Mesia-Vela Sonia, Sanchez Rosa I, Reuhl Kenneth R, Conney Allan H, Kauffman Frederick C
Laboratory for Cellular and Biochemical Toxicology, 41 Gordon Road, Piscataway, NJ 08854, USA.
Toxicology. 2004 Aug 5;200(2-3):103-11. doi: 10.1016/j.tox.2004.03.009.
Excess production of H2O2 has been implicated in oncogenesis. The object of the present study was twofold: first, to determine the influence of chronic estradiol (E2) on the activities of selected hepatic antioxidant enzymes in female ACI rats, a strain that is highly sensitive to the induction of estrogen dependent mammary tumors; secondly, to evaluate the actions of dietary clofibrate, a peroxisome proliferator, on activities of these enzymes in control and E2-treated ACI rats. Enzymes selected for study were: NAD(P)H quinone oxidoreductase (NQO1), glutathione S-transferase (GST) and glutathione peroxidase (GPx). Cytosolic catalase (CAT) was also measured as an index of peroxisome proferation in control and E2- treated animals. E2 was administered chronically over 6 and 12 week periods from cholesterol pellet implants containing either 1 or 3 mg E2. Animals were fed AIN-76A diets with or without 0.4% clofibrate over the experimental period. NQO1 and GST but not GPx were induced to varying degrees (NQO1 about 300%, and GST about 45-97%) by chronic E2-treatment. E2-induced increases in these activities were completely prevented in rats exposed to dietary clofibrate. Dietary clofibrate also caused slight but significant reductions in baseline activities of NQO1, GST and GPx in control animals. Serum E2 levels, increased approximately 540% in a dose-dependent manner, and were not altered by dietary clofibrate. It is concluded that chronic E2 treatment markedly induces several important hepatic antioxidant enzymes in female ACI rats, and induction of these activities by E2 is inhibited completely by dietary clofibrate. Both of these actions have the potential to markedly influence the profile of E2 metabolites exported from the liver to E2 sensitive extrahepatic tissues and influence the initiation and progression of hormone-dependent tumors.
过氧化氢（H2O2）的过量产生与肿瘤发生有关。本研究的目的有两个：第一，确定慢性雌二醇（E2）对雌性ACI大鼠（一种对雌激素依赖性乳腺肿瘤诱导高度敏感的品系）中选定的肝脏抗氧化酶活性的影响；第二，评估膳食氯贝丁酯（一种过氧化物酶体增殖剂）对对照和E2处理的ACI大鼠中这些酶活性的作用。选择进行研究的酶有：NAD(P)H醌氧化还原酶（NQO1）、谷胱甘肽S-转移酶（GST）和谷胱甘肽过氧化物酶（GPx）。还测量了细胞溶质过氧化氢酶（CAT），作为对照和E2处理动物中过氧化物酶体增殖的指标。通过含有1或3mg E2的胆固醇丸植入物，在6周和12周的时间内长期给予E2。在实验期间，给动物喂食含或不含0.4%氯贝丁酯的AIN-76A饮食。慢性E2处理可使NQO1和GST但不使GPx有不同程度的诱导（NQO1约为300%，GST约为45 - 97%）。在暴露于膳食氯贝丁酯的大鼠中，E2诱导的这些活性增加被完全阻止。膳食氯贝丁酯还使对照动物中NQO1、GST和GPx的基线活性略有但显著降低。血清E2水平以剂量依赖性方式增加约540%，且不受膳食氯贝丁酯的影响。结论是，慢性E2处理可显著诱导雌性ACI大鼠中的几种重要肝脏抗氧化酶，并且E2对这些活性的诱导被膳食氯贝丁酯完全抑制。这两种作用都有可能显著影响从肝脏输出到对E2敏感的肝外组织的E2代谢产物谱，并影响激素依赖性肿瘤的起始和进展。
