title: Impaired 17,20-Lyase Activity in Male Mice Lacking Cytochrome b5 in Leydig Cells.
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 Cyb5(flox/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.
authors.affiliation: 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.), University of Texas Southwestern Medical Center, Dallas, Texas 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, Michigan 48109; and the Institute of Metabolism and Systems Research (B.A.H., W.A.), University of Birmingham, Birmingham B15 2TT, United Kingdom.
authors.forename: Varun
authors.initials: V
authors.lastname: Sondhi
authors.affiliation: 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.), University of Texas Southwestern Medical Center, Dallas, Texas 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, Michigan 48109; and the Institute of Metabolism and Systems Research (B.A.H., W.A.), University of Birmingham, Birmingham B15 2TT, United Kingdom.
authors.forename: Bryn M
authors.initials: BM
authors.lastname: Owen
authors.affiliation: 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.), University of Texas Southwestern Medical Center, Dallas, Texas 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, Michigan 48109; and the Institute of Metabolism and Systems Research (B.A.H., W.A.), University of Birmingham, Birmingham B15 2TT, United Kingdom.
authors.forename: Jiayan
authors.initials: J
authors.lastname: Liu
authors.affiliation: 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.), University of Texas Southwestern Medical Center, Dallas, Texas 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, Michigan 48109; and the Institute of Metabolism and Systems Research (B.A.H., W.A.), University of Birmingham, Birmingham B15 2TT, United Kingdom.
authors.forename: Robert
authors.initials: R
authors.lastname: Chomic
authors.affiliation: 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.), University of Texas Southwestern Medical Center, Dallas, Texas 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, Michigan 48109; and the Institute of Metabolism and Systems Research (B.A.H., W.A.), University of Birmingham, Birmingham B15 2TT, United Kingdom.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Kliewer
authors.affiliation: 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.), University of Texas Southwestern Medical Center, Dallas, Texas 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, Michigan 48109; and the Institute of Metabolism and Systems Research (B.A.H., W.A.), University of Birmingham, Birmingham B15 2TT, United Kingdom.
authors.forename: Beverly A
authors.initials: BA
authors.lastname: Hughes
authors.affiliation: 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.), University of Texas Southwestern Medical Center, Dallas, Texas 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, Michigan 48109; and the Institute of Metabolism and Systems Research (B.A.H., W.A.), University of Birmingham, Birmingham B15 2TT, United Kingdom.
authors.forename: Wiebke
authors.initials: W
authors.lastname: Arlt
authors.affiliation: 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.), University of Texas Southwestern Medical Center, Dallas, Texas 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, Michigan 48109; and the Institute of Metabolism and Systems Research (B.A.H., W.A.), University of Birmingham, Birmingham B15 2TT, United Kingdom.
authors.forename: David J
authors.initials: DJ
authors.lastname: Mangelsdorf
authors.affiliation: 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.), University of Texas Southwestern Medical Center, Dallas, Texas 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, Michigan 48109; and the Institute of Metabolism and Systems Research (B.A.H., W.A.), University of Birmingham, Birmingham B15 2TT, United Kingdom.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Auchus
mesh_terms: D019326:17-alpha-Hydroxyprogesterone / Q000097:blood; D000818:Animals; D015786:Cytochromes b5 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005298:Fertility; D007985:Leydig Cells / Q000201:enzymology*; D008297:Male; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D013254:Steroid 17-alpha-Hydroxylase / Q000378:metabolism*
chemical_list: D019326:17-alpha-Hydroxyprogesterone; D015786:Cytochromes b5; D013254:Steroid 17-alpha-Hydroxylase