5α-Dihydroprogesterone
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| IUPAC name
5α-Pregnane-3,20-dione
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| Systematic IUPAC name
(1S,3aS,3bR,5aS,9aS,9bS,11aS)-1-Acetyl-9a,11a-dimethylhexadecahydro-7H-cyclopenta[a]phenanthren-7-one | |
| Other names
Allopregnanedione
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| Identifiers | |
3D model (JSmol)
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| ChEBI | |
| ChemSpider | |
| ECHA InfoCard | 100.008.453 |
PubChemCID
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| UNII | |
CompTox Dashboard(EPA)
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| Properties | |
| C21H32O2 | |
| Molar mass | 316.485g·mol−1 |
Except where otherwise noted, data are given for materials in theirstandard state(at 25 °C [77 °F], 100 kPa).
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5α-Dihydroprogesterone(5α-DHP,allopregnanedione,[1]or5α-pregnane-3,20-dione) is anendogenousprogestogenandneurosteroidthat issynthesizedfromprogesterone.[2][3]It is also anintermediatein the synthesis ofallopregnanoloneandisopregnanolonefrom progesterone.
5α-DHP is metabolized by thealdo-keto reductases(AKRs)AKR1C1,AKR1C2,andAKR1C4with high catalytic efficiency.[4]AKR1C1 preferentially forms 20α-hydroxy-5α-pregnane-3-one while AKR1C2 preferentially forms allopregnanolone.[4]Similarly AKR1C1 reduces and consequently inactivates allopregnanolone into5α-pregnane-3α,20α-diol.[4]In contrast to the other AKRs,AKR1C3has low catalytic efficiency for reduction of 5α-DHP.[4]These AKRs are highly expressed in the humanliverandmammary glandbut have relatively modest expression in the humanbrainanduterus.[5]
5α-DHP is anagonistof theprogesterone receptorand apositive allosteric modulatorof theGABAAreceptor(albeit with anaffinityfor thisreceptorthat is regarded as relatively low (in comparison to 3α-hydroxylated progesteronemetabolitessuch as allopregnanolone andpregnanolone)).[2][3][6][7]It has also been found to act as anegative allosteric modulatorof theGABAA-rho receptor.[8]The steroid has been found to possess 82% of the affinity of progesterone for the progesterone receptor inrhesus monkeyuterus.[9]5α-Dihydroprogesterone has been said to possess about 33% of the relativeprogestogenicpotencyof progesterone.[10]In addition, it is a weak agonist of thepregnane X receptor(PXR) (EC50>10,000 μM), with approximately six-fold lower potency relative to its 5β-isomer,5β-dihydroprogesterone.[11]
Allopregnanolone is transformed back into 5α-DHP by3α-hydroxysteroid oxidoreductase,and conversion of allopregnanolone into 5α-DHP is responsible for the progestogenic activity of allopregnanolone.[6][12][13]5α-DHP, via the progesterone receptor, and allopregnanolone, via theGABAAreceptor,act together to inducelordosisin animals.[12][13]A study found that 41% of allopregnanolone that was administered via injection was transformed into 5α-DHP in the rat brain.[12]
Levels of 5α-DHP have been quantified.[14]
Chemistry
[edit]See also
[edit]References
[edit]- ^Finn, Deborah A.; Purdy, Robert H. (2007). "Neuroactive Steroids in Anxiety and Stress".Handbook of Contemporary Neuropharmacology.doi:10.1002/9780470101001.hcn026.ISBN978-0470101001.
- ^abMellon SH (October 2007)."Neurosteroid regulation of central nervous system development".Pharmacol. Ther.116(1): 107–24.doi:10.1016/j.pharmthera.2007.04.011.PMC2386997.PMID17651807.
