Several investigators have suggested that certain hydroxylated metabolites of 17 -estradiol (E 2 ) are the proximate carcinogens that induce mammary carcinomas in estrogensensitive rodent models. The studies reported here were designed to examine the carcinogenic potential of different levels of E 2 and the effects of genotoxic metabolites of E 2 in an in vivo model sensitive to E 2 -induced mammary cancer. The potential induction of mammary tumors was determined in female ACI rats subcutaneously implanted with cholesterol pellets containing E 2 (1, 2, or 3 mg), or 2-hydroxyestradiol (2-OH E 2 ), 4-hydroxyestradiol (4-OH E 2 ), 16 -hydroxyestradiol (16 -OH E 2 ), or 4-hydoxyestrone (4-OH E 1 ) (equimolar to 2 mg E 2 ). Treatment with 1, 2, or 3 mg E 2 resulted in the first appearance of a mammary tumor between 12 and 17 weeks, and a 50% incidence of mammary tumors was observed at 36, 19, and 18 weeks respectively. The final cumulative mammary tumor incidence in rats treated with 1, 2, or 3 mg E 2 for 36 weeks was 50%, 73%, and 100% respectively. Treatment of rats with pellets containing 2-OH E 2 , 4-OH E 2 , 16 -OH E 2 , or 4-OH E 1 did not induce any detectable mammary tumors. The serum levels of E 2 in rats treated with a 1 or 3 mg E 2 pellet for 12 weeks was increased 2-to 6-fold above control values (30 pg/ml). Treatment of rats with E 2 enhanced the hepatic microsomal metabolism of E 2 to E 1 , but did not influence the 2-or 4-hydroxylation of E 2 . In summary, we observed a dosedependent induction of mammary tumors in female ACI rats treated continuously with E 2 ; however, under these conditions 2-OH E 2 , 4-OH E 2 , 16 -OH E 2 , and 4-OH E 1 were inactive in inducing mammary tumors.
Fatty acyl-coenzyme A:estradiol acyltransferase in liver microsomes catalyzes the formation of estradiol fatty acid esters. These estrogen esters are extremely lipophilic and have prolonged hormonal activity because they are slowly metabolized and slowly release estradiol. Our previous studies showed that treatment of female rats with clofibrate or gemfibrozil (peroxisome proliferators commonly used as hypolipidemic drugs) markedly stimulated the liver microsomal esterification of estradiol. Although clofibrate administration is a potent inducer of liver microsomal fatty acyl-coenzyme A:estradiol acyltransferase in rats, it is a poor inducer in mice. In contrast to these observations, Wy-14,643 (an exceptionally potent prototypical peroxisome proliferator) is a strong inducer of fatty acyl-coenzyme A:estradiol acyltransferase in mice. To explore the role of PPARalpha in the induction of fatty acyl-coenzyme A:estradiol acyltransferase and fatty acyl-coenzyme A:testosterone acyltransferase activities by peroxisome proliferators, we fed 0.1% Wy-14,643 to female wild-type and PPARalpha null mice for 11 d. The liver microsomal acyl-coenzyme A:estradiol acyltransferase and acyl-coenzyme A:testosterone acyltransferase activities were increased 4- to 5-fold in wild-type mice fed Wy-14,643, but no increase was observed in null mice. These results demonstrate that induction of acyl-coenzyme A:estradiol acyltransferase and acyl-coenzyme A:testosterone acyltransferase activities by a prototypical peroxisome proliferator is dependent on PPARalpha.
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