Induction of drug-metabolizing enzymes by phenobarbitone : structural and biochemical aspects

Two aspects of the induction of microsomal monooxygenases by phenobarbitone have been investigated. First, structural associations between mitochondria and single cisternae of rough endoplasmic reticulum (mitochondria--RER complexes) may operate as functional units in the biosynthesis of cytochrome P-450. This was deduced from (i) studies on the subcellular distribution of the phenobarbitone-induced incorporation of leucine into microsomal proteins including apocytochromes P-450 and (ii) the incorporation of labelled delta-aminolaevulinic acid into the haem prosthetic group of cytochrome P-450. Secondly, in hepatocytes from chick embryo in primary monolayer culture, induction of cytochrome P-450-haemoproteins was markedly influenced by changes in the proliferative activity of hepatocytes. Inducibility of cytochrome P-450 by phenobarbitone and by beta-naphthoflavone was decreased in cultures with 'spontaneous' or experimentally increased proliferative activity of hepatocytes. Treatment with inhibitors of DNA synthesis increased the induction response.