Effects of retinoids on metabolizing enzymes and on binding of benzo(a)pyrene to rat tissue DNA

• Published in: Cancer research (Chicago, Ill.) Vol. 47; no. 19; pp. 5014 - 5020
• Main Authors: MCCARTHY, D. J, LINDAMOOD III, C, HILL, D. L
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01-10-1987
• Subjects: Animals; Aryl Hydrocarbon Hydroxylases - biosynthesis; Azo Compounds - pharmacology; Benzo(a)pyrene - metabolism; Biological and medical sciences; Butylated Hydroxytoluene - pharmacology; Carcinogenesis, carcinogens and anticarcinogens; Chemical agents; Cytochrome P-450 Enzyme System - biosynthesis; DNA - metabolism; Dose-Response Relationship, Drug; Glutathione Transferase - biosynthesis; Isoenzymes - analysis; Male; Medical sciences; Molecular Weight; Quinone Reductases - biosynthesis; Rats; Retinoids - pharmacology; Tumors; Rat; Cytochrome P450; Interaction; Rodentia; Retinoids; Polycyclic aromatic compound; Metabolism; Carcinogen; In vivo; Vertebrata; Mammalia; Glutathione transferase; Animal; Carcinogenesis initiation
• ISSN: 0008-5472; 1538-7445

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.