Role of CYP27A1 in progesterone metabolism in vitro and in vivo

Escher, Genevieve; Vögeli, Isabelle; Escher, Robert; Tuckey, Robert C; Erickson, Sandra; Krozowski, Zygmunt; Frey, Felix J (2009). Role of CYP27A1 in progesterone metabolism in vitro and in vivo. American journal of physiology - endocrinology and metabolism, 297(4), E949-E955. Bethesda, Md.: American Physiological Society 10.1152/ajpendo.00298.2009

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In the kidney, progesterone is inactivated to 20alpha-dihydro-progesterone (20alpha-DH-progesterone) to protect the mineralocorticoid receptor from progesterone excess. In an attempt to clone the enzyme with 20alpha-hydroxysteroid activity using expression cloning in CHOP cells and a human kidney expression library, serendipitously cDNA encoding CYP27A1 was isolated. Overexpression of CYP27A1 in CHOP cells decreased progesterone conversion to 20alpha-DH-progesterone in a dose-dependent manner, an effect enhanced by cotransfection with adrenodoxin and adrenodoxin reductase. Incubation of CHOP cells with 27-hydroxycholesterol, a product of CYP27A1, increased the ratio of progesterone/20alpha-DH-progesterone in a concentration-dependent manner, indicating that the effect of CYP27A1 overexpression was mediated by 27-hydroxycholesterol. In order to analyze whether these observations are relevant in vivo, progesterone and 20alpha-DH-progesterone were measured by GC-MS in 24-h urine of CYP27A1 gene knock out (ko) mice and their control wild type (wt) and heterozygote (hz) littermates. In CYP27A1 ko mice, urinary progesterone concentrations were decreased, 20alpha-DH-progesterone increased and the progesterone/20alpha-DH-progesterone ratio decreased threefold (p<0.001). Thus, CYP27A1 modulates progesterone concentrations. The underlying mechanism is inhibition of 20alpha-hydroxysteroid dehydrogenase by 27-hydroxycholesterol. Key words: Progesterone, sterol 27-hydroxylase, 27-hydroxycholesterol, 20a-steroid dehydrogenase, 20a-DH-progesterone.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Dermatology, Urology, Rheumatology, Nephrology, Osteoporosis (DURN) > Clinic of Nephrology and Hypertension

UniBE Contributor:

Escher, Geneviève and Frey, Felix Julius

ISSN:

0193-1849

Publisher:

American Physiological Society

Language:

English

Submitter:

Factscience Import

Date Deposited:

04 Oct 2013 15:14

Last Modified:

08 Jun 2016 10:54

Publisher DOI:

10.1152/ajpendo.00298.2009

PubMed ID:

19671838

Web of Science ID:

000270139400014

URI:

https://boris.unibe.ch/id/eprint/32420 (FactScience: 197599)

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