Impaired 17,20-Lyase Activity in Male Mice Lacking Cytochrome b5 in Leydig Cells.

Mon, 2016-08-22 14:31 -- voskuhlt
TitleImpaired 17,20-Lyase Activity in Male Mice Lacking Cytochrome b5 in Leydig Cells.
Publication TypeJournal Article
Year of Publication2016
AuthorsSondhi V, Owen BM, Liu J, Chomic R, Kliewer SA, Hughes BA, Arlt W, Mangelsdorf DJ, Auchus RJ
JournalMol Endocrinol
Volume30
Issue4
Pagination469-78
Date Published2016 Apr
ISSN1944-9917
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.

DOI10.1210/me.2015-1282
Alternate JournalMol. Endocrinol.
PubMed ID26974035
PubMed Central IDPMC4814474
Grant List0900567 / / Medical Research Council / United Kingdom
105545/Z/14/Z / / Wellcome Trust / United Kingdom
DK089503 / DK / NIDDK NIH HHS / United States
R01GM086596 / GM / NIGMS NIH HHS / United States
U24 DK097153 / DK / NIDDK NIH HHS / United States
/ / Howard Hughes Medical Institute / United States