(副腎皮質ホルモン前駆体;神経ステロイド)レグネノロン

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2014/04/14 15:09:07」(JST)

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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.^{[citation needed]}

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. Its esterified version, 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.^[1] Pregnenolone product can be separated from cholesterol substrate using Sephadex LH-20 minicolumns.^[1]

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.^[2] Pregnenolone is also being considered as a potential treatment for schizophrenia.^[3]

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. 2 major behavioral problems are associated with regular cannabis use in humans: cognitive deficits and a general loss of motivation(http://www.eurekalert.org/pub_releases/2014-01/ind-mdt010214.php , http://en.wikipedia.org/wiki/Pregnenolone , http://en.wikipedia.org/wiki/Tetrahydrocannabinol and http://en.wikipedia.org/wiki/Cannabis)

Additional images

Cholesterol
Progesterone

References

^ ^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.
^ 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.
^ 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.
^ 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. PMID 1387199.
^ 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.
^ http://www.eurekalert.org/pub_releases/2014-01/ind-mdt010214.php

UpToDate Contents

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1. 副腎ステロイド生合成 adrenal steroid biosynthesis
2. 微細欠失症候群（12番～22番染色体） microdeletion syndromes chromosomes 12 to 22
3. 血清および唾液中のコルチゾールの測定 measurement of cortisol in serum and saliva
4. 男性生殖生理学 male reproductive physiology
5. 正常な副腎皮質性第二次性徴 normal adrenarche

English Journal

Pregnane X receptor agonists enhance intestinal epithelial wound healing and repair of the intestinal barrier following the induction of experimental colitis.

Terc J1, Hansen A1, Alston L1, Hirota SA2.Author information 1Departments of Physiology & Pharmacology, University of Calgary, 3330 Hospital Dr. NW, Health Sciences Room 1802, Calgary, Alberta T2N4N1, Canada; Microbiology, Immunology & Infectious Diseases, University of Calgary, 3330 Hospital Dr. NW, Health Sciences Room 1802, Calgary, Alberta T2N4N1, Canada.2Departments of Physiology & Pharmacology, University of Calgary, 3330 Hospital Dr. NW, Health Sciences Room 1802, Calgary, Alberta T2N4N1, Canada; Microbiology, Immunology & Infectious Diseases, University of Calgary, 3330 Hospital Dr. NW, Health Sciences Room 1802, Calgary, Alberta T2N4N1, Canada. Electronic address: simon.hirota@ucalgary.ca.AbstractThe intestinal epithelial barrier plays a key role in the maintenance of homeostasis within the gastrointestinal tract. Barrier dysfunction leading to increased epithelial permeability is associated with a number of gastrointestinal disorders including the inflammatory bowel diseases (IBD) - Crohn's disease and ulcerative colitis. It is thought that the increased permeability in patients with IBD may be driven by alterations in the epithelial wound healing response. To this end considerable study has been undertaken to identify signaling pathways that may accelerate intestinal epithelial wound healing and normalize the barrier dysfunction observed in IBD. In the current study we examined the role of the pregnane X receptor (PXR) in modulating the intestinal epithelial wound healing response. Mutations and reduced mucosal expression of the PXR are associated with IBD, and others have reported that PXR agonists can dampen intestinal inflammation. Furthermore, stimulation of the PXR has been associated with increased cell migration and proliferation, two of the key processes involved in wound healing. We hypothesized that PXR agonists would enhance intestinal epithelial repair. Stimulation of Caco-2 intestinal epithelial cells with rifaximin, rifampicin and SR12813, all potent agonists of the PXR, significantly increased wound closure. This effect was driven by p38 MAP kinase-dependent cell migration, and occurred in the absence of cell proliferation. Treating mice with a rodent specific PXR agonist, pregnenolone 16α-carbonitrile (PCN), attenuated the intestinal barrier dysfunction observed in the dextran sulphate sodium (DSS) model of experimental colitis, an effect that occurred independent of the known anti-inflammatory effects of PCN. Taken together our data indicate that the activation of the PXR can enhance intestinal epithelial repair and suggest that targeting the PXR may help to normalize intestinal barrier dysfunction observed in patients with IBD. Furthermore, our data provide additional insight into the potential mechanisms through which rifaximin elicits its clinical efficacy in the treatment of IBD.
European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.Eur J Pharm Sci.2014 May 13;55:12-9. doi: 10.1016/j.ejps.2014.01.007. Epub 2014 Jan 29.
The intestinal epithelial barrier plays a key role in the maintenance of homeostasis within the gastrointestinal tract. Barrier dysfunction leading to increased epithelial permeability is associated with a number of gastrointestinal disorders including the inflammatory bowel diseases (IBD) - Crohn's
PMID 24486481

Ligand-based virtual screening to predict inhibitors against metastatic lymph node 64.

