REGULATION OF CYTOCHROME-P450 EXPRESSION BY INHIBITORS OF HYDROXYMETHYLGLUTARYL-COENZYME-A REDUCTASE IN PRIMARY CULTURED RAT HEPATOCYTES AND IN RAT-LIVER

It was previously demonstrated that treatment of primary cultured rat hepatocytes with lovastatin, an inhibitor of 3-hydroxy-3-methylglutary l-CoA (HMG-CoA) reductase, induced the mRNAs for several cytochromes P 450 (P450s), including CYP2B1/2, CYP3A1/2, and CYP4A. In this study, w e have compared the effects of lovastatin with those of three addition al HMG-CoA reductase inhibitors (simvastatin, pravastatin, and the str ucturally dissimilar drug fluvastatin) on P450 expression in primary c ultured rat hepatocytes, and we have also characterized the effects of in vivo treatment with fluvastatin on P450 expression in rat liver. T reatment of cultured hepatocytes with lovastatin, simvastatin, or fluv astatin increased CYP2B1/2, CYP3A1/2, and CYP4A mRNA and immunoreactiv e protein levels over the dose range (3x10(-6) to 3x10(-5) M) required to increase the amount of HMG-CoA reductase mRNA. The increases in CY P2B1/2 levels produced by 3x10(-5) M fluvastatin treatment were larger than those produced by lovastatin or simvastatin treatment or by trea tment with 10(-4) M phenobarbital. In contrast, treatment of cultured hepatocytes with 3x10(-5) M lovastatin, simvastatin, or fluvastatin in creased CYP3A1/2 and CYP4A mRNA and immunoreactive protein to lower le vels than those produced by treatment with 10(-5) M dexamethasone or 1 0(-4) M ciprofibrate. Treatment of cultured hepatocytes with pravastat in had little or no effect on the amount of any of the P450s examined, although this drug induced HMG-CoA reductase mRNA as effectively as d id fluvastatin. Incubation of hepatocytes with 10(-4) M fluvastatin in creased CYP1A1 mRNA to 67% of the level induced by treatment with 10(- 5) M beta-naphthoflavone. Doses of 50 or 100 mg/kg/day fluvastatin adm inistered for 3 days to rats increased the hepatic levels of CYP2B1/2 and CYP4A mRNA and immunoreactive protein, although to much lower leve ls than those produced by treatment with phenobarbital or ciprofibrate , respectively. Treatment of rats with fluvastatin had no effect on he patic levels of CYP3A1/2 mRNA or immunoreactive protein. However, trea tment with 50 mg/kg/day fluvastatin induced CYP1A1 mRNA and protein, T he effects of fluvastatin treatment on P450 expression seen in primary cultured rat hepatocytes thus largely recapitulated the effects seen in vivo. The differences in effects among the HMG-CoA reductase inhibi tors suggest that simple inhibition of HMG-CoA reductase cannot explai n all of the effects of these drugs on P450 expression.