Induction of hepatic cytochrome P450s responsible for the metabolism of xenobiotics by nicardipine and other calcium channel antagonists in the male rat

Abstract

1. The effects of nicardipine and three other calcium channel antagonists, nifedipine, diltiazem and verapamil, on hepatic gene expression of cytochrome P450s (P450), CYP1A1, CYP1A2, CYP2B1, CYP2B2, CYP3A1 and CYP3A2 in male rats were examined by an RT-PCR method. 2. Treatment of rats with nicardipine resulted in a significant increase in hepatic expression of all the P450 genes examined. Other calcium channel antagonists, nifedipine, diltiazem and verapamil, also enhanced the gene expression of CYP2B1, CYP2B2, CYP3A1 and CYP3A2, although these showed no capacity for activating CYP1A1 and CYP1A2 genes. 3. We have demonstrated for the first time that nicardipine activated not only the genes of CYP2B1, CYP2B2, CYP3A1 and CYP3A2, but also those of CYP1A1 and CYP1A2 in the rat liver and have further suggested that calcium channel antagonists may show a common capacity for activating the genes of CYP2B1, CYP2B2, CYP3A1 and CYP3A2. Furthermore, this increased expression of P450 genes was demonstrated to contribute to increase in the protein level of the corresponding P450s.