigung und den Bereich des überproportionalen Abfalls experimentell zu zeigen. In einer heterogenen Population kann die 0 0- sis-Wirkungs-Kurve zusätzliche "Wellen" bekommen und wird dadurch grundsätzlich flacher. Im Extremfall ergibt sich eine lineare Dosis-Wirkungs-Beziehung unabhängig vom Wirkmechanismus des Kanzerogens. Diese Proportionalität zwischen tiefster Dosis und Effekt wird bei genotoxischen Kanzerogenen aus mechanistischen Gründen schon für eine homogene Population postuliert, doch kann dies in einer heterogenen Population auch bei epigenetischen Kanzerogenen in Frage kommen.
KW  - Toxikologie
Y1  - 1990
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-80046
ER  - 
TY  - JOUR
A1  - Lutz, Werner K.
A1  - Brändle, E.
A1  - Zbinden, G.
T1  - Effect of gum Arabic on aminopyrine demethylation in rats
N2  - Stimulation of aminopyrine demethylation induced in rats by oral or i.p. administration of phenobarbital was partially inhibited in animals receiving daily treatments of 2 x 200 mg/kg gum Arabic p.o.
KW  - Toxikologie
Y1  - 1978
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-61146
ER  - 
TY  - JOUR
A1  - Baertsch, A.
A1  - Lutz, Werner K.
A1  - Schlatter, C.
T1  - Effect of inhalation exposure regimen on DNA binding potency of 1,2-dichloroethane in the rat
N2  - 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.
KW  - Toxikologie
KW  - 1
KW  - 2-Dichloroethane
KW  - Carcinogens
KW  - DNA
KW  - binding
KW  - Rat
KW  - Inhalation
KW  - Dose response
Y1  - 1991
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-60743
ER  - 
TY  - JOUR
A1  - Viviani, A.
A1  - Däniken, A. von
A1  - Schlatter, C.
A1  - Lutz, Werner K.
T1  - Effect of selected induction of microsomal and nuclear aryl hydrocarbon monooxygenase and epoxide hydrolase as well as cytoplasmic glutathione S-epoxide transferase on the covalent binding of the carcinogen benzo(a)pyrene to rat liver DNA in vivo
N2  - Groups of four adult male rats [ZUR:SIV -Z] were pretreated with corn oil (control; 2 ml/kg/day i. p. for 3 days), trans-stilbene-oxide (SO; 200 mg/kg/day i. p. for 2 days), 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; 10 \(\mu\)g/kg i. p. once, 4 days before killing), phenobarbital (PB; 1 gjliter in the drinking water for 8 days), and dieldrin (20 mg/kg/day i. p. for 3 or 9 days). They received an injection of [G-\(^3\)H]benzo(a)pyrene (BaP, 31 \(\mu\)g/kg, 7.4. 10\(^9\) dpm/kg; i. v.) 16 h before killing. In the liver of each rat, five enzymatic activities and the covalent binding of BaP to DNA have been determined. The rnicrosomal aryl hydrocarbon monooxygenase activity (AHM) ranged frorn 75% of control (SO) to 356% (TCDD), the nuclear AHM from 63% (SO) to 333% (TCDD). Microsomal epoxide hydrolase activity (EH) was induced up to 238% (PB), nuclear EH ranged from 86% (TCDD) to 218% (PB). A different extent of induction was observed in the two compartments. Highest induction of glutathione S-epoxide transferase activity (GST) was found with PB (202%). The DNA binding of BaP was modulated within 79% (dieldrin, 9 days) and 238% of control (TCDD). An enzyme digest of control DNA was analysed by Sephadex LH-20 chromatography. Multiple linear regression analysis with all data expressedas o/o of control yielded the following equation: DNA Binding = 1.49 · Microsomal AHM- 1.07 · Nuclear AHM+ 0.33 · Microsomal EH- 0.52 · N uclear EH+ 0.11 · Cytoplasmic GST + 58.2. From this analysis it is concluded that (1) AHM located in the endoplasmic reticulum is most important in the formation of DNA-binding metabolites, (2) EH in the same compar.tment is not determinative in thls respect nor has it a protective effect, (3) both membrane-bound enzyme activities located in the nucleus may inactivate potential ultimate carcinogens, and ( 4) cytoplasmic GST probably cannot reduce DNA binding due to its subcellular localization.
KW  - Toxikologie
KW  - Carcinogen
KW  - Benzo(a)pyrene-DNA binding
KW  - Enzyme induction
KW  - Aryl hydrocarbon rnonooxygenase
KW  - Epoxide hydrolase
KW  - Glutathione Stransferase
Y1  - 1980
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-61114
ER  - 
TY  - JOUR
A1  - Zimmermann, U.
A1  - Stopper, Helga
T1  - Elektrofusion und Elektropermeabilisierung von Zellen : Eine neuartige Methode der Biotechnologie zur gezieltenVeränderung der genetischen Eigenschaften von Zellen
N2  - No abstract available
KW  - Toxikologie
Y1  - 1987
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-63514
ER  -