Further studies on the relationship of the stimulatory effects of phenobarbital and 3,4-benzpyrene on hepatic heme synthesis to their effects on hepatic microsomal drug oxidations

Abstract

The administration of either phenobarbital or 3,4-benzpyrene to rats resulted in the rapid and marked induction of δ-aminolevulinic acid synthetase (EC 2.3.1.13), the proposed initial and rate-limiting enzyme in the hepatic heme biosynthetic pathway. Enhanced formation of δ-aminolevulinic acid was followed sequentially by an enhancement of the liver's capacity to synthesize microsomal heme in vivo, increases in the content of cytochrome P-450 and protoheme in hepatic microsomes and stimulation of certain hepatic microsomal drug oxidations. Changes in the hepatic microsomal levels of cytochrome P-450 paralleled, in part, changes in the activity of hepatic δ-aminolevulinic acid synthetase and in the capacity of the liver to synthesize microsomal heme in vivo, suggesting that the rate of hepatic heme synthesis may control the rate of synthesis of hepatic microsomal cytochome P-450. Increases in the hepatic microsomal content of cytochrome b 5, however, followed a different time course from that observed from either cytochrome P-450 or protoheme. The simultaneous administration of maximum stimulatory doses of phenobarbital and 3,4-benzpyrene did not result in an additive stimulation of δ-aminolevulinic acid synthetase activity, indicating that phenobarbital and 3,4-benzpyrene induce δ-aminolevulinic acid synthetase by the same or closely related mechanisms. However, the stimulatory effects of these agents on cytochrome P-450 and on the N-demethylation of 3-methyl-4-monomethylaminoazobenzene were additive, suggesting that differences may exist in the mechanism by which phenobarbital and 3,4-benzpyrene induce hepatic microsomal cytochrome P-450 and enhance certain hepatic microsomal drug oxidations.