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The Population Council (H.-B.G., R.-S.G., A.M., M.P.H.) and Rockefeller University (M.P.H.), 1230 York Avenue, New York, New York 10021; and Department of Obstetrics and Gynecology (V.L.), State University of New York, Health Science Center-Brooklyn, Brooklyn, New York 11203
Address all correspondence and requests for reprints to: Matthew P. Hardy, The Population Council, Center for Biomedical Research, 1230 York Avenue, New York, New York 10021. E-mail: hardy{at}popcbr.rockefeller.edu
We have proposed that the 11ß-hydroxysteroid dehydrogenase
(11ß-HSD) of Leydig cells protects against glucocorticoid-induced
inhibition of testosterone (T) production. However, Leydig cells
express type I 11ß-HSD, which has been shown to be reductive in liver
parenchymal cells. Because reduction would have the opposite effect of
activating glucocorticoid, the present study was designed to determine:
1) whether Leydig cell 11ß-HSD is primarily oxidative or reductive;
and 2) whether oxidative and reductive activities are separately
modified by known regulators of Leydig cell steroidogenic function.
Leydig cells and liver parenchymal cells were purified from mature male
Sprague-Dawley rats (250 g BW), and 11ß-HSD oxidative and reductive
activities were measured using radiolabeled substrates and TLC of
triplicate media samples from 1-h incubations immediately after cell
isolation. Enzyme activities also were examined in purified Leydig
cells at the end of 3 days of culture in vitro in the
presence of LH (10 ng/ml), dexamethasone (DEX, 100 nM), T
(50 nM), or epidermal growth factor (EGF, 50 ng/ml). In
confirmation of previous reports, the reductive activity of 11ß-HSD
was predominant over oxidation in liver parenchymal cells. In contrast,
11ß-HSD oxidative activity prevailed over reduction in Leydig cells
by a ratio of 2:1. The activities of 11ß-HSD also were analyzed in
Leydig cells that were purified 7 days after endogenous glucocorticoid
levels were suppressed by adrenalectomy (ADX). Oxidative activity
declined in Leydig cells after ADX (22.53 ± 1.12
pmol/h·106 cells, mean ± SEM
vs. 31.47 ± 1.48 pmol/h·106 cells in
sham-operated controls, P < 0.05), whereas there
was no change in reductive activity. This indicated that
physiologically active corticosterone is involved in maintaining the
predominance of 11ß-HSD oxidation. When enzyme activities were
analyzed in Leydig cells after 3 days of hormonal treatment in
vitro, oxidation and reduction were observed to change in
opposing directions. Culture of Leydig cells from sham-operated control
rats with either LH, T, or EGF resulted in declines in oxidative
activity from 33.35 ± 0.77 to 28.24 ± 1.93, 27.30 ±
0.96, and 24.13 ± 1.02 pmol/h·106 cells (
±
SE), respectively. However, EGF stimulated 11ß-HSD
reductive activity in cultured Leydig cells from both control (from
18.97 ± 1.10 to 27.16 ± 0.71 pmol/h·106 cells
and ADX rats (from 16.51 ± 0.75 to 23.56 ± 0.84
pmol/h·106 cells). Among the hormonal treatments, only
DEX increased oxidative activity and simultaneously decreased reductive
activity in Leydig cells from ADX rats. This increase accentuated the
predominance of oxidative activity in Leydig cells, with a ratio of
oxidative to reductive activity of 4:1 after DEX treatment, compared
with 2:1 in controls that were untreated. We conclude that 11ß-HSD
activity in Leydig cells is primarily oxidative. Moreover, oxidation
and reduction are regulated separately by hormones.
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