Epoxide hydratase and benzo(A)pyrene monooxygenase activities in liver, kidney and lung after treatment of rats with epoxides of widely varying structures

Abstract

The effect of treatment with various epoxides on epoxide hydratase and benzo(a)pyrene monooxygenase activities in rat liver, kidney and lung was tested with the aim possibly to find a selective inducer of epoxide hydratase. In a first series of epoxides, good substrates of epoxide hydratase and relatively small molecules did not lead to an increase in epoxide hydratase activity in any organ tested. Treatment with the poor substrates dieldrin and trans-stilbene oxide(TSO), however, increased epoxide hydratase activity in the liver and with TSO also in the kidney (3-fold). In contrast to all other epoxide hydratase inducers so far discovered, TSO did not affect the benzo(a)pyrene monooxygenase activities, even after doses leading to maximal induction of epoxide hydratase ( ~ 350 per cent of controls). In an attempt to find an even more potent selective inducer of epoxide hydratase several trans-stilbene oxide derivatives were synthesized. All modifications of the TSO molecule led to compounds which were less effective inducers of liver epoxide hydratase than the parent compound and also either increased or drastically decreased the benzo(a)pyrene monooxygenase activities. With TSO, 4-methoxy-TSO, 4-chloro-TSO and 4-nitro-TSO the tests were extended to three other parameters of the monooxygenase system, the cytochrome P450 content, the NADPH-cytochrome c reductase and the aminopyrine N-demethylase activities. All these derivatives but not TSO itself affected part of the monooxygenase system. Thus, with respect to five measured monooxygenase parameters TSO was found to be a selective inducer of epoxide hydratase in rat liver. An influence of TSO on the pattern of the various cytochrome P450 forms not leading to observable changes in monooxygenase activity towards two substrates known to be preferential substrates of different cytochrome P450 forms (aminopyrine and benzo(a)pyrene) is unlikely but cannot be excluded.