Metabolism of the synthetic progestogen norethynodrel by human ketosteroid reductases of the aldo–keto reductase superfamily
Open accessAbstract
Human ketosteroid reductases of the aldo-keto reductase (AKR) superfamily, i.e. AKR1C1-4, are implicated in the biotransformation of synthetic steroid hormones. Norethynodrel (NOR, 17α-ethynyl-17β-hydroxy-estra-5(10)-en-3-one), the progestin component of the first marketed oral contraceptive, is known to undergo rapid and extensive metabolism to 3α- and 3β-hydroxymetabolites. The ability of the four human AKR1C enzymes to catalyze the metabolism of NOR has now been characterized. AKR1C1 and AKR1C2 almost exclusively converted NOR to 3β-hydroxy NOR, while AKR1C3 gave 3β-hydroxy NOR as the main product and AKR1C4 predominantly formed 3α-hydroxy NOR. Individual AKR1C enzymes also displayed distinct kinetic properties in the reaction of NOR. In contrast, norethindrone (NET), the Δ(4)-isomer of NOR and the most commonly used synthetic progestogen, was not a substrate for the AKR1C enzymes. NOR is also structurally identical to the hormone replacement therapeutic tibolone (TIB), except TIB has a methyl group at the 7α-position. Product profiles and kinetic parameters for the reduction of NOR catalyzed by each individual AKR1C isoform were identical to those for the reduction of TIB catalyzed by the respective isoform. These data suggest that the presence of the 7α-methyl group has a minimal effect on the stereochemical outcome of the reaction and kinetic behavior of each enzyme. Results indicate a role of AKR1C in the hepatic and peripheral metabolism of NOR to 3α- and 3β-hydroxy NOR and provide insights into the differential pharmacological properties of NOR, NET and TIB.
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AKR1 enzymes act on conjugated steroids and on synthetic therapeutic steroids.
“In addition, these enzymes act on conjugated steroids and synthetic steroids used as therapeutics”
From Role of aldo-keto reductase family 1 (AKR1) enzymes in human steroid metabolism (2014) · cites this paper as [12]
AKR1 enzymes are involved in the metabolism of tibolone, norethynodrel, dydrogesterone, budesonide and flunisolide.
“AKR1 enzymes are involved in the metabolism of tibolone and the progestins, norethynodrel and dydrogesterone (Table 4, Figure 6), as well as the synthetic glucocorticoids budesonide and flunisolide”
From Role of aldo-keto reductase family 1 (AKR1) enzymes in human steroid metabolism (2014) · cites this paper as [12]
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- Authors
- Jin, Y., Duan, L., Chen, M., Penning, T. M., & Kloosterboer, H. J.
- Affiliations
- University of Pennsylvania (US)
- Organon (Netherlands) (NL)
- Corresponding author
- Jin, Yi
- Venue
- The Journal of Steroid Biochemistry and Molecular Biology
- Publisher
- Elsevier BV
- Published
- 2012-04
- Volume
- 129
- Issue
- 3-5
- Pages
- 139-144
- ISSN
- 0960-0760 (ISSN-L)
- PMC
- PMC3303946
- OpenAlex
- W1998191628
- Cited by
- 18
- References
- 37
- Citations by year
- 2025: 1 · 2024: 1 · 2023: 1 · 2022: 2 · 2021: 3 · 2020: 1 · 2018: 1 · 2017: 1 · 2016: 3 · 2015: 1 · 2014: 1 · 2013: 2
- FWCI
- 0.46
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The Journal of Steroid Biochemistry and Molecular Biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (R01-DK47015, R01DK047015)
- National Institute of Environmental Health Sciences (P30-ES13408, P30ES013508)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Aldose Reductase and Taurine
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Steroid Chemistry and Biochemistry
- Keywords
- norethynodrel, aldo-keto reductase superfamily, AKR1C1, AKR1C2, AKR1C3, AKR1C4, steroid metabolism, norethisterone, tibolone, stereoselectivity, enzyme kinetics, progestogens, oral contraceptives, biotransformation
- MeSH terms
- Aldo-Keto Reductase Family 1 Member C3, Contraceptives, Oral, Synthetic, Humans, Hydroxyprostaglandin Dehydrogenases, Hydroxysteroid Dehydrogenases, Hydroxysteroids, Kinetics, Models, Molecular, Norethynodrel, Oxidation-Reduction, Oxidoreductases, Protein Binding, 20-Hydroxysteroid Dehydrogenases, 3-Hydroxysteroid Dehydrogenases, 3-alpha-Hydroxysteroid Dehydrogenase (B-Specific)
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