6533b83afe1ef96bd12a7b93

RESEARCH PRODUCT

Metabolic Inactivation of Reactive Metabolites

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ABSTRACT Many compounds which are not electrophilically reactive as such are transformed by mammalian enzymes to reactive metabolites which are, in many cases, responsible for cytotoxic, mutagenic and/or carcinogenic effects of the compounds in question. The essential role of activating systems in this situation has become common knowledge during the last decade. However, many reactive metabolites are also subject to inactivation by mammalian enzymes. This important parameter is frequently not taken into account. Compounds possessing aromatic or olefinic moieties are very widely occurring and activation of these often proceeds via an electrophilically reactive epoxide. This may be transformed to electrophilically non-reactive diols by epoxide hydratase or to glutathione conjugates by glutathione S-transferases. The former system is limited by the fact that in some special cases (e.g. location of the epoxide at an angular benzoring of a polycyclic hydrocarbon opposite a bay region) the inactivation of the epoxide yields a dihydrodiol which is the precursor of an (even more reactive) dihydrodiol-epoxide. The glutathione S-transferase system is limited by its location in the cytosol fraction, which diminishes its efficiency in inactivating epoxides derived from large lipophilic compounds. Even with compounds where the efficiency of these inactivating systems is limited as discussed above (e.g. benzo(a)pyrene), they still are of decisive importance. Depending on the quantity and quality of monooxygenase forms present in a situation in question, epoxide hydratase can play the role of an inactivating or of a predominantly coactivating system. However, with the majority of epoxides, both the epoxide hydratase and glutathione S-transferase enzymes represent simple and effective inactivating mechanisms. Activities of activating and inactivating enzymes are often decisive for species differences in toxic effects. As enzyme activities become more accurately known in different species, strains, sexes, organs and developmental stages, they will become of predictive value. However, other mechanisms such as differences in repair or other host defense mechanisms will also contribute substantially to differences in toxic manifestations in these different situations.