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PPAR-Dependent Induction of Liver Microsomal Esterification of Estradiol and Testosterone by a Prototypical Peroxisome Proliferator

Laboratory for Cancer Research, Department of Chemical Biology, College of Pharmacy, Rutgers, The State University of New Jersey (S.X., B.T.Z., V.T., A.H.C.), Piscataway, New Jersey 08854; Department of Pharmacology, University of North Carolina (I.R., R.T.), Chapel Hill, North Carolina 27599; Department of Veterinary Science, Center for Molecular Toxicology, Pennsylvania State University (J.M.P.), University Park, Pennsylvania 16802; and Laboratory of Metabolism, National Cancer Institute, National Institutes of Health (F.J.G.), Bethesda, Maryland 20892

Address all correspondence and requests for reprints to: Dr. Allan H. Conney, Laboratory for Cancer Research, Department of Chemical Biology, College of Pharmacy, Rutgers, The State University of New Jersey, 164 Frelinghuysen Road, Piscataway, New Jersey 08854-8020. E-mail: aconney{at}rci.rutgers.edu

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 PPAR 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 PPAR 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 PPAR.

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