@article{LutzDeuberCaviezeletal.1988,
  author    = {Lutz, Werner K. and Deuber, R. and Caviezel, M. and Sagelsdorff, P. and Friederich, U. and Schlatter, C.},
  title     = {Trenbolone growth promotant: covalent DNA binding in rat liver and in Salmonella typhimurium, and mutagenicity in the Ames test},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-60897},
  year      = {1988},
  abstract  = {DNA binding in vivo: (6,7-\(^3\)H]ß-trenbolone (ß-TBOH) was administered p.o. and i.p. to rats. After 8 or 16 h, DNA was isolated from the livers and purified to constant specific radioactivity. Enzymatic digestion to deoxyribonucleotides and separation by HPLC revealed about 90\% ofthe DNA radioactivity eluting in the form of possible TBOH-nucleotide adducts. The extent of this genotoxicity, expressed in units of the Covalent Binding Index, CBI = (~mol TBOH bound per mol nucleotide)/(mmol TBOH administered per kg body weight) spanned from 8 t~ 17, i. e. was in the range found with weak genotoxic carcmogens. Ames test: low doses of ß-TBOH increased the number of revertants in Salmonella strain TAl 00 reproducibly and m a dose-dependent manner. The mutagenic potency was 0.2 revertants per nmol after preincubation of the bacteria (20 min at 37° C) with doses between 30 and 60 \(\mu\)g per plate (47 and 94 \(\mu\)g/ml preincubation mixture). Above this dose, the number of revertants decreased to control values, accompanied by a reduction in survival. The addition of rat liver S9 inhibited the mutagenicity. DNA binding in vitro: calf thymus DNA was incubated with tritiated ß-TBOH with and without rat liver S9 Highest DNA radioactivities were determined in the absence of the "activation" system. Addition of inactive S9 (without cofactors) reduced the DNA binding by a factor of up to 20. Intermediate results were found with active S9. DNA binding in Salmonella: ß-TBOH was irreversibly bound to DNA isolated from S. typhimurium TA100 after incubation of bacteria with [\(^3\)H]ß-TBOH. Conclusions: Covalent DNA binding appears to be the mechanism of an activation-independent ("direct") mutagenicity of TBOH which is not easily detected because of the bactericidal activity. The genotoxicity risk arising from exposure of humans to trenbolone residues in meat was estimated using the in vivo data and compared to that from the exposure to unavoidable genotoxins aflatoxin B1 and dimethylnitrosamine. It ts concluded that trenbolone residues represent only a low genotoxic risk.},
  subject      = {Toxikologie},
  language  = {en}
}
@article{BoeschFriederichLutzetal.1987,
  author    = {B{\"o}sch, R. and Friederich, U. and Lutz, Werner K. and Brocker, E. and Bachmann, M. and Schlatter, C.},
  title     = {Investigations on DNA binding in rat liver and in Salmonella and on mutagenicity in the Ames test by emodin, a natural anthraquinone},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-60913},
  year      = {1987},
  abstract  = {Emodin (1,6,8-trihydroxy-3-methylanthraquinone), an important aglycone found in natural anthraquinone glycosides frequently used in Iaxative drugs, was mutagenic in the Salmonellajmammalian microsome assay (Ames test) with a specificity for strain TA1537. The mutagenic activity was activationdependent with an optimal amount of S9 from Aroclor 1254-treated male Sprague-Dawley rats of 20\% in the S9 mix (v jv) for 10 p.g emodin per plate. Heat inactivation of the S9 for 30 min at 60 ° C prevented mutagenicity. The addition of the cytochrome P-448 inhibitor 7,8-benzoflavone (18.5 nmoles per plate) reduced the mutagenic activity of 5.0 p.g emodin per plate to about one third, whereas the P-450 inhibitor metyrapone (up to 1850 nmoles per plate) was without effect. To test whether a metabolite" binds covalently to Salmonella DNA, [10-\(^{14}\)C]emodin was radiosynthesized, large batches of bacteria were incubated with [10-\(^{14}\)C]emodin and DNA was isolated. [G- \(^{3}\)H]Aflatoxin B1 (AFB1) was used as a positive control mutagen known to act via DNA binding. DNA obtained after aflatoxin treatment could be purified to constant specific activity. With emodin, the specific activity of DNA did not remain constant after repeated precipitations so that it is unlikely that the mutagenicity of emodin is due to covalent interaction of a metabolite with DNA. The antioxidants vitamin C and E or glutathione did not reduce the mutagenicity. Emodin was also negative with strain TA102. Thus, oxygen radicals are probably not involved. When emodin was incubated with S9 alone for up to 50 h before heat-inactivation of the enzymes and addition of bacteria, the mutagenic activity did not decrease. It is concluded that the mutagenicity of emodin is due to a chemically stable, oxidized metabolite forming physico-chemical associations with DNA, possibly of the intercalative type. In order to check whether an intact mammalian organism might be able to activate emodin to a DNA-binding metabolite, radiolabelled emodin was administered by oral gavage to male SD rats and liver DNA was isolated after 72 h. Very little radioactivity was associated with the DNA. Considering that DNA radioactivity could also be due to sources other than covalent interactions, an upper limit for the · covalent binding index, CBI = (p.moles chemical bound per moles DNA nucleotides)/(mmoles chemical administered per kg body weight) of 0.5 is deduced. This is 104 times below the CBI of AFB1. The demonstration of a lack of covalent interaction with DNA bothin Salmonellaandin rat liver is discussed in terms of a reduced hazard posed by emodin as a mutagenic drug in use in humans.},
  subject      = {Toxikologie},
  language  = {en}
}