Role of microsomal retinol/sterol dehydrogenase-like short-chain dehydrogenases/reductases in the oxidation and epimerization of 3alpha-hydroxysteroids in human tissues

Allopregnanolone (ALLO) and androsterone (ADT) are naturally occurring 3alpha-hydroxysteroids that act as positive allosteric regulators of gamma-aminobutyric acid type A receptors. In addition, ADT activates nuclear farnesoid X receptor and ALLO activates pregnane X receptor. At least with respect...

Full description

Saved in:
Bibliographic Details
Published in:Endocrinology (Philadelphia) 2007-05, Vol.148 (5), p.2148-2156
Main Authors: Belyaeva, Olga V, Chetyrkin, Sergei V, Clark, Amy L, Kostereva, Natalia V, SantaCruz, Karen S, Chronwall, Bibie M, Kedishvili, Natalia Y
Format: Article
Language:English
Subjects:
3-alpha-Hydroxysteroid Dehydrogenase (B-Specific) - genetics
3-alpha-Hydroxysteroid Dehydrogenase (B-Specific) - metabolism
Brain - enzymology
Cell Line
Enzyme Activation
Female
Gene Expression Regulation, Enzymologic
Humans
Hydroxysteroids - metabolism
Immunohistochemistry
Kidney - cytology
Kidney - enzymology
Liver - enzymology
Lung - enzymology
Male
Microsomes - enzymology
NAD - metabolism
Ovary - enzymology
Oxidation-Reduction
Spleen - enzymology
Testis - enzymology
Transfection
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Allopregnanolone (ALLO) and androsterone (ADT) are naturally occurring 3alpha-hydroxysteroids that act as positive allosteric regulators of gamma-aminobutyric acid type A receptors. In addition, ADT activates nuclear farnesoid X receptor and ALLO activates pregnane X receptor. At least with respect to gamma-aminobutyric acid type A receptors, the biological activity of ALLO and ADT depends on the 3alpha-hydroxyl group and is lost upon its conversion to either 3-ketosteroid or 3beta-hydroxyl epimer. Such strict structure-activity relationships suggest that the oxidation or epimerization of 3alpha-hydroxysteroids may serve as physiologically relevant mechanisms for the control of the local concentrations of bioactive 3alpha-hydroxysteroids. The exact enzymes responsible for the oxidation and epimerization of 3alpha-hydroxysteroids in vivo have not yet been identified, but our previous studies showed that microsomal nicotinamide adenine dinucleotide-dependent short-chain dehydrogenases/reductases (SDRs) with dual retinol/sterol dehydrogenase substrate specificity (RoDH-like group of SDRs) can oxidize and epimerize 3alpha-hydroxysteroids in vitro. Here, we present the first evidence that microsomal nicotinamide adenine dinucleotide-dependent 3alpha-hydroxysteroid dehydrogenase/epimerase activities are widely distributed in human tissues with the highest activity levels found in liver and testis and lower levels in lung, spleen, brain, kidney, and ovary. We demonstrate that RoDH-like SDRs contribute to the oxidation and epimerization of ALLO and ADT in living cells, and show that RoDH enzymes are expressed in tissues that have microsomal 3alpha-hydroxysteroid dehydrogenase/epimerase activities. Together, these results provide further support for the role of RoDH-like SDRs in human metabolism of 3alpha-hydroxysteroids and offer a new insight into the enzymology of ALLO and ADT inactivation.
ISSN:0013-7227