| First Author | Escher G | Year | 2009 |
| Journal | Am J Physiol Endocrinol Metab | Volume | 297 |
| Issue | 4 | Pages | E949-55 |
| PubMed ID | 19671838 | Mgi Jnum | J:159579 |
| Mgi Id | MGI:4443278 | Doi | 10.1152/ajpendo.00298.2009 |
| Citation | Escher G, et al. (2009) Role of CYP27A1 in progesterone metabolism in vitro and in vivo. Am J Physiol Endocrinol Metab 297(4):E949-55 |
| abstractText | 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 to 20alpha-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 20alpha-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, 20alpha-DH-progesterone increased, and the progesterone-to-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. |
