Species differences in activating and inactivating enzymes related to the control of mutagenic metabolites.
Microsomal monooxygenases catalyze the biosynthesis of epoxides from olefinic and aromatic compounds whilst microsomal epoxide hydratase and cytoplasmic glutathione S-transferases are responsible for their further biotransformation. Although catalytically very efficient the cytoplasmic glutathione S-transferases play, due to their subcellular localization, a minor role in the inactivation of epoxides derived from large lipophilic compounds and were, therefore, not included in this study. It was shown with such a lipophilic compound, benzo(a)pyrene, as a model substance and with liver enzyme mediated bacterial mutagenesis as biological endpoint that species and strain differences in epoxide hydratase and monooxygenases are reflected in very dramatic differences in mutagenicity of benzo(a)pyrene which varied from extremely potent to a degree which could easily be overlooked. In order to investigate whether the differences in enzyme activities were causally linked to the observed differences in mutagenicity, the enzyme activities were modulated by inhibition and induction. These manipulations were always accompanied by the corresponding changes in mutagenicity. It is concluded that species such as mice which possess high monooxygenase activity but very low epoxide hydratase activity are much more susceptible than man to those toxic effects which are mediated by metabolically formed epoxides which are substrates of epoxide hydratase. In this regard, it is especially noteworthy that mice possess a much lower hepatic epoxide hydratase activity than man.
D000818:Animals; D001580:Benzopyrenes / Q000378:metabolism* / Q000494:pharmacology; D001711:Biotransformation; D003374:Coumarins; D004851:Epoxide Hydrolases / Q000378:metabolism*; D005260:Female; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology; D051379:Mice; D008862:Microsomes, Liver / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D009153:Mutagens; D010088:Oxidoreductases / Q000378:metabolism*; D010634:Phenobarbital / Q000494:pharmacology; D051381:Rats; D012486:Salmonella typhimurium / Q000187:drug effects; D013045:Species Specificity
D001580:Benzopyrenes; D003374:Coumarins; D009153:Mutagens; D008748:Methylcholanthrene; D006899:Mixed Function Oxygenases; D010088:Oxidoreductases; D004851:Epoxide Hydrolases; D010634:Phenobarbital