Induction of cytochrome P-450 isozymes by hexachlorobenzene in rats and aromatic hydrocarbon (Ah)-responsive mice.
Hexachlorobenzene (HCB) differs markedly from other chlorinated benzenes (CBs) as an inducer of cytochrome P-450 (P-450) isozymes as determined by radioimmunoassay and immunoblotting. At greater than 99% pure, HCB induced both the phenobarbital-inducible forms, cytochromes P-450b + e (70 chi), and the 3-methylcholanthrene-inducible forms, cytochromes P-450c (58 chi) and P-450d (8 chi), in rat liver microsomes. The concentration of P-450d was considerably greater than that of P-450c in HCB-induced rat liver. In contrast to HCB, all lower chlorinated benzenes tested were PB-type inducers. Hexachlorobenzene increased the amounts of translatable messenger RNAs (mRNAs) for P-450b, P-450c, and P-450d in rat liver polysomes, suggesting that it increases the synthesis of these proteins. Evidence that HCB interacted with the putative Ah receptor for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) was equivocal. Western blots of liver microsomes from Ah-responsive C57BL/6J (B6) and nonresponsive DBA/2J (D2) mice demonstrated that HCB produced a large increase in P3-450 and a very small increase in P1-450 in the responsive strain. The increase in P1-450 was not observed after HCB administration to nonresponsive mice, but a small increase in P3-450 was noted. These findings suggested that HCB may act through the Ah receptor. However, HCB was at best a very weak competitor for specific binding of [3H]-TCDD to the putative receptor in rat or mouse hepatic cytosol in vitro, producing decreases in binding of [3H]-TCDD only at very high concentrations (10(-6) to 10(-5) M).
Linko
P
P
National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709.
Yeowell
H N
HN
Gasiewicz
T A
TA
Goldstein
J A
JA
D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D002722:Chlorobenzenes / Q000633:toxicity*; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D004790:Enzyme Induction / Q000187:drug effects; D006581:Hexachlorobenzene / Q000032:analysis / Q000633:toxicity*; D007527:Isoenzymes / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D000072317:Polychlorinated Dibenzodioxins / Q000378:metabolism; D011132:Polyribosomes / Q000201:enzymology / Q000378:metabolism; D014176:Protein Biosynthesis / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D018336:Receptors, Aryl Hydrocarbon; D011955:Receptors, Drug / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism
D002722:Chlorobenzenes; D007527:Isoenzymes; D000072317:Polychlorinated Dibenzodioxins; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D011955:Receptors, Drug; D006581:Hexachlorobenzene; D003577:Cytochrome P-450 Enzyme System