Impaired 17,20-lyase activity in male mice lacking cytochrome b5 in leydig cells

Varun Sondhi, Bryn M. Owen, Jiayan Liu, Robert Chomic, Steven A. Kliewer, Beverly A. Hughes, Wiebke Arlt, David J. Mangelsdorf, Richard J. Auchus

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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.

Original languageEnglish (US)
Pages (from-to)469-478
Number of pages10
JournalMolecular Endocrinology
Volume30
Issue number4
DOIs
StatePublished - Apr 1 2016

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Steroid 17-alpha-Hydroxylase
Cytochromes b5
Leydig Cells
17-alpha-Hydroxyprogesterone
Testis
Androgens
Fertility
Ideal Body Weight
Organ Size
Chorionic Gonadotropin
Mixed Function Oxygenases
Biochemistry
Cytochrome P-450 Enzyme System
Testosterone
Mammals
Estrogens
Animal Models
Steroids
Urine

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology

Cite this

Sondhi, V., Owen, B. M., Liu, J., Chomic, R., Kliewer, S. A., Hughes, B. A., ... Auchus, R. J. (2016). Impaired 17,20-lyase activity in male mice lacking cytochrome b5 in leydig cells. Molecular Endocrinology, 30(4), 469-478. https://doi.org/10.1210/me.2015-1282

Impaired 17,20-lyase activity in male mice lacking cytochrome b5 in leydig cells. / Sondhi, Varun; Owen, Bryn M.; Liu, Jiayan; Chomic, Robert; Kliewer, Steven A.; Hughes, Beverly A.; Arlt, Wiebke; Mangelsdorf, David J.; Auchus, Richard J.

In: Molecular Endocrinology, Vol. 30, No. 4, 01.04.2016, p. 469-478.

Research output: Contribution to journalArticle

Sondhi, V, Owen, BM, Liu, J, Chomic, R, Kliewer, SA, Hughes, BA, Arlt, W, Mangelsdorf, DJ & Auchus, RJ 2016, 'Impaired 17,20-lyase activity in male mice lacking cytochrome b5 in leydig cells', Molecular Endocrinology, vol. 30, no. 4, pp. 469-478. https://doi.org/10.1210/me.2015-1282
Sondhi, Varun ; Owen, Bryn M. ; Liu, Jiayan ; Chomic, Robert ; Kliewer, Steven A. ; Hughes, Beverly A. ; Arlt, Wiebke ; Mangelsdorf, David J. ; Auchus, Richard J. / Impaired 17,20-lyase activity in male mice lacking cytochrome b5 in leydig cells. In: Molecular Endocrinology. 2016 ; Vol. 30, No. 4. pp. 469-478.
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