Prasanna H R, Magee P N, Harrington G W, Hart R W
Fels Research Institute, Temple University School of Medicine, Philadelphia, Pennsylvania.
J Toxicol Environ Health. 1989;27(4):467-76. doi: 10.1080/15287398909531316.
The influence of the anticarcinogen dehydroepiandrosterone (DHEA) on the metabolism and macromolecular interactions of the potent hepatocarcinogen dimethylnitrosamine (NDMA) was investigated. Male Sprague-Dawley rats (2-3 mo old) were fed DHEA for 14 d at a dietary level of 0.8%. Compared with pair-fed controls, the liver weights of the DHEA-treated animals increased significantly (11.7 vs. 7.1 g) with increases, per total liver, in proteins including those of cytosol and microsomes as well as cytochromes P-450 and b5. DNA content of the liver, however, remained constant. Five hours after a single ip dose of [14C]NDMA (30 mg/kg body wt, 42 microCi/rat) DNA methylation was reduced in the DHEA-fed animals as measured by 7-methyl- and O6-methylguanine per mole of guanine, by 39 and 31%, respectively. The rate of NDMA metabolism was slightly higher in the DHEA-fed rats as determined in vivo by the exhalation of 14CO2 and by the declining concentrations of NDMA in the blood. The incorporation of radioactivity from [14C]NDMA into hepatic proteins in vivo was greater (2.1-fold) in the DHEA-fed rats. Our results suggest that feeding rats with the adrenal steroid DHEA enhances the metabolic activation of NDMA in vivo, and that the increased association of NDMA-derived metabolites with increased hepatic cellular proteins may be partially responsible for protection of hepatic DNA from NDMA-induced damage.
研究了抗癌物质脱氢表雄酮（DHEA）对强效肝癌致癌物二甲基亚硝胺（NDMA）代谢及大分子相互作用的影响。给2 - 3月龄的雄性斯普拉格 - 道利大鼠喂食含0.8% DHEA的饲料，持续14天。与配对喂食的对照组相比，经DHEA处理的动物肝脏重量显著增加（11.7克对7.1克），肝脏中包括胞质溶胶、微粒体蛋白以及细胞色素P - 450和b5在内的蛋白质总量增加。然而，肝脏的DNA含量保持不变。单次腹腔注射[14C]NDMA（30毫克/千克体重，42微居里/只大鼠）5小时后，通过每摩尔鸟嘌呤中的7 - 甲基鸟嘌呤和O6 - 甲基鸟嘌呤测量发现，喂食DHEA的动物肝脏DNA甲基化分别降低了39%和31%。通过呼出14CO2以及血液中NDMA浓度的下降来测定，喂食DHEA的大鼠体内NDMA代谢速率略高。喂食DHEA的大鼠体内[14C]NDMA放射性掺入肝脏蛋白的量更大（2.1倍）。我们的结果表明，给大鼠喂食肾上腺类固醇DHEA可增强体内NDMA的代谢活化，并且NDMA衍生代谢物与肝脏细胞蛋白增加的关联增加可能部分负责保护肝脏DNA免受NDMA诱导的损伤。
