Structure-activity relationships of chlorinated benzenes as inducers of hepatic cytochrome P-450 isozymes in the rat.
This study compared the ability of hexachlorobenzene (HCB) and of other chlorinated benzenes to induce cytochrome P-450 isozymes in rat liver. HCB (greater than 99% pure) induced both the phenobarbital-inducible forms (cytochrome P-450b and P-450e) and the 3-methylcholanthrene (3-MC)-inducible forms (P-450c and P-450d) of cytochrome P-450. However, HCB differed from many 3-MC-type inducers by inducing P-450d preferentially over P-450c. In contrast to HCB, the lower chlorinated benzenes did not induce significant amounts of P-450c or P-450d in the rat, but were phenobarbital-type inducers, inducing P-450b and P-450e. These data indicate that the hepatic effects of HCB differ markedly from those of other chlorinated benzenes. However, chlorinated dibenzodioxins also induce P-450c and P-450d in the rat, and although chlorinated dibenzodioxins and dibenzofurans contaminate certain commercial products, none were detected by gas chromatography/mass spectrometry (detection limit 0.5 ppm) in the HCB used in this study. The evidence that HCB interacted with the receptor for 2,3,7,8-tetrachlorodibenzo-para-dioxin (TCDD) was equivocal. At a concentration of 10(-6) M, HCB produced a slight decrease (18%) in the binding of 3H-TCDD to this protein in vitro, but had no effect at lower concentrations. However, as an inducer of two 3-MC-inducible isozymes of P-450, HCB was clearly more effective in aromatic-hydrocarbon-responsive mice (C57Bl/6J) than in non-responsive mice (DBA/2J), suggesting that HCB may act through the Ah receptor.
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis; D001572:Benzofurans / Q000494:pharmacology; D002722:Chlorobenzenes / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D004790:Enzyme Induction; D006581:Hexachlorobenzene / Q000494:pharmacology; D007527:Isoenzymes / Q000096:biosynthesis*; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D000072317:Polychlorinated Dibenzodioxins / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D011108:Polymers; D051381:Rats; D013329:Structure-Activity Relationship
D001572:Benzofurans; D002722:Chlorobenzenes; D007527:Isoenzymes; D000072317:Polychlorinated Dibenzodioxins; D011108:Polymers; C016068:polychlorodibenzofuran; D006581:Hexachlorobenzene; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases