Dokument-ID Dokumenttyp Verfasser/Autoren Herausgeber Haupttitel Abstract Auflage Verlagsort Verlag Erscheinungsjahr Seitenzahl Schriftenreihe Titel Schriftenreihe Bandzahl ISBN Quelle der Hochschulschrift Konferenzname Quelle:Titel Quelle:Jahrgang Quelle:Heftnummer Quelle:Erste Seite Quelle:Letzte Seite URN DOI Abteilungen OPUS4-5201 Wissenschaftlicher Artikel Grunicke, H.; Pyerin, W.; Eisenbrand, G.; Havemann, K.; Rabes, H. M.; Molling, K.; Schwab, M.; Lutz, Werner K.; Wahrendorf, J.; Schirrmacher, V. 7th International Symposium of the Division of Experimental Cancer Research (AEK) of the German Cancer Society : [Meeting report] No abstract available 1994 urn:nbn:de:bvb:20-opus-60651 Institut für Pharmakologie und Toxikologie OPUS4-5474 Wissenschaftlicher Artikel Huber, K. W.; Lutz, Werner K. Methylation of DNA in stomach and small intestine of rats after oral administration of methylamine and nitrite 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. 1984 urn:nbn:de:bvb:20-opus-60984 Institut für Pharmakologie und Toxikologie OPUS4-5478 Wissenschaftlicher Artikel Huber, K. W.; Lutz, Werner K. Methylation of DNA by incubation with methylamine and nitrite 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. 1984 urn:nbn:de:bvb:20-opus-61011 Institut für Pharmakologie und Toxikologie OPUS4-5511 Wissenschaftlicher Artikel Lutz, Werner K.; Winkler, F. K.; Dunitz, J. D. Crystal structure of the antibiotic monensin similarities and differences betweeen free acid and metal complex 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. 1971 urn:nbn:de:bvb:20-opus-61228 Institut für Pharmakologie und Toxikologie OPUS4-5513 Wissenschaftlicher Artikel Lutz, Werner K.; Wipf, H. K.; Simon, W. Alkalikationen-Spezifität und Träger-Eigenschaftender Antibiotica Nigerfein und Monensin 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. 1970 urn:nbn:de:bvb:20-opus-61233 Institut für Pharmakologie und Toxikologie OPUS4-5200 Wissenschaftlicher Artikel Fischer, W. H.; Lutz, Werner K. Short communication : Mouse skin papilloma formation by chronic dermal application of 7,12-dimethylbenz[a]anthracene is not reduced by diet restriction No abstract available 1994 urn:nbn:de:bvb:20-opus-60644 Institut für Pharmakologie und Toxikologie OPUS4-6117 Wissenschaftlicher Artikel Lutz, Werner K.; Poetzsch, J.; Schlatter, J.; Schlatter, C. The real role of risk assessment in cancer risk management Rtgulatory aclio11s Iaken to reduu tht risk of harmfultffects of exposure to chemieals ofltn arenot commensurDtt with the toxicologicDf risk SJsstS&ment. A numbtr of factors relating to psychology, sociology, economics Dntl politics rather than science and medicine afftct tht final decision. Wemer Lutz and colleagues illustratt the situation using tht feuktmia-indudng chtmiCJJI benzene as an examplt. 1991 urn:nbn:de:bvb:20-opus-60730 Institut für Pharmakologie und Toxikologie OPUS4-5416 Wissenschaftlicher Artikel Cantoreggi, S.; Dietrich, D. R.; Lutz, Werner K. Induction of cell proliferation in the forestomach of F344 rats following subchronic administration of styrene 7,8-oxide and butylated hydroxyanisole 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. 1993 urn:nbn:de:bvb:20-opus-60669 Institut für Pharmakologie und Toxikologie OPUS4-5417 Wissenschaftlicher Artikel Fischer, W. H.; Beland, P. E.; Lutz, Werner K. DNA adducts, cell proliferation and papilloma latency time in mouse skin after repeated dermal application of DMBA and TPA '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 1993 urn:nbn:de:bvb:20-opus-60673 Institut für Pharmakologie und Toxikologie OPUS4-5475 Wissenschaftlicher Artikel Caviezel, M.; Lutz, Werner K.; Minini, U.; Schlatter, C. Interaction of estrone and estradiol with DNA and protein of liver and kidney in rat and hamster in vivo and in vitro (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. 1984 urn:nbn:de:bvb:20-opus-60995 Institut für Pharmakologie und Toxikologie