MEPYRAMINE, A HISTAMINE H1 RECEPTOR ANTAGONIST, INHIBITS THE METABOLIC-ACTIVITY OF RAT AND HUMAN P450 2D FORMS

The interaction of antihistaminics, including mepyramine, with rat hep atic cytochrome P450s (P450s) was investigated. We first investigated mepyramine binding to eight forms of rat hepatic P450s. Mepyramine bou nd specifically to P450 2D1, which suggests that it inhibits P450 2D a ctivity. Histamine H1 receptor antagonists (mepyramine, diphenhydramin e, chlorpheniramine and triprolidine) inhibited the lidocaine 3-hydrox ylation activity catalyzed by P450 2D1 but did not inhibit the testost erone hydroxylation activities catalyzed by P450s other than P450 2D f orms. The K-i values of these antagonists for the catalytic activity o f P450 2D1 were low and were similar to those of quinine and quinidine , which are specific inhibitors of P450 2D forms. The K-i value of mep yramine was especially low, at 34 nM. Furthermore, the effects of mepy ramine on human P450 2D6 were investigated. Among the ten forms of hum an P450 expressed in yeast, mepyramine bound specifically to P450 2D6 in a binding assay. In human hepatic microsomes, mepyramine inhibited the debrisoquine 4-hydroxylation activity catalyzed by P450 2D6. These results indicate that histamine H1 receptor antagonists such as mepyr amine are potent inhibitors of P450 2D forms because of their high aff inity for these enzymes.