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.
D000622:Aminolevulinic Acid / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D002642:Chick Embryo; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D004721:Endoplasmic Reticulum / Q000201:enzymology; D006418:Heme / Q000096:biosynthesis; D006420:Hemeproteins / Q000096:biosynthesis; D008099:Liver / Q000187:drug effects / Q000201:enzymology* / Q000648:ultrastructure; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology*; D008928:Mitochondria / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000096:biosynthesis*; D010634:Phenobarbital / Q000494:pharmacology*; D051381:Rats
D006420:Hemeproteins; D006418:Heme; D000622:Aminolevulinic Acid; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D010634:Phenobarbital