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Epidermal Keratinocytes: A Source of 5- Dihydrotestosterone Production in Human Skin^*

Cecil H. and Ida Green Center for Reproductive Biology Sciences and the Departments of Obstetrics and Gynecology and Dermatology, The University of Texas Health Science Center, Southwestern Medical School Dallas, Texas 75235

Address all correspondence and requests for reprints to: Dr. Leon Milewich, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical School, 5323 Harry Hines Boulevard, Dallas, Texas 75235.

The major products of testosterone, androstenedione, and progesterone metabolism by human epidermal keratinocytes are 5-reduced steroids, viz. 5-dihydrotestosterone, 5-androstanedione, and 5-dihydroprogesterone, respectively. The rates of metabolite formation by these cells were linear with incubation time up to 3 h. The apparent K_m of keratinocyte 5-reductase was 1.3 µM for androstenedione and 1.5 µM for progesterone. 5-Reductase activity was found only in particulate subcellular fractions of a homogenate of epidermal keratinocytes when assayed with tritium-labeled progesterone as the substrate and NADPH as the cofactor. In addition to 5-reductase activity, other enzymatic activities found in epidermal keratinocytes were 17β-hydroxysteroid oxidoreductase and 3β-hydroxysteroid oxidoreductase. These enzymes were expressed in the formation of androstenedione from testosterone, testosterone from androstenedione, isoandrosterone from androstenedione, and 3β-hydroxy- 5-pregnan-20-one from progesterone. The apparent K_m of 17β-hydroxysteroid oxidoreductase for androstenedione in epidermal keratinocytes was 10µM. When measured at weekly intervals, the rates of product formation from testosterone, androstenedione, or progesterone by cultured epidermal keratinocytes increased several-fold with advancing time in culture up to 3 weeks. The results of these studies suggest that epidermal keratinocytes are a major site of synthesis of biologically potent androgens in human skin, viz. testosterone from androstenedione and 5-dihydrotestosterone from testosterone. Skin is a target organ for 5-dihydrotestosterone action, and thus, thelocal formation of 5-dihydrotestosterone may play an important role in the regulation of proliferation and differentiation of keratinocytes.

^* This work was supported in part by USPHS Grants AM-27257, AM-19101, and AI-17363.

Received August 1, 1985.

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