Microsomal Short‐Chain Dehydrogenases/Reductases (SDRs) in the Oxidation and Epimerization of 3α‐Hydroxysteroids

• Published in: The FASEB journal 2007-04, Vol.21 (5), p.A663-A663
• Main Authors: Kedishvili, Natalia Y, Belyaeva, Olga V, Chetyrkin, Sergei V, Kostereva, Natalia V, Chronwall, Bibie M
• Format: Article
• Language: English
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fasebj.21.5.A663-a

Allopregnanolone (ALLO) and androsterone (ADT) act as positive allosteric regulators of GABAA receptors. Androsterone also activates nuclear farnesoid X receptor. The biological activity of ALLO and ADT depends on the 3α‐hydroxyl group and is lost upon its conversion to either 3‐ketosteroid or 3α‐hydroxyl epimer. Such strict structure‐activity relationships suggest that the oxidation or epimerization of 3α‐hydroxysteroids may serve as physiologically relevant mechanisms for the control of local concentrations of bioactive 3α‐hydroxysteroids. The exact enzymes responsible for the oxidation and epimerization of 3α‐hydroxysteroids in vivo are not known, but our previous studies showed that microsomal NAD+‐dependent RoDH‐like SDRs can oxidize and epimerize 3α‐hydroxysteroids in vitro. Here, we present the first evidence that microsomal NAD+‐dependent 3α‐hydroxysteroid dehydrogenase/epimerase activities are widely distributed in human tissues with the highest levels found in liver and testis and lower levels in lung, spleen, brain, kidney and ovary. We demonstrate that RoDHs contribute to the oxidation and epimerization of ALLO and ADT in living cells, and show that these enzymes are expressed in tissues that have microsomal 3α‐hydroxysteroid dehydrogenase/epimerase activities. Together, these results provide further support for the role of RoDH‐like SDRs in human metabolism of 3α‐hydroxysteroids and offer a new insight into the enzymology of ALLO and ADT inactivation.