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3ß-Hydroxysteroid Dehydrogenase/⁵⁴-Isomerase Activity Associated with the Human 17ß-Hydroxysteroid Dehydrogenase Type 2 Isoform¹

Department of Pathology, Tohoku University School of Medicine (T.S., H.S.), Sendai 980-8575, Japan; Cecil H. and Ida Green Center for Reproductive Biology Sciences, University of Texas Southwestern Medical Center (S.A.), Dallas, Texas 75235; and Department of Reproductive and Developmental Sciences (Clinical Biochemistry), University of Edinburgh (J.I.M.), Edinburgh, United Kingdom EH3 9YW

Address all correspondence and requests for reprints to: Prof. J. Ian Mason, Department of Reproductive and Developmental Sciences (Clinical Biochemistry), University of Edinburgh, Royal Infirmary of Edinburgh, Lauriston Place, Edinburgh, United Kingdom EH3 9YW. E-mail: j.i.mason{at}ed.ac.uk

The type 2 isoform of human 17ß-hydroxysteroid dehydrogenase (17ßHSD2) efficiently catalyzes the oxidative metabolism of androgens and estrogens, and it is expressed in a large series of human peripheral tissues. To obtain a better understanding of the regulation of local steroid biosynthesis and metabolism in human tissues, we have established a dual steroidogenic activity of the 17ßHSD2 enzyme after transfection of human 17ßHSD2-transfected human embryonic kidney (293) cells. After transient transfection, the metabolism of testosterone, pregnenolone, and dehydroepiandrosterone (DHEA) in intact transfected 293 cells was evaluated by TLC-based radiometric assays. 17ßHSD2-transfected cells converted 91% of testosterone (1 µmol/L) into androstenedione in a 2-h incubation period. In addition, pregnenolone (1 µmol/L) was converted to progesterone (18.5%), whereas DHEA (1 µmol/L) was metabolized to androstenedione (8.3% conversion) in a 15-h incubation period. The kinetics of the 3ß-hydroxysteroid dehydrogenase (3ßHSD) and 17ßHSD2 activities using cell homogenate protein of stably transfected 293 cells indicated that the catalytic efficiency (apparent catalytic efficiency = maximum velocity/K_m) of this 3ßHSD activity is approximately 2000-fold (pregnenolone as substrate) or 3000-fold (DHEA as substrate) weaker than that of 17ßHSD2 activity. It is noteworthy, however, that the apparent catalytic efficiency of the HSD3B2 gene product is only approximately 50-fold higher than that of the 3ßHSD aspect of the 17ßHSD2 gene product. Pregnenolone or DHEA effectively inhibited 17ßHSD2 activity in a noncompetitive fashion. Furthermore, the potent 5-reductase/3ßHSD inhibitor, 17ß-N,N-diethylcarbamoyl-4-methyl-4-aza-5-androstane-3-one, inhibited neither 3ßHSD nor 17ßHSD2 activities. We conclude that human 17ßHSD2 enzyme exhibits 3ßHSD activity. Notwithstanding that this 3ßHSD activity is reduced compared to 17ßHSD oxidative activity, it may account for at least some of the reports of 3ßHSD activity found in human peripheral tissues that express notable amounts of the 17ßHSD2 isozyme as well as in individuals with severe classic 3ßHSD deficiency.

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