Differential expression of rat microsomal epoxide hydrolase gene by imidazole and triazole antimycotic agents

Previous studies from this laboratory revealed that imidazole antimycotic agents, including ketoconazole and clotrimazole, induce microsomal epoxide hydrolase (mEH) and that the mEH induction involves large increases in mRNA with transcriptional activation. To establish whether these compounds elevate mEH mRNA levels in a dose-related manner and whether triazole antimycotic agents, fluconazole and itraconazole, affect mEH gene expression to similar extents, hepatic mEH mRNA levels were quantified in rats by RNA blot analyses using an mEH cDNA probe. Treatment of rats (males) with ketoconazole caused approximately 4-, 10-, and 11-fold increases in mEH mRNA levels at 24-hr posttreatment at the doses of 50, 100, and 200 mg/kg body weight, respectively, whereas mEH mRNA levels were increased approximately 18-fold at 24 hr after a single administration of clotrimazole at 50 mg/kg body weight or at greater doses, with EC50 value being noted as 20 mg/kg body weight. Fluconazole elevated mEH mRNA levels by 2-, 3-, and 6-fold at the doses of 50, 100, and 200 mg/kg body weight, respectively. However, hepatic microsomes isolated from rats treated with fluconazole for 3 days failed to exhibit significant elevation in mEH protein levels, as assessed by immunoblot analyses. No significant increase in mEH mRNA nor protein levels was observed at 1 or 3 days after treatment of rats with itraconazole (200 mg/kg body weight/day). To characterize gender-related differences in hepatic mEH gene expression in response to azole antimycotic agents, the effects of ketoconazole and clotrimazole were examined in females.(ABSTRACT TRUNCATED AT 250 WORDS)