- ^abGuidotti A, Dong E, Matsumoto K, Pinna G, Rasmusson AM, Costa E (November 2001). "The socially-isolated mouse: a model to study the putative role of allopregnanolone and 5alpha-dihydroprogesterone in psychiatric disorders".Brain Res. Brain Res. Rev.37(1–3): 110–5.doi:10.1016/s0165-0173(01)00129-1.PMID11744079.S2CID22202599.
- ^abcdRižner TL, Penning TM (January 2014)."Role of aldo-keto reductase family 1 (AKR1) enzymes in human steroid metabolism".Steroids.79:49–63.doi:10.1016/j.steroids.2013.10.012.PMC3870468.PMID24189185.
- ^Penning TM, Burczynski ME, Jez JM, Hung CF, Lin HK, Ma H, Moore M, Palackal N, Ratnam K (October 2000)."Human 3alpha-hydroxysteroid dehydrogenase isoforms (AKR1C1-AKR1C4) of the aldo-keto reductase superfamily: functional plasticity and tissue distribution reveals roles in the inactivation and formation of male and female sex hormones".Biochem. J.351(Pt 1): 67–77.doi:10.1042/bj3510067.PMC1221336.PMID10998348.
- ^abRupprecht R, Reul JM, Trapp T, et al. (September 1993). "Progesterone receptor-mediated effects of neuroactive steroids".Neuron.11(3): 523–30.doi:10.1016/0896-6273(93)90156-l.PMID8398145.S2CID11205767.
- ^Ocvirk, Rok; Pearson Murphy, Beverley E.; Franklin, Keith B.J.; Abbott, Frances V. (2008). "Antinociceptive profile of ring A-reduced progesterone metabolites in the formalin test".Pain.138(2): 402–409.doi:10.1016/j.pain.2008.01.019.ISSN0304-3959.PMID18343034.S2CID32370572.
- ^Johnston GA (2002)."Medicinal chemistry and molecular pharmacology of GABA(C) receptors"(PDF).Curr Top Med Chem.2(8): 903–13.doi:10.2174/1568026023393453.PMID12171579.Archived fromthe original(PDF)on December 26, 2010.
- ^Illingworth DV, Elsner C, De Groot K, Flickinger GL, Mikhail G (February 1977). "A specific progesterone receptor of myometrial cytosol from the rhesus monkey".J. Steroid Biochem.8(2): 157–60.doi:10.1016/0022-4731(77)90040-1.PMID405534.
- ^Rogerio A. Lobo; Jennifer Kelsey; Robert Marcus (22 May 2000).Menopause: Biology and Pathobiology.Academic Press. pp. 433–.ISBN978-0-08-053620-0.
- ^Lehmann JM, McKee DD, Watson MA, Willson TM, Moore JT, Kliewer SA (1998)."The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions".J. Clin. Invest.102(5): 1016–23.doi:10.1172/JCI3703.PMC508967.PMID9727070.
- ^abcBeyer C, González-Flores O, Ramírez-Orduña JM, González-Mariscal G (February 1999). "Indomethacin inhibits lordosis induced by ring A-reduced progestins: possible role of 3alpha-oxoreduction in progestin-facilitated lordosis".Horm Behav.35(1): 1–8.doi:10.1006/hbeh.1998.1457.PMID10049597.S2CID11520064.
- ^abBeyer C, Gonzalez-Flores O, Gonzalez-Mariscal G (November 1995). "Ring A reduced progestins potently stimulate estrous behavior in rats: paradoxical effect through the progesterone receptor".Physiol. Behav.58(5): 985–93.doi:10.1016/0031-9384(95)00141-5.PMID8577898.S2CID25967801.
- ^Trabert B, Falk RT, Stanczyk FZ, McGlynn KA, Brinton LA, Xu X (September 2015)."Reproducibility of an assay to measure serum progesterone metabolites that may be related to breast cancer risk using liquid chromatography-tandem mass spectrometry".Horm Mol Biol Clin Investig.23(3): 79–84.doi:10.1515/hmbci-2015-0026.PMC4966666.PMID26353176.