Chitrala KN1, Yeguvapalli S.Author information 1Department of Zoology, Sri Venkateswara University , Tirupati, Andhra Pradesh , India.AbstractAbstract Conversion of cholesterol to pregnenolone is the rate-limiting step in steroidogenesis, which is mediated by StAR protein. The mammalian genome contains 15 START domain proteins (StARD1-StARD15) of which C-terminal cytosolic START domain of metastatic lymph node 64 (MLN64 or StARD3), is known to mobilize cholesterol and proposed to participate in steroidogenesis. Being a key in steroidogenesis, it is of interest to identify new inhibitors that are able to bind MLN64 protein. In the present study, we used ligand-based virtual screening approach to identify ligands from the ZINC database with D(-)-Tartaric Acid (TAR) serving as a template.
Journal of receptor and signal transduction research.J Recept Signal Transduct Res.2014 Apr;34(2):92-6. doi: 10.3109/10799893.2013.862269. Epub 2013 Dec 9.
Abstract Conversion of cholesterol to pregnenolone is the rate-limiting step in steroidogenesis, which is mediated by StAR protein. The mammalian genome contains 15 START domain proteins (StARD1-StARD15) of which C-terminal cytosolic START domain of metastatic lymph node 64 (MLN64 or StARD3), is kno
PMID 24320143

Identification and stress-induced expression of three 3β-hydroxysteroid dehydrogenases from Erysimum crepidifolium Rchb. and their putative role in cardenolide biosynthesis.

Munkert J1, Ernst M1, Müller-Uri F1, Kreis W2.Author information 1Pharmaceutical Biology, Department Biology, Friedrich-Alexander University Erlangen-Nürnberg, Staudtstr. 5, 91058 Erlangen, Germany.2Pharmaceutical Biology, Department Biology, Friedrich-Alexander University Erlangen-Nürnberg, Staudtstr. 5, 91058 Erlangen, Germany; ECROPS Erlangen Center of Plant Science, Germany. Electronic address: wolfgang.kreis@fau.de.Abstract3β-Hydroxysteroid dehydrogenases (3βHSD) are supposed to be involved in cardenolide biosynthesis in plants. Erysimum crepidifolium Rchb., a member of the Brassicaceae accumulating cardenolides, is a close relative to Arabidopsis thaliana. Full length cDNAs encoding for three individual 3βHSDs (EcHSD1, EcHSD2, EcHSD3) were isolated from E. crepidifolium leaves. EcHSD1 and EcHSD2 encode proteins assembled from 257 amino acids whereas EcHSD3 encodes a protein assembled from 260 amino acids. All three proteins qualify as members of the short-chain dehydrogenases/reductases family of proteins (SDRs). EcHSD1 and EcHSD2 shared a high amino acid sequence identity of about 86% and 91% with putative 3βHSDs of A. thaliana (AT2G47140 and AT2G47130). EcHSD3 showed high homology to the A. thaliana SDRs AT2G47150 (74%) and AT2G47120 (81%). All three EcHSD genes were expressed in Escherichia coli and the recombinant enzymes were characterized biochemically. All three recombinant EcHSDs catalyzed the dehydrogenation of pregnenolone and the 3-reduction of 5α/β-pregnane-3,20-dione when NAD and NADH were used as cosubstrates, respectively. After exposure to different stress conditions, no increased transcription was seen for EcHSD1 whereas EcHSD2 was expressed four times higher under osmotic stress than under control conditions. EcHSD3 expression was 10 times and 6 times higher after osmotic stress and MeJA treatment, respectively, than in controls.
Phytochemistry.Phytochemistry.2014 Apr;100:26-33. doi: 10.1016/j.phytochem.2014.01.006. Epub 2014 Feb 7.
3β-Hydroxysteroid dehydrogenases (3βHSD) are supposed to be involved in cardenolide biosynthesis in plants. Erysimum crepidifolium Rchb., a member of the Brassicaceae accumulating cardenolides, is a close relative to Arabidopsis thaliana. Full length cDNAs encoding for three individual 3βHSDs (Ec
PMID 24512841

Japanese Journal

Effect of Polyphenols on Production of Steroid Hormones from Human Adrenocortical NCI-H295R Cells

