The substituted pyridines metyrapone and nicotinamide are inducers of 5-aminolevulinate synthase and cytochrome P-450 in hepatocyte culture

Abstract

The effects of metyrapone and nicotinamide, two substituted pyridines, were studied in cultured chick embryo hepatocytes, a system characterized by preserved inducibility of cytochrome P-450 hemoproteins. Both metyrapone and nicotinamide caused a dose-dependent increase in cytochrome P-450 concentration. Their inducing potencies differed by one to two orders of magnitude and correlated with the known difference in the binding affinity of these two pyridines to cytochrome P-450. The increase of cytochrome P-450 concentration after metyrapone and nicotinamide was additive to the induction of cytochrome P-450 by phenobarbital and β-naphthoflavone and was abolished by cycloheximide. Treatment of hepatocyte cultures with metyrapone resulted in an increase in a microsomal protein with an apparent mol. wt of 52,000. In addition, induction of cytochrome P-450 by the substituted pyridines was associated with enhanced 5-aminolevulinate synthase, the rate-limiting enzyme of heme biosynthesis. These data suggest that in cultured chick embryo hepatocytes the substituted pyridines metyrapone and nicotinamide induce cytochrome P-450.