Inhibition of testicular microsomal cytochrome P-450 (17 alpha-hydroxylase/C-17,20-lyase) by estrogens
Abstract
Highly purified cytochrome P-450 from neonatal pig testicular microsomes is capable of catalyzing both 17 alpha-hydroxylation and C-17,20-lyase activity. Estradiol was found to inhibit both activities of the purified enzyme with delta 4 and with delta 5 substrates (progesterone, pregnenolone, and the corresponding 17 alpha-hydroxysteroids). For the delta 4 series, inhibition of lyase is competitive and that of 17 alpha-hydroxylase is noncompetitive; for the delta 5 series, inhibition was noncompetitive for both activities. Ki values for lyase activity were determined from enzyme kinetics (5.0 microM for the delta 4 substrate and 20 microM for the delta 5 substrate). Estradiol produces a typical type I spectral shift with the pure enzyme (Ks = 3.0 microM where Ks is the concentration of steroid required to give half maximal spectral shift), so that Ki values were also determined directly from binding studies by using substrate-induced difference spectroscopy. Fifty per cent inhibition of the maximal spectral shift induced by the 17 alpha-hydroxysubstrates (Ki) are 3.8 and 7.6 microM for the delta 4 and delta 5 substrates, respectively. Values for Ki are higher with the substrates of 17 alpha-hydroxylase (progesterone and pregnen...Continue Reading
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