Androgen and estrogen biosynthesis in mammals requires the 17,20-lyase activity of cytochrome P450 17A1 (steroid 17-hydroxylase/17,20-lyase, CYP17A1). 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 Cyb5(flox/flox):Sf1-Cre (LeyKO) mice. The LeyKO male mice had normal body weights, testis and sex organ weights, and fertility compared to littermates. Basal serum and urine steroid profiles of LeyKO males were not significantly different than littermates. In contrast, marked 17-hydroxyprogesterone (17OHP) accumulation (100-fold basal) and reduced testosterone synthesis (27% of littermates) were observed following hCG stimulation in LeyKO animals. Testis homogenates from LeyKO mice showed reduced 17,20-lyase activity and a 3-fold increased 17-hydroxylase/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 17OHP accumulation in the mouse testis; however, the b5-independent 17,20-lyase activity of mouse P450 17A1 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.
Molecular endocrinology (Baltimore, Md.). 2016 Mar 14 [Epub ahead of print]
Varun Sondhi, Bryn M Owen, Jiayan Liu, Robert Chomic, Steven A Kliewer, Beverly A Hughes, Wiebke Arlt, David J Mangelsdorf, Richard J Auchus
Departments of Pharmacology (V.S., B.M.O., S.A.K., D.J.M.) and Molecular Biology (S.A.K.) and the Howard Hughes Medical Institute (D.J.M.), UT Southwestern Medical Center, Dallas, TX 75390; Departments of Internal Medicine and Pharmacology (J.L., R.J.A.) and the Michigan Metabolomics and Obesity Center (R.C.), University of Michigan, Ann Arbor, MI 48109; and the Institute of Metabolism and Systems Research, University of Birmingham, Birmingham B15 2TT, United Kingdom (B.A.H., W.A.)., Departments of Pharmacology (V.S., B.M.O., S.A.K., D.J.M.) and Molecular Biology (S.A.K.) and the Howard Hughes Medical Institute (D.J.M.), UT Southwestern Medical Center, Dallas, TX 75390; Departments of Internal Medicine and Pharmacology (J.L., R.J.A.) and the Michigan Metabolomics and Obesity Center (R.C.), University of Michigan, Ann Arbor, MI 48109; and the Institute of Metabolism and Systems Research, University of Birmingham, Birmingham B15 2TT, United Kingdom (B.A.H., W.A.)., Departments of Pharmacology (V.S., B.M.O., S.A.K., D.J.M.) and Molecular Biology (S.A.K.) and the Howard Hughes Medical Institute (D.J.M.), UT Southwestern Medical Center, Dallas, TX 75390; Departments of Internal Medicine and Pharmacology (J.L., R.J.A.) and the Michigan Metabolomics and Obesity Center (R.C.), University of Michigan, Ann Arbor, MI 48109; and the Institute of Metabolism and Systems Research, University of Birmingham, Birmingham B15 2TT, United Kingdom (B.A.H., W.A.)., Departments of Pharmacology (V.S., B.M.O., S.A.K., D.J.M.) and Molecular Biology (S.A.K.) and the Howard Hughes Medical Institute (D.J.M.), UT Southwestern Medical Center, Dallas, TX 75390; Departments of Internal Medicine and Pharmacology (J.L., R.J.A.) and the Michigan Metabolomics and Obesity Center (R.C.), University of Michigan, Ann Arbor, MI 48109; and the Institute of Metabolism and Systems Research, University of Birmingham, Birmingham B15 2TT, United Kingdom (B.A.H., W.A.)., Departments of Pharmacology (V.S., B.M.O., S.A.K., D.J.M.) and Molecular Biology (S.A.K.) and the Howard Hughes Medical Institute (D.J.M.), UT Southwestern Medical Center, Dallas, TX 75390; Departments of Internal Medicine and Pharmacology (J.L., R.J.A.) and the Michigan Metabolomics and Obesity Center (R.C.), University of Michigan, Ann Arbor, MI 48109; and the Institute of Metabolism and Systems Research, University of Birmingham, Birmingham B15 2TT, United Kingdom (B.A.H., W.A.)., Departments of Pharmacology (V.S., B.M.O., S.A.K., D.J.M.) and Molecular Biology (S.A.K.) and the Howard Hughes Medical Institute (D.J.M.), UT Southwestern Medical Center, Dallas, TX 75390; Departments of Internal Medicine and Pharmacology (J.L., R.J.A.) and the Michigan Metabolomics and Obesity Center (R.C.), University of Michigan, Ann Arbor, MI 48109; and the Institute of Metabolism and Systems Research, University of Birmingham, Birmingham B15 2TT, United Kingdom (B.A.H., W.A.)., Departments of Pharmacology (V.S., B.M.O., S.A.K., D.J.M.) and Molecular Biology (S.A.K.) and the Howard Hughes Medical Institute (D.J.M.), UT Southwestern Medical Center, Dallas, TX 75390; Departments of Internal Medicine and Pharmacology (J.L., R.J.A.) and the Michigan Metabolomics and Obesity Center (R.C.), University of Michigan, Ann Arbor, MI 48109; and the Institute of Metabolism and Systems Research, University of Birmingham, Birmingham B15 2TT, United Kingdom (B.A.H., W.A.)., Departments of Pharmacology (V.S., B.M.O., S.A.K., D.J.M.) and Molecular Biology (S.A.K.) and the Howard Hughes Medical Institute (D.J.M.), UT Southwestern Medical Center, Dallas, TX 75390; Departments of Internal Medicine and Pharmacology (J.L., R.J.A.) and the Michigan Metabolomics and Obesity Center (R.C.), University of Michigan, Ann Arbor, MI 48109; and the Institute of Metabolism and Systems Research, University of Birmingham, Birmingham B15 2TT, United Kingdom (B.A.H., W.A.)., Departments of Pharmacology (V.S., B.M.O., S.A.K., D.J.M.) and Molecular Biology (S.A.K.) and the Howard Hughes Medical Institute (D.J.M.), UT Southwestern Medical Center, Dallas, TX 75390; Departments of Internal Medicine and Pharmacology (J.L., R.J.A.) and the Michigan Metabolomics and Obesity Center (R.C.), University of Michigan, Ann Arbor, MI 48109; and the Institute of Metabolism and Systems Research, University of Birmingham, Birmingham B15 2TT, United Kingdom (B.A.H., W.A.).