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Androgen Formation and Metabolism in the Pulmonary Epithelial Cell Line A549: Expression of 17ß-Hydroxysteroid Dehydrogenase Type 5 and 3-Hydroxysteroid Dehydrogenase Type 3¹

Laboratories of Ontogeny and Reproduction (P.R.P., C.G., N.F., Y.T.), of Molecular Endocrinology (X.-F.H., V.L.-T.), and of Health and Environment (D.N.), CHUQ, PCHUL; Departments of Ob/Gyn (C.H.B.), HealthPartners Regions Hospital St. Paul, Minnesota 55101; Ob/Gyn-CRBR (Y.T.) and Anatomy/Physiology (D.N., V.L.-T.), Faculty of Medicine, Laval University, Québec, Canada G1V 4G2

Address all correspondence and requests for reprints to: Dr. Yves Tremblay, Laboratory of Ontogeny and Reproduction-CRBR, Rm. T-1–58, Centre Hospitalier Universitaire de Québec, Pavillon CHUL, 2705 Laurier Boulevard, Québec, Canada G1V 4G2. E-mail: yves.tremblay{at}crchul.ulaval.ca

Surfactant synthesis within developing fetal lung type II cells is affected by testosterone and 5-dihydrotestosterone (5-DHT). The pulmonary epithelial cell line A549, isolated from a human lung carcinoma, like normal lung type II cell, produces disaturated phosphatidylcholines and has been widely used for studying the regulation of surfactant production. Androgen receptor has been detected in A549 cells; however, the capacity of these cells for androgen synthesis and metabolism has not been investigated at molecular level. This study was undertaken to identify the steroidogenic enzymes involved in the formation and metabolism of androgens from adrenal C19 steroid precursors in A549 cells. When cultured in the presence of normal FCS, A549 intact cells converted DHEA to androstenediol, androstenedione principally to testosterone, and 5-DHT to 5-androstane 3,17ß-diol. High levels of 17ß-hydroxysteroid dehydrogenase (HSD) and 3-HSD activities were detected in both cytosol and microsomes isolated from homogenates. Analysis of A549 RNA indicated the presence of 17ß-HSD type 4 and type 5, and of 3-HSD type 3 messenger RNAs. Very low levels of 3ß-HSD type 1 and 5-reductase type 1 messenger RNAs and activities were detected. With regard to active androgen formation, there was little or no capacity for the conversion of DHEA to 5-DHT. In contrast, androstenedione was rapidly transformed to testosterone. The pattern of steroid metabolism was not affected by the use of charcoal-stripped FCS or by the synthetic glucocorticoid dexamethasone. Together, our findings show that A549 cells express a pattern of steroid metabolism in which 17ß-HSD type 5 and 3-HSD type 3 are the predominant enzymes. The level of androgens is regulated at the level of catalysis in intact cells such that the intracellular level of testosterone is stabilized, whereas 5-DHT is rapidly inactivated by reduction to 3,17ß-diol. This pattern of androgen metabolism has implications for the relative importance of testosterone and 5-DHT in normal lung development and surfactant production.

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