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Paralogues of Porcine Aromatase Cytochrome P450: A Novel Hydroxylase Activity Is Associated with the Survival of a Duplicated Gene

Department of Population Health and Reproduction, University of California School of Veterinary Medicine (C.J.C., S.M.M., A.J.C.), Davis, California 95616; Children’s Hospital of Oakland Research Institute (J.M., C.H.S.), Oakland, California 94609; Department of Veterinary Physiology and Pharmacology, Texas A&M University (D.M., S.S.), College Station, Texas 77843; and U.S. Department of Agriculture, Agricultural Research Service, Roman L. Hruska U.S. Meat Animal Research Center (T.W., J.J.F.), Clay Center, Nebraska 68933

Address all correspondence and requests for reprints to: Dr. Alan Conley, VM-PHR, School of Veterinary Medicine, 1114 Tupper Hall, University of California, Davis, California 95616. E-mail: ajconley{at}ucdavis.edu.

The gonadal and placental paralogues of porcine aromatase cytochrome P450 (P450arom) were examined for novel catalytic properties to shed light on the evolutionary survival of duplicated copies of an enzyme critical to reproduction. Recombinant gonadal P450arom catalyzed the formation of a novel metabolite from testosterone, identified by gas chromatography/mass spectrometry and biochemical analyses as 1ß-hydroxytestosterone (1ßOH-T), in almost equal proportion to 17ß-estradiol (E₂). This activity was absent in reactions with the porcine placental paralogue (or other orthologues) of P450arom and was minimal with androstenedione. Incubations with both porcine enzymes and with bovine and human P450arom demonstrated that 1ßOH-T was not aromatizable, and 1ßOH-T activated the androgen receptor of prostate cancer cells in vitro. Porcine testicular and follicular granulosa tissues synthesized 1ßOH-T, which was also detected in testicular venous plasma. These results constitute the first of identification of a novel, perhaps potent, nonaromatizable metabolite of testosterone, whose synthesis (paradoxically) can be definitively ascribed to the activity of the gonadal paralogue of porcine P450arom. It probably represents an evolutionary gain of function associated with fixation and the survival of the genes after CYP19 duplication. Novel activities and adaptive functions may exist among other duplicated vertebrate aromatases.

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