McCarthy D J, Lindamood C, Hill D L
Cancer Res. 1987 Oct 1;47(19):5014-20.
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.
对醋酸视黄酯、13-顺式视黄酸（13cisRA）和N-(4-羟基苯基)-视黄酰胺（4HPR）进行了检测，以研究它们对细胞色素P450、胞质谷胱甘肽-S-转移酶和醌还原酶肝脏水平的体内影响。当经口给予斯普拉格-道利大鼠时，所有类视黄醇均导致芳烃羟化酶水平显著降低，但13cisRA和4HPR分别导致胞质醌还原酶和谷胱甘肽-S-转移酶水平升高。对给予类视黄醇动物肝脏微粒体蛋白的十二烷基硫酸钠-聚丙烯酰胺凝胶扫描显示，染色条带的强度和数量均有变化。对于给予13cisRA动物的微粒体，一氧化碳和辛胺差光谱的最大吸收也有其他变化。与对照组相比，给予13cisRA动物的微粒体蛋白对(+)-7S-反式-7,8-二氢[7-14C]苯并(a)芘-7,8-二醇的NADPH依赖性结合减少了62%。十二烷基硫酸钠-聚丙烯酰胺凝胶的荧光自显影显示，代谢物结合的主要减少发生在凝胶的Mr 50,000区域。体外(+)-7S-反式-7,8-二氢[7-14C]苯并(a)芘-7,8-二醇与微粒体蛋白的NADPH依赖性结合减少以及肝脏芳烃羟化酶水平降低与体内苯并(a)芘与大鼠肝脏DNA的结合减少相关。当在第8天给予致癌物并在24小时后采集组织时，给予13cisRA、醋酸视黄酯或4HPR 7天的动物，苯并(a)芘与肝脏DNA的结合分别减少了38%、27%和40%，与胃DNA的结合分别减少了29%、32%和21%。给予13cisRA和4HPR的大鼠中，与肺DNA的结合分别减少了23%和11%。在与肾脏的结合方面未观察到差异。因此，类视黄醇通过改变致癌物的代谢，可能会影响致癌作用的起始阶段。
