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 17beta-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.