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

Abstract

Administration of 0.4% clofibrate in the diet stimulated estradiol (E 2)-induced mammary carcinogenesis in the August-Copenhagen Irish (ACI) rat without having an effect on serum levels of E 2. This treatment stimulated by several-fold the NAD(P)H-dependent oxidative metabolism of E 2 and oleyl-CoA-dependent esterification of E 2 to 17β-oleyl-estradiol by liver microsomes. Glucuronidation of E 2 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. E 2 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 E 2-induced mammary adenocarcinomas. Collectively, these results suggest that the stimulatory effect of clofibrate on hepatic esterification of E 2 with fatty acids coupled with the inhibition of protective phase 2 enzymes, may in part, enhance E 2-dependent mammary carcinogenesis in the ACI rat model.