Vol. 290, Issue 3, 1436-1441, September 1999

Effect of Calcium Channel Antagonists Nifedipine and Nicardipine on Rat Cytochrome P-450 2B and 3A Forms¹

Richard C. Zangar, Janice Rice Okita, Hyesook Kim, Paul E. Thomas, Alan Anderson, Robert J. Edwards, David L. Springer and Richard T. Okita

Pacific Northwest National Laboratory, Richland, Washington (R.C.Z., D.L.S.); Washington State University, Pullman, Washington (J.R.O., R.T.O.); Wayne State University, Detroit, Michigan (H.K.); Rutgers University, Piscataway, New Jersey (P.E.T.); Centre de Recherche de L' Hôtel-Dieu de Québec, Canada (A.A.); and Imperial College School of Medical, Hammersmith Campus, London (R.J.E.)

Calcium channel antagonists are widely prescribed for treatment of hypertension. In this study, we examined whether treatment with the calcium channel antagonists, nicardipine, nifedipine or diltiazem, alters cytochrome P-450 2B or 3A (CYP2B or CYP3A, respectively) expression in rat liver. Western blot analyses were undertaken using antibodies specific for one or several members of these cytochrome P-450 subfamilies. Nicardipine was found to be an effective inducer of CYP3A; in particular, CYP3A23 was increased ~36-fold following treatment with 100 mg of nicardipine/kg/day. Nicardipine induced CYP2B forms up to ~3.1-fold. Nifedipine did not alter CYP3A expression but did increase CYP2B expression such that total CYP2B, CYP2B1, and CYP2B2v (a splice variant of CYP2B2) were increased ~5- to 15-fold after treatment with 100 mg of nifedipine/kg/day, with increases in benzyloxyresorufin O-dealkylase and erythromycin N-demethylase activities, respectively. The distinct differences in cytochrome P-450 induction profile induced by nicardipine and nifedipine suggest that they may enhance cytochrome P-450 expression by different mechanisms unrelated to their effects on calcium channels.