Dietary clofibrate stimulates the formation and size of estradiol-induced breast tumors in female August-Copenhagen Irish (ACI) rats

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• 作者：Sonia Mesia-Vela ; Rosa I. Sanchez ; Kathleen G. Roberts ; Kenneth R. Reuhl ; Allan H. Conney ; Frederick C. Kauffman
• 关键词：Breast cancer ; Clofibrate (2-(4-chlorophenoxy)-2-methyl-propanoic acid ; ethyl ester) ; Estradiol
• 刊名：Toxicology
• 出版年：2008
• 出版时间：3 April 2008
• 年：2008
• 卷：246
• 期：1
• 页码：63-72
• 全文大小：778 K

文摘

Administration of 0.4 % clofibrate in the diet stimulated estradiol (E₂)-induced mammary carcinogenesis in the August-Copenhagen Irish (ACI) rat without having an effect on serum levels of E₂. This treatment stimulated by several-fold the NAD(P)H-dependent oxidative metabolism of E₂ and oleyl-CoA-dependent esterification of E₂ to 17β-oleyl-estradiol by liver microsomes. Glucuronidation of E₂ by microsomal glucuronosyltransferase was increased moderately. In contrast, the activity of NAD(P)H quinone reductase 1 (NQO1), a representative monofunctional phase 2 enzyme, was significantly decreased in liver cytosol of rats fed clofibrate. Decreases in hepatic NQO1 in livers of animals fed clofibrate were noted before the appearance of mammary tumors. E₂ was delivered in cholesterol pellets implanted in 7–8-week-old female ACI rats. The animals received AIN-76A diet containing 0.4 % clofibrate for 6, 12 or 28 weeks. Control animals received AIN-76A diet. Dietary clofibrate increased the number and size of palpable mammary tumors but did not alter the histopathology of the E₂-induced mammary adenocarcinomas. Collectively, these results suggest that the stimulatory effect of clofibrate on hepatic esterification of E₂ with fatty acids coupled with the inhibition of protective phase 2 enzymes, may in part, enhance E₂-dependent mammary carcinogenesis in the ACI rat model.