Induction of porphyria in cultured chick-embryo hepatocytes by halogenated aromatic compounds.
Chick-embryo liver cells in culture were used to study the mechanism by which hexachlorobenzene (HCB) and other chlorobenzenes cause hepatic porphyria with accumulation of uroporphyrin (URO). The actions of the chlorobenzenes were similar to those of 3,4,3',4'-tetrachlorobiphenyl (TCB), but pretreatment with 3-methylcholanthrene (MC) or hexachlorobenzene was needed for maximum accumulation of URO. HCB was as potent and almost as rapid as the biphenyl in causing URO accumulation, but tetrachlorobenzenes caused little URO accumulation. Ellipticine, an inhibitor of cytochrome P-448, stopped the accumulation of URO. A mechanism is proposed for the action of the chlorobenzenes that involves binding to cytochrome P-448 and production of active oxygen species that oxidize uroporphyrinogen.
D000818:Animals; D002478:Cells, Cultured; D002642:Chick Embryo; D002722:Chlorobenzenes / Q000633:toxicity*; D019388:Cytochrome P-450 CYP1A2; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D003580:Cytochromes / Q000096:biosynthesis; D004790:Enzyme Induction / Q000187:drug effects; D006581:Hexachlorobenzene / Q000633:toxicity*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008748:Methylcholanthrene / Q000494:pharmacology; D011164:Porphyrias / Q000139:chemically induced*; D014578:Uroporphyrins / Q000096:biosynthesis
D002722:Chlorobenzenes; D003580:Cytochromes; D014578:Uroporphyrins; D006581:Hexachlorobenzene; D008748:Methylcholanthrene; D003577:Cytochrome P-450 Enzyme System; C017170:Cyp1a2 protein, rat; D019388:Cytochrome P-450 CYP1A2