Testosterone-Enhanced Oxygen-Mediated Degradation of P-45017αin Mouse Leydig Cell Cultures*

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Abstract
The present study investigated the process by which the microsomal cytochrome P-450 17α-hydroxylase enzyme (P-45017α) activity in Leydig cells is decreased by steroid products in an oxygen-dependent manner. Leydig cells were maintained in primary culture at ambient (19% O2) or reduced (1% O2) oxygen tension and treated with 8-bromo-cAMP or steroids for 48 h. The amount and activity of P-45017α present in the treated cells were measured to determine whether changes in the activity of the enzyme due to treatment correlated with changes in the amount of the enzyme protein. At ambient oxygen tension the amount of P-45017α declined in Leydig cells treated with cAMP, and this decrease could be prevented when cultures were maintained at reduced oxygen tension. Treatment of cultures with testosterone caused an oxygen-sensitive decrease in the amount of the enzyme similar in extent to the cAMP-induced decrease. Reductions in the amount of P-45017α corresponded to reductions in the activity of the enzyme. The decline in the amount of P-45017α was due to increased decay of the enzyme protein and not to a decrease in the rate of synthesis of P-450. In contrast to testosterone, neither estradiol nor cortisol affected the amount of P-45017α. The data are consistent with the proposal that steroid products acting as pseudosubstrates cause decreases in P-45017α activity by enhancing oxygen radicalmediated damage to the enzyme. The damaged enzyme resulting from this process is more prone to degradation than is the intact protein. (Endocrinology122: 2257–2264, 1988)

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