Antimutagenesis by shift in monooxygenase isoenzymes and induction of epoxide hydrolase.
The widely occurring aromatic and olefinic structural elements can be transformed into epoxides by microsomal monooxygenases. These epoxides may react with nucleophilic centers in the cell and thereby covalently bind to DNA, RNA and protein. Such a reaction may lead to cytotoxicity, allergy, mutagenicity and/or carcinogenicity, depending on the properties of the epoxide in question. An important contributing factor is the presence and relative activity of enzymes controlling the concentration of such epoxides. There are several microsomal monooxygenases which differ in activity and substrate specificity. On individual substrates individual cytochromes P-450 often preferentially attack at one specific site different from that attacked by others. Some of these pathways lead to reactive products, others are detoxification pathways. Also important are the enzymes which metabolize epoxides, such as epoxide hydrolases and glutathione transferases. Such enzymes can act as inactivating and in some specific cases also as co-activating enzymes. Moreover, precursor-sequestering enzymes such as dihydrodiol dehydrogenase, glucuronosyl transferases and sulfotransferases are important for the control of reactive epoxides. These enzymes themselves are subject to control by many endogenous and exogenous factors. By virtue of their contribution to the control of mutagenic metabolites such modulators can exert antimutagenic activity. An especially interesting antimutagen, whose mechanism of antimutagenic action is modulation of mutagen-metabolizing enzymes, is trans-stilbene oxide. This agent selectively induces the synthesis of some specific cytochrome P-450 isoenzymes at the expense of others, so that the metabolism of benzo[a]pyrene is shifted from the route leading to the highly mutagenic 7,8-dihydrodiol 9,10-epoxides to the route leading to the much less mutagenic 4,5-epoxide. Moreover, the same agent potently induces microsomal epoxide hydrolase which inactivates the latter epoxide. The combined effects lead to a drastic antimutagenic effect, the molecular mechanism of which is given by these changes in mutagen-metabolizing enzymes.
Oesch
F
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Institute of Toxicology, University of Mainz, F.R.G.
D000818:Animals; D004790:Enzyme Induction; D004851:Epoxide Hydrolases / Q000096:biosynthesis*; D008658:Inactivation, Metabolic; D007527:Isoenzymes / Q000378:metabolism*; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D009153:Mutagens; D009154:Mutation
D007527:Isoenzymes; D009153:Mutagens; D006899:Mixed Function Oxygenases; D004851:Epoxide Hydrolases