A number of widely used drugs, e.g. antifungal agents, histamine H2 antagonists, adrenergic antagonists, contain the imidazole ring in their structure. It is now recognized that such drugs can selectively inhibit some cytochrome P-450 dependent mono-oxygenase activities, and thus slow down oxidative metabolism of certain drugs, but it is not well know that imidazoles can enhance epoxide hydrolase (EH) activity with some substrates. Thus, imidazoles can alter rates and patterns of drug metabolism, depending on the biotransformation pathways affected. Recent studies showed that imidazole derivatives with small lipophilic substituents can alter patterns of benzo(a)-pyrene (BaP) metabolism in hepatic microsomes from 3-methylcholanthrene induced rats at pH 7.4, apparently by enhancing EH activity with BaP-9, 10-oxide without affecting cytochrome P-450 dependent oxidation. The purpose of the present study is to investigate the molecular interaction of EH and imidazole derivatives.
The aims are to determine what structural features are required in (i) the imidazole derivative and (ii) the epoxide substrate in order for the interaction of EH and imidazole derivative to result in increased hydrolysis of an epoxide. Imidazole derivatives of varying lipophilicities and pKa's will be tested for their ability to enhance microsomal EH activity with styrene oxide as substrate. The most effective imidazoles will then be tested for their ability to enhance EH activity with larger epoxide substrates based on the styrene oxide molecule, namely cis-Beta-methyl styrene oxide, cis stilbene oxide, phenanthrene 9, 10-oxide and BaP-4, 5-oxide, and also with other selected epoxides. Studies showed that imidazole derivatives were less potent activators of the purified EH than of EH activity in microsomes. It is proposed to determine which microsomal components are needed to reconstitute the enhancement, and to study the mechanism of the enhancement. The results of these studies will provide a rational basis for further experiments designed to understand the in vivo significance of the interactions of imidazole-containing drugs with xenobiotic-metabolizing enzymes.
| James, M O (1988) Acute and subacute effects of miconazole nitrate on hepatic styrene oxide hydrolase and cytochrome P-450-dependent monooxygenase activities in male and female AKR/J mice. Toxicology 50:269-81 |
| Riley, C M; James, M O (1986) Determination of ketoconazole in the plasma, liver, lung and adrenal of the rat by high-performance liquid chromatography. J Chromatogr 377:287-94 |
