Dietary clofibrate stimulates the formation and size of estradiol-induced breast tumors in female August-Copenhagen Irish (ACI) rats.
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.
Mesia-Vela
Sonia
S
Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA.
Sanchez
Rosa I
RI
Roberts
Kathleen G
KG
Reuhl
Kenneth R
KR
Conney
Allan H
AH
Kauffman
Frederick C
FC
D000818:Animals; D002994:Clofibrate / Q000008:administration & dosage / Q000633:toxicity*; D004032:Diet; D004958:Estradiol / Q000819:agonists* / Q000097:blood / Q000378:metabolism; D005260:Female; D000960:Hypolipidemic Agents / Q000008:administration & dosage / Q000633:toxicity*; D015674:Mammary Neoplasms, Animal / Q000139:chemically induced* / Q000473:pathology; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism; D051381:Rats; D011912:Rats, Inbred ACI
D000960:Hypolipidemic Agents; D004958:Estradiol; D016660:NAD(P)H Dehydrogenase (Quinone); C507703:NQO1 protein, rat; D002994:Clofibrate