title: Effects of retinoids on metabolizing enzymes and on binding of benzo(a)pyrene to rat tissue DNA.
abstract: Retinyl acetate, 13-cis-retinoic acid (13cisRA), and N-(4-hydroxyphenyl)-retinamide (4HPR) were assayed for their in vivo effects on hepatic levels of cytochrome P450, cytosolic glutathione-S-transferase, and quinone reductase. When given p.o. to Sprague-Dawley rats, all of the retinoids caused significant suppression in the levels of arylhydrocarbon hydroxylase, yet 13cisRA and 4HPR caused elevations in cytosolic levels of quinone reductase and glutathione-S-transferase, respectively. Scans of sodium dodecyl sulfate-polyacrylamide gels of microsomal proteins from the livers of retinoid-dosed animals showed changes in both the intensities and the number of stained bands. For microsomes from 13cisRA-dosed animals, there were additional changes in the absorption maximum of the carbon monoxide and octylamine difference spectra. There was, compared to controls, a 62% reduction in the NADPH-dependent binding of (+)-7S-trans-7,8-dihydro[7-14C]benzo(a)pyrene-7,8-diol to microsomal proteins from 13cisRA-dosed animals. Fluorography of the sodium dodecyl sulfate-polyacrylamide gels showed that the major reduction in metabolite binding occurred in the Mr 50,000 region of the gel. The reduction in the NADPH-dependent binding of (+)-7S-trans-7,8-dihydro[7-14C]benzo(a)pyrene-7,8-diol to microsomal proteins in vitro and the reduction in hepatic arylhydrocarbon hydroxylase levels correlated with a reduction in the in vivo binding of benzo(a)pyrene to rat liver DNA. Animals dosed for 7 days with 13cisRA, retinyl acetate, or 4HPR showed a 38, 27, and 40% reduction in binding of benzo(a)pyrene to liver DNA and a 29, 32, and 21% reduction in binding to stomach DNA, respectively, when the carcinogen was administered on the eighth day, and the tissues were harvested 24 h later. Binding to lung DNA was reduced by 23 and 11%, respectively, in the 13cisRA- and 4HPR-dosed rats. No differences were observed in binding to kidney. Thus, retinoids, by altering the metabolism of carcinogens, could influence the initiation stage of carcinogenesis.
mesh_terms: D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis; D001391:Azo Compounds / Q000494:pharmacology; D001564:Benzo(a)pyrene / Q000378:metabolism*; D002084:Butylated Hydroxytoluene / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D004247:DNA / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005982:Glutathione Transferase / Q000096:biosynthesis; D007527:Isoenzymes / Q000032:analysis; D008297:Male; D008970:Molecular Weight; D011808:Quinone Reductases / Q000096:biosynthesis; D051381:Rats; D012176:Retinoids / Q000494:pharmacology*
chemical_list: D001391:Azo Compounds; D007527:Isoenzymes; D012176:Retinoids; D002084:Butylated Hydroxytoluene; D001564:Benzo(a)pyrene; D004247:DNA; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; D011808:Quinone Reductases; D005982:Glutathione Transferase; C033006:sudan III