In:
American Journal of Physiology-Endocrinology and Metabolism, American Physiological Society, Vol. 297, No. 4 ( 2009-10), p. E949-E955
Abstract:
In the kidney, progesterone is inactivated to 20α-dihydro-progesterone (20α-DH-progesterone) to protect the mineralocorticoid receptor from progesterone excess. In an attempt to clone the enzyme with 20α-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 20α-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 to 20α-DH-progesterone in a concentration-dependent manner, indicating that the effect of CYP27A1 overexpression was mediated by 27-hydroxycholesterol. To analyze whether these observations are relevant in vivo, progesterone and 20α-DH-progesterone were measured by gas chromatography-mass spectometry in 24-h urine of CYP27A1 gene knockout (ko) mice and their control wild-type and heterozygote littermates. In CYP27A1 ko mice, urinary progesterone concentrations were decreased, 20α-DH-progesterone increased, and the progesterone-to-20α-DH-progesterone ratio decreased threefold ( P 〈 0.001). Thus CYP27A1 modulates progesterone concentrations. The underlying mechanism is inhibition of 20α-hydroxysteroid dehydrogenase by 27-hydroxycholesterol.
Type of Medium:
Online Resource
ISSN:
0193-1849
,
1522-1555
DOI:
10.1152/ajpendo.00298.2009
Language:
English
Publisher:
American Physiological Society
Publication Date:
2009
detail.hit.zdb_id:
1477331-4
SSG:
12
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