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PMID:21232532

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Citation

Hevir, N, Vouk, K, Sinkovec, J, Ribič-Pucelj, M and Rižner, TL (2011) Aldo-keto reductases AKR1C1, AKR1C2 and AKR1C3 may enhance progesterone metabolism in ovarian endometriosis. Chem. Biol. Interact. 191:217-26

Abstract

Endometriosis is a very common disease that is characterized by increased formation of estradiol and disturbed progesterone action. This latter is usually explained by a lack of progesterone receptor B (PR-B) expression, while the role of pre-receptor metabolism of progesterone is not yet fully understood. In normal endometrium, progesterone is metabolized by reductive 20α-hydroxysteroid dehydrogenases (20α-HSDs), 3α/β-HSDs and 5α/β-reductases. The aldo-keto reductases 1C1 and 1C3 (AKR1C1 and AKR1C3) are the major reductive 20α-HSDs, while the oxidative reaction is catalyzed by 17β-HSD type 2 (HSD17B2). Also, 3α-HSD and 3β-HSD activities have been associated with the AKR1C isozymes. Additionally, 5α-reductase types 1 and 2 (SRD5A1, SRD5A2) and 5β-reductase (AKR1D1) are responsible for the formation of 5α- and 5β-reduced pregnanes. In this study, we examined the expression of PR-AB and the progesterone metabolizing enzymes in 31 specimens of ovarian endometriosis and 28 specimens of normal endometrium. Real-time PCR analysis revealed significantly decreased mRNA levels of PR-AB, HSD17B2 and SRD5A2, significantly increased mRNA levels of AKR1C1, AKR1C2, AKR1C3 and SRD5A1, and negligible mRNA levels of AKR1D1. Immunohistochemistry staining of endometriotic tissue compared to control endometrium showed significantly lower PR-B levels in epithelial cells and no significant differences in stromal cells, there were no significant differences in the expression of AKR1C3 and significantly higher AKR1C2 levels were seen only in stromal cells. Our expression analysis data at the mRNA level and partially at the cellular level thus suggest enhanced metabolism of progesterone by SRD5A1 and the 20α-HSD and 3α/β-HSD activities of AKR1C1, AKR1C2 and AKR1C3.

Links

PubMed Online version:10.1016/j.cbi.2011.01.003

Keywords

20-Hydroxysteroid Dehydrogenases/genetics; 20-Hydroxysteroid Dehydrogenases/metabolism; 3-Hydroxysteroid Dehydrogenases/genetics; 3-Hydroxysteroid Dehydrogenases/metabolism; 3-Oxo-5-alpha-Steroid 4-Dehydrogenase/genetics; Adult; Down-Regulation; Endometriosis/genetics; Endometriosis/metabolism; Endometriosis/pathology; Estradiol Dehydrogenases/genetics; Female; Gene Expression Regulation, Enzymologic; Humans; Hydroxyprostaglandin Dehydrogenases/genetics; Hydroxyprostaglandin Dehydrogenases/metabolism; Hydroxysteroid Dehydrogenases/genetics; Hydroxysteroid Dehydrogenases/metabolism; Membrane Proteins/genetics; Progesterone/metabolism; RNA, Messenger/genetics; RNA, Messenger/metabolism; Receptors, Progesterone/metabolism; Up-Regulation

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:AK1C2

enables

GO:0004032: alditol:NADP+ 1-oxidoreductase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:AK1C2

enables

GO:0047086: ketosteroid monooxygenase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:AK1C2

involved_in

GO:0042448: progesterone metabolic process

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:AK1C1

enables

GO:0004032: alditol:NADP+ 1-oxidoreductase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:AK1C1

enables

GO:0047086: ketosteroid monooxygenase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:AK1C1

involved_in

GO:0042448: progesterone metabolic process

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:AK1C3

enables

GO:0047086: ketosteroid monooxygenase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:AK1C3

involved_in

GO:0042448: progesterone metabolic process

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:AK1C3

enables

GO:0004032: alditol:NADP+ 1-oxidoreductase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:AK1C3

involved_in

GO:0055114: oxidation-reduction process

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

See also

References

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