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Inhibition of Leydig Tumor Cell Steroidogenesis by 10-Propargylestr-4-ene-3,17-dione, an Irreversible Aromatase Inhibitor¹

Department of Biochemistry, Vanderbilt University, Nashville, Tennessee 37232 [S. J. Z., M. E. B., M. H. M., D. P.]; REPSCEND Laboratories and Department of Biochemistry, University of Miami School of Medicine, Miami, Florida 33101 [S. J. Z., M. E. B., M. H. M., D. P.]; and Department of Pharmacology, Washington University, St. Louis, Missouri 63140 [D. F. C.]

The murine Leydig cell tumor (M5480A) was assayed for the presence of aromatase activity and for the effects of 10-propargylestr-4-ene-3,17-dione (PED), an aromatase inhibitor, on steroidogenesis. Microsomal preparations from these tumors contained low levels of aromatase activity which was PED sensitive. In addition, these Leydig tumor cells were maintained in primary culture and incubated under basal and gonadotropin-stimulated conditions with various doses of PED. Medium levels of progesterone, a major product of these cells, were found to decrease in a dose- and time-dependent manner upon addition of PED. To determine whether the observed effect was due to reduced synthesis or to increased metabolism of progesterone, tritiated progesterone was added to these cell cultures. Analysis of culture medium by high-performance liquid chromatography suggested that PED dramatically reduced the conversion of labeled progesterone to testosterone. Furthermore, examination of medium pregnenolone levels revealed diminished amounts of this steroid as well. Taken together, these results suggest that PED or its metabolites inhibit Leydig tumor cell steroidogenesis at several sites. Thus, in addition to its role as an aromatase inhibitor, this agent also has effects prior to pregnenolone production, as well as other effects in the pathway between progesterone and testosterone.

¹ Supported by the NIH (Research Grants AM33973 and CA23582; Training Grants CA09131, HD07043, and HD07129; and Center Grant HD05797 for provision of tissue culture facilities).

² Present address: Reproductive Sciences and Endocrinology Laboratories and the Department of Biochemistry, University of Miami School of Medicine, Miami, FL 33101.

³ To whom requests for reprints should be addressed, at REPSCEND Labs (D-5), University of Miami School of Medicine, P. O. Box 016960, Miami, FL 33101.

⁴ Cellular and Molecular Biology Predoctoral Trainee at Vanderbilt University (GM07319) and at the University of Miami.

⁵ Recipient of a Research Career Development Award from the NIH.

Received 11/30/84. Revised 6/18/85. Accepted 6/25/85.