Structural features of imidazole derivatives that enhance styrene oxide hydrolase activity in rat hepatic microsomes

The present study is an investigation of the in vitro effects of several model imidazole compounds and three antifungal drugs on styrene oxide hydrolase activity in hepatic microsomes from control, PB-induced, and 3MC-induced rats. We first determined the influence of the position of substitution of a phenyl group in the imidazole or imidazoline ring on the ability of 10(-3) M concentration of the imidazole derivative to enhance microsomal epoxide hydrolase activity. This study showed that 1-phenylimidazole enhanced epoxide hydrolase activity to the greatest extent and that, for any one imidazole derivative, the extent of enhancement was similar for microsomes from untreated, PB-induced, or 3MC-induced rats. We next studied the potency and maximum effectiveness of several N-1-substituted imidazole derivatives with differing lipophilicities and pKa values. Hansch analysis showed that potency for activating epoxide hydrolase correlated with both lipophilicity and electron-withdrawing effects of imidazole ring substituents. The most potent compounds had aryl or aralkyl substitutents at the 1-position of imidazole and pKa in the range 7-9 and were clotrimazole, ketoconazole, miconazole, 1-benzylimidazole, and 1-(4-hydroxyphenyl)imidazole. These compounds enhanced styrene oxide hydrolase by 100% at concentrations less than 2 X 10(-4)M. 1-Benzylimidazole increased both Km and Vmax and abolished the inhibition observed at high concentrations of styrene oxide.