Pregnenolone

Pregnenolone

Systematic (IUPAC) name
3β-hydroxypregn-5-en-20-one
Clinical data
AHFS/Drugs.com	International Drug Names
Routes of administration	oral, transdermal
Legal status	Commercially available
Identifiers
CAS Number	145-13-1
ATC code	none
PubChem	CID 8955
IUPHAR/BPS	2376
DrugBank	DB02789
ChemSpider	8611
UNII	73R90F7MQ8
ChEBI	CHEBI:16581
ChEMBL	CHEMBL253363
Chemical data
Formula	C21H32O2
Molar mass	316.483 g/mol
SMILES CC(=O)[C@H]1CC[C@@H]2[C@@]1(CC[C@H]3[C@H]2CC=C4[C@@]3(CC[C@@H](C4)O)C)C
InChI InChI=1S/C21H32O2/c1-13(22)17-6-7-18-16-5-4-14-12-15(23)8-10-20(14,2)19(16)9-11-21(17,18)3/h4,15-19,23H,5-12H2,1-3H3/t15-,16-,17+,18-,19-,20-,21+/m0/s1 Key:ORNBQBCIOKFOEO-QGVNFLHTSA-N
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Pregnenolone (3β-hydroxypregn-5-en-20-one), also known as P5, is an endogenous steroid hormone. It is the precursor of the progestogens, mineralocorticoids, glucocorticoids, androgens, and estrogens, as well as the neuroactive steroids. In addition, pregnenolone is biologically active in its own right, acting as a neurosteroid.^[1]

Chemistry

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. The sulfated derivative, pregnenolone sulfate, is water-soluble.

Biology

Biosynthesis

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]

Steroidogenesis, showing pregnenolone near top left.

Production of pregnenolone from cholesterol and further metabolism. Reaction: pregnenolone → progesterone.

Prohormone activity

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

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.^[1]

Interestingly, unlike pregnenolone, pregnenolone sulfate is a negative allosteric modulator of the GABA_A receptor^[4] as well as a positive allosteric modulator of the NMDA receptor.^[5][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]

Pregnenolone, a molecule produced by the brain, acts as a natural defense mechanism against effects of cannabis/marijuana in animals.^[8] Pregnenolone prevents THC/Tetrahydrocannabinol, the main active principle in cannabis, from fully activating its brain receptor, the CB1 receptor, that when overstimulated by THC/Tetrahydrocannabinol causes the intoxicating effects of cannabis/marijuana.

Additional images

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  Cholesterol

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  Progesterone

References

1. 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.
2. 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.
3. 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. doi:10.1016/S0165-0173(01)00135-7. PMID 11744095.
4. Majewska MD, Mienville JM, Vicini S (August 1988). "Neurosteroid pregnenolone sulfate antagonizes electrophysiological responses to GABA in neurons". Neuroscience Letters 90 (3): 279–84. doi:10.1016/0304-3940(88)90202-9. PMID 3138576.
5. 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.
6. Irwin RP, Maragakis NJ, Rogawski MA, Purdy RH, Farb DH, Paul SM (July 1992). "Pregnenolone sulfate augments NMDA receptor mediated increases in intracellular Ca2+ in cultured rat hippocampal neurons". Neurosci Lett 141 (1): 30–4. doi:10.1016/0304-3940(92)90327-4. PMID 1387199.
7. 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.
8. http://www.eurekalert.org/pub_releases/2014-01/ind-mdt010214.php