Inductive effect on hepatic enzymes and toxicity of congeners of PCBs and PCDFs.
The present paper describes a marked induction of liver microsomal cytochrome P-450 and cytosolic DT-diaphorase to cause possible disorder of steroid homeostasis and promotion of carcinogenicity of 4-nitroquinoline N-oxide (4-NQO) in rats by pretreatment with 3,4,5,3',4'-pentachlorobiphenyl (PenCB) or 2,3,4,7,8-pentachlorodibenzofuran (PenCDF). The animals were sacrificed 5 days after the pretreatment. These induction experiments showed that 7 alpha-hydroxylation of both progesterone and testosterone in liver microsomes was selectively increased to a great extent, but hydroxylations at the 2 alpha-, 6 beta- and 16 alpha-positions were depressed, together with 5 alpha-reduction. From the same microsomes, three of the strongly induced P-450 isozymes, i.e., high- and low-spin P-448s and P-452, were purified. The last isozyme was most responsible for 7 alpha-hydroxylation of testosterone. The pretreatment, also increased activity of DT-diaphorase and reduction of 4-NQO about 10-fold in liver 9000g supernatants. This reduction of 4-NQO was solely catalyzed by DT-diaphorase and the only product was 4-hydroxylaminoquinoline N-oxide, a proximate carcinogen, indicating that the pretreatment strongly increased production of a proximate carcinogen from 4-NQO. Such an enhancement of the metabolic activation of 4-NQO by the pretreatment was also observed to some extent in the lung and the skin. Persistency of PenCB and PenCDF in the liver of rats was also discussed.
D015112:4-Nitroquinoline-1-oxide / Q000378:metabolism; D000818:Animals; D001572:Benzofurans / Q000494:pharmacology*; D002273:Carcinogens; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D004790:Enzyme Induction; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000096:biosynthesis; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology*; D011078:Polychlorinated Biphenyls / Q000494:pharmacology*; D011808:Quinone Reductases / Q000096:biosynthesis; D051381:Rats; D011919:Rats, Inbred Strains; D013256:Steroids / Q000378:metabolism
D001572:Benzofurans; D002273:Carcinogens; D007527:Isoenzymes; D013256:Steroids; D015112:4-Nitroquinoline-1-oxide; D003577:Cytochrome P-450 Enzyme System; D011078:Polychlorinated Biphenyls; D011808:Quinone Reductases; C023035:3,4,5,3',4'-pentachlorobiphenyl; C038890:2,3,4,7,8-pentachlorodibenzofuran