Abstract
Androgen and estrogen biosynthesis in mammals requires the 17,20-lyase activity of cytochrome P450 17A1 (steroid 17-hydroxylase/17,20-lyase). Maximal 17,20-lyase activity in vitro requires the presence of cytochrome b5 (b5), and rare cases of b5 deficiency in human beings causes isolated 17,20-lyase deficiency. To study the consequences of conditional b5 removal from testicular Leydig cells in an animal model, we generated Cyb5flox/flox:Sf1-Cre (LeyKO) mice. The LeyKO male mice had normal body weights, testis and sex organ weights, and fertility compared with littermates. Basal serum and urine steroid profiles of LeyKO males were not significantly different than littermates. In contrast, marked 17-hydroxyprogesterone accumulation (100-fold basal) and reduced testosterone synthesis (27% of littermates) were observed after human chorionic gonadotropin stimulation in LeyKO animals. Testis homogenates from LeyKO mice showed reduced 17,20-lyase activity and a 3-fold increased 17-hydroxylase to 17,20-lyase activity ratio, which were restored to normal upon addition of recombinant b5. We conclude that Leydig cell b5 is required for maximal androgen synthesis and to prevent 17-hydroxyprogesterone accumulation in the mouse testis; however, the b5-independent 17,20-lyase activity of mouse steroid 17-hydroxylase/17,20-lyase is sufficient for normal male genital development and fertility. LeyKO male mice are a good model for the biochemistry but not the physiology of isolated 17,20-lyase deficiency in human beings.
Highlights
Androgen biosynthesis requires the enzyme steroid 17-hydroxylase/17,20-lyase (P450 17A1, CYP17A1) to convert 21-carbon steroids to 19-carbon steroids
Because the 17,20-lyase activity is the sole gateway to all androgens, the potent P450 17A1 inhibitor abiraterone was developed for the treatment of castration-resistant prostate cancer [2,3]
Abundant biochemical and limited genetic data have shown that the small hemo-protein b5 provides functions as a cofactor in methemoglobin reduction, fatty acid desaturation, and several cytochrome P450-catalyzed reactions in the metabolism of xenobiotics and steroid hormones
Summary
Androgen biosynthesis requires the enzyme steroid 17-hydroxylase/17,20-lyase (P450 17A1, CYP17A1) to convert 21-carbon steroids to 19-carbon steroids. The 17,20-lyase reaction, shows species-specific substrate preferences, with human P450 17A1 catalyzing the conversion of 17-hydroxypregnenolone to dehydroepiandrosterone about 50-fold more efficiently than. The 17,20-lyase reaction is more vulnerable than the 17-hydroxylase reaction to disruption from the abundance of its electron transfer protein cytochrome P450-oxidoreductase (POR) [1], to mutations in POR, and to phospholipid composition. Multiple studies since the 1960s have confirmed the importance of b5 as a modifier of various cytochrome P450 activities, its mechanism of action remains controversial and might vary with P450 isoforms and substrates. Similar to the substrate-specific modulation of activity observed with b5 and other P450s, b5 stimulates the 17, 20-lyase reaction rate >10-. Unlike other forms of isolated 17,20-lyase deficiency, patients with b5 defects demonstrate complete preservation of 17-hydroxylase activity, confirming the in vivo importance of b5 in stimulating the 17-20-lyase reaction. Lyase reaction and the production of 19-carbon sex steroids from 21-carbon precursors
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