Substrate Specificity of Human 3(20).ALPHA.-Hydroxysteroid Dehydrogenase for Neurosteroids and Its Inhibition by Benzodiazepines.
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In this report, we compared kinetic constants and products in the reduction of the neurosteroids, 3alpha,5alpha-tetrahydroprogesterone (3alpha,5alpha THP) and 3alpha,5alpha-tetrahydrodeoxycorticosterone (3alpha,5alpha-THDOC), and their precursors, 5alpha-dihydroprogesterone (5alpha-DHP), 5alpha-dihydrodeoxycorticosterone (5alpha-DHDOC) and progesterone, by three isoenzymes (AKR1C1, AKR1C2 and AKR1C3) of human 3alpha-hydroxysteroid dehydrogenase. AKR1C1 efficiently reduced 3alpha,5alpha-THP, 5alpha-DHP and progesterone to their 20alpha-hydroxy metabolites, and slowly converted 5alpha-DHDOC to 3alpha,5alpha-THDOC. AKR1C2 exhibited low 20-ketoreductase activity for 3alpha,5alpha-THP and moderate 3-ketoreductase activity for 5alpha-DHP and 5alpha-DHDOC. 3alpha,5alpha-THDOC was not reduced by the two isoenzymes. No significant activity for the steroids was detected with AKR1C3. The results suggest that AKR1C2 is involved in the neurosteroid synthesis, but AKR1C1 decreases the neurosteroid concentrations in human brain by inactivating 3alpha,5alpha-THP and eliminating the precursors from the synthetic pathways. In addition, we found that the several benzodiazepines inhibited the three isoenzymes noncompetitively with respect to the substrate. Although cloxazolam was a potent and specific inhibitor of AKR1C3, diazepam, estazolam, flunitrazepam, medazepam and nitrazepam, that inhibited AKR1C1 and AKR1C2, may influence the neurosteroid metabolism.
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Kinetic data suggest that in brain AKR1C2 forms the potent neurosteroid allopregnanolone, while AKR1C1 is involved in its inactivation.
“The kinetic data thus suggest that in brain AKR1C2 catalyzes formation of the potent neurosteroid allopregnanolone, while AKR1C1 is involved in its inactivation”
From Role of aldo-keto reductase family 1 (AKR1) enzymes in human steroid metabolism (2014) · cites this paper as [43]
AKR1C3 has low kcat values for reduction of 5α-DHP and 20α-hydroxy-5α-pregnane-3-one.
“AKR1C3 has low kcat values for the reduction of 5α-DHP and 20α-hydroxy-5α-pregnane-3-one”
From Role of aldo-keto reductase family 1 (AKR1) enzymes in human steroid metabolism (2014) · cites this paper as [43]
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- Authors
- Usami, N., Yamamoto, T., Shintani, S., Higaki, Y., Ishikura, S., Patagiri, Y., & Hara, A.
- Affiliations
- Gifu Pharmaceutical University (JP)
- Gifu University Hospital (JP)
- Venue
- Biological and Pharmaceutical Bulletin
- Publisher
- Pharmaceutical Society of Japan
- Published
- 2002
- Volume
- 25
- Issue
- 4
- Pages
- 441-445
- ISSN
- 0918-6158 (ISSN-L)
- 1347-5215
- OpenAlex
- W2050245091
- Cited by
- 59
- References
- 21
- Citations by year
- 2026: 3 · 2025: 3 · 2021: 2 · 2020: 1 · 2019: 2 · 2017: 5 · 2016: 2 · 2014: 2 · 2013: 2 · 2012: 3
- FWCI
- 1.09
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Biological and Pharmaceutical Bulletin (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Aldose Reductase and Taurine
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Steroid Chemistry and Biochemistry
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal Regulation and Hypertension
- Keywords
- 3α-hydroxysteroid dehydrogenase, AKR1C1, AKR1C2, AKR1C3, neurosteroids, 5alpha-dihydroprogesterone, substrate specificity, enzyme kinetics, non-competitive inhibition, benzodiazepines, diazepam, human brain
- MeSH terms
- Benzodiazepines, Corticosterone, Enzyme Inhibitors, Humans, Isoenzymes, Pregnanediones, Pregnanolone, Substrate Specificity, 3-Hydroxysteroid Dehydrogenases, 5-alpha-Dihydroprogesterone, 3-alpha-Hydroxysteroid Dehydrogenase (B-Specific)
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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