Pregnenolone
From Wikipedia, the free encyclopedia
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| Systematic (IUPAC) name | |
| 3β-hydroxypregn-5-en-20-one | |
| Clinical data | |
| AHFS/Drugs.com | International Drug Names |
| Pregnancy cat. | ? |
| Legal status | Commercially available |
| Identifiers | |
| CAS number | 145-13-1  |
| ATC code | None |
| PubChem | CID 8955 |
| IUPHAR ligand | 2376 |
| DrugBank | DB02789 |
| UNII | 73R90F7MQ8 |
| ChEMBL | CHEMBL253363  |
| Chemical data | |
| Formula | C21H32O2 |
| Mol. mass | 316.483 g/mol |
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Pregnenolone, 3beta-Hydroxypregn-5-en-20-one is an endogenous steroid hormone involved in the steroidogenesis of progestogens, mineralocorticoids, glucocorticoids, androgens, and estrogens, as well as the neuroactive steroids. As such it is a prohormone, though it also has biological effects of its own, behaving namely as a neuroactive steroid in its own right with potent anxiolytic effects.[1]
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Chemistry [edit]
Like other steroids, pregnenolone consists of four interconnected cyclic hydrocarbons. It contains ketone and hydroxyl functional groups, two methyl branches, and a double bond at C5, in the B cyclic hydrocarbon ring. Like many steroid hormones, it is hydrophobic. Its esterified version, pregnenolone sulfate, is water-soluble.
Biology [edit]
Biosynthesis [edit]
Pregnenolone is synthesized from cholesterol. This conversion involves hydroxylation at the side-chain at C20 and C22 positions, with cleavage of the side-chain. The enzyme performing this task is cytochrome P450scc, located in the mitochondria, and controlled by anterior pituitary tropic hormones, such as ACTH, FSH, LH.
To assay conversion of cholesterol to pregnenolone, radiolabelled cholesterol has been used.[2] Pregnenolone product can be separated from cholesterol substrate using Sephadex LH-20 minicolumns.[2]
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Prohormone activity [edit]
Pregnenolone undergoes further steroid metabolism in one of three ways.
- Pregnenolone can be converted to progesterone. The critical enzyme step is two-fold using a 3-beta-hydroxysteroid dehydrogenase and a delta 4-5 isomerase. The latter transfers the double bond from C5 to C4 on the A ring. Progesterone is the entry into the delta-4-pathway, resulting in production of 17-hydroxy progesterone and androstenedione, precursor to testosterone and estrone. Aldosterone and corticosteroids are also derived from progesterone or its derivatives.
- Pregnenolone can be converted to 17-hydroxy-pregnenolone by the enzyme 17α-hydroxylase (CYP17A1). Using this pathway, termed delta-5 pathway, the next step is conversion to dehydroepiandrosterone (DHEA) using a desmolase. DHEA is the precursor of androstenedione.
- Pregnenolone can be converted to androsta-5,16-dien-3 beta-ol by 16-ene synthetase.
Neurosteroid activity [edit]
Pregnenolone and its sulfate, like DHEA and its sulfate and progesterone, belong to the group of neurosteroids that are found in high concentrations in certain areas of the brain, and are synthesized there. Neurosteroids affect synaptic functioning, are neuroprotective, and enhance myelinization. Pregnenolone and its sulfate ester are under investigation for their potential to improve cognitive and memory functioning.[3] Pregnenolone is also being considered as a potential treatment for schizophrenia.[4]
Interestingly, unlike pregnenolone, pregnenolone sulfate is a negative allosteric modulator of the GABAA receptor[5] as well as a positive allosteric modulator of the NMDA receptor.[6] In addition, it has been shown to activate the transient receptor potential M3 (TRPM3) ion channel in hepatocytes and pancreatic islets causing calcium entry and subsequent insulin release.[7]
Additional images [edit]
References [edit]
- ^ Bitran D, Dugan M, Renda P, Ellis R, Foley M (December 1999). "Anxiolytic effects of the neuroactive steroid pregnanolone (3 alpha-OH-5 beta-pregnan-20-one) after microinjection in the dorsal hippocampus and lateral septum". Brain Research 850 (1-2): 217–24. PMID 10629767.
- ^ a b Hanukoglu, I; Jefcoate, CR (1980). "Pregnenolone separation from cholesterol using Sephadex LH-20 mini-columns". Journal of Chromatography A 190 (1): 256–262. doi:10.1016/S0021-9673(00)85545-4. ISSN 00219673.
- ^ Vallée M, Mayo W, Le Moal M (November 2001). "Role of pregnenolone, dehydroepiandrosterone and their sulfate esters on learning and memory in cognitive aging". Brain Research. Brain Research Reviews 37 (1-3): 301–12. PMID 11744095.
- ^ Marx CE, Bradford DW, Hamer RM, et al. (September 2011). "Pregnenolone as a novel therapeutic candidate in schizophrenia: emerging preclinical and clinical evidence". Neuroscience 191: 78–90. doi:10.1016/j.neuroscience.2011.06.076. PMID 21756978.
- ^ Majewska MD, Mienville JM, Vicini S (August 1988). "Neurosteroid pregnenolone sulfate antagonizes electrophysiological responses to GABA in neurons". Neuroscience Letters 90 (3): 279–84. PMID 3138576.
- ^ Wu FS, Gibbs TT, Farb DH (September 1991). "Pregnenolone sulfate: a positive allosteric modulator at the N-methyl-D-aspartate receptor". Molecular Pharmacology 40 (3): 333–6. PMID 1654510.
- ^ Wagner TF, Loch S, Lambert S, et al. (December 2008). "Transient receptor potential M3 channels are ionotropic steroid receptors in pancreatic beta cells". Nature Cell Biology 10 (12): 1421–30. doi:10.1038/ncb1801. PMID 18978782.
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