[Mechanisms in inactivating reactive metabolic products of drugs (author's transl)]

An in vitro test system was used to study the relative contribution of epoxides metabolically produced from aromatic or olefinic drugs to the total of mutagenically reactive metabolites. As an epoxide-specific tool the enzyme epoxide hydratase was purified to homogeneity. Using several aromatic and olefinic hydrocarbons as model substrates the following was observed, exceptions being discussed in the main text: 1. Epoxides represent the most important and generally the almost exclusive metabolites responsible for the observed toxic endpoint. 2. These epoxides generally are efficiently inactivated by epoxide hydratase. The rather narrow limitations of exceptions are outlined in detail. 3. Amongst the enzymes metabolizing epoxides, for the substrates investigated epoxide hydratase represents the system which is most critical for the control of tissue levels of epoxides. 4. Several practical consequences following from these facts are outlined in the last paragraph of this paper. 5. A generalization from these model experiments will be justified only after further experimental validation.