Hasegawa Eri,Nakagawa Saori,Sato Momoe [他]
Biological & pharmaceutical bulletin 36(2), 228-237, 2013-02-00
NAID 40019558450

A condensed phenylpropanoid glucoside and pregnane saponins from the roots of Hemidesmus indicus

Zhao Zhimin,Matsunami Katsuyoshi,Otsuka Hideaki [他]
Journal of natural medicines 67(1), 137-142, 2013-00-00
NAID 40019527742

Effect of Polyphenols on Production of Steroid Hormones from Human Adrenocortical NCI-H295R Cells

Hasegawa Eri,Nakagawa Saori,Sato Momoe,Tachikawa Eiichi,Yamato Susumu
Biological and Pharmaceutical Bulletin 36(2), 228-237, 2013
… Here we cultured forskolin-stimulated NCI-H295R, a human adrenocortical carcinoma cell line, in the presence of a polyphenol and employed GC-MS to simultaneously determine the levels of nine steroid hormones (pregnenolone, progesterone, deoxycorticosterone, aldosterone, 17α-hydroxyprogesterone, dehydroepiandrosterone, androstenedione, testosterone, and estradiol) in cell culture supernatant. …
NAID 130003361368

Related Pictures

★リンクテーブル★

リンク元	「副腎皮質ホルモン」「プレグネノロン」
拡張検索	「pregnenolone 16alpha-carbonitrile」「pregnenolone carbonitrile」「17-alpha-hydroxypregnenolone」

「副腎皮質ホルモン」

Pregnenolone
Systematic (IUPAC) name
	3β-hydroxypregn-5-en-20-one
Clinical data
AHFS/Drugs.com	International Drug Names
Legal status	Commercially available
Identifiers
CAS number	145-13-1
ATC code	None
PubChem	CID 8955
IUPHAR ligand	2376
DrugBank	DB02789
UNII	73R90F7MQ8
ChEBI	CHEBI:16581
ChEMBL	CHEMBL253363
Chemical data
Formula	C21H32O2
Mol. mass	316.483 g/mol
	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 ;
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　　[★]

英: adrenocortical hormone
同: 副腎皮質ステロイド adrenocorticoids
関: 副腎皮質刺激ホルモン放出ホルモン、副腎皮質刺激ホルモン; ステロイド
関: 副腎、副腎皮質、ステロイド、コルチコステロイド、ステロイドホルモン、コルチコイド。副腎皮質ホルモン剤

図：SP.891(組織),892(構造式)
副腎皮質の球状層、索状層、網状層で合成される

種類(主要なもののみ)

電解質コルチコイド

球状層から分泌される。アルドステロン

糖質コルチコイド

索状層から分泌される。コルチゾール

副腎アンドロジェン

網状層から分泌される。アンドロステンジオン

コレステロール cholesterol
↓CYP11A1
プレグネノロン pregnenolone	－－→ CYP17 17α-hydroxylase	17α-ヒドロキシプレグネノロン 17α-hydroxypregnenolone	－－→ CYP17 17α-hydroxylase	デヒドロエピアンドロステロン dehydroepiandrosterone DHEA
↓3β-HSD 3β-hydroxysteroid dehydrogenase		↓3β-HSD		↓3β-HSD
プロゲステロン progesterone	－－→ CYP17 17α-hydroxylase	17α-ヒドロキシプロゲステロン 17α-hydroxyprogesterone	－－→ CYP17 17α-hydroxylase	アンドロステンジオン androstenedione Δ⁴androstene-3,17-dion
↓CYP21 21-hydroxylase		↓CYP21 21-hydroxylase
デオキシコルチコステロン deoxycorticosterone		11-デオキシコルチゾール 11-deoxycortisol
↓CYP11B2　11β-hydroxylase		↓CYP11B1　11β-hydroxylase
コルチコステロン corticosterone		コルチゾール cortisol
↓CYP11B2 18-hydroxylase
18-ヒドロキシコルチコステロン 18-hydroxycorticosterone
↓CYP11B2 18-hydroxydehydrogenase
アルドステロン aldosterone

球状増 zona glomerulosa		索状層 zona fasciculata		網状層 zona reticularis

臨床関連

21-hydroxylaseが正常に機能しないことにより生じる (L.320)

薬理学

副腎皮質ホルモン製剤

副腎皮質から分泌されるホルモン (SP.895)

名称		血漿濃度 (ng/ml)	1日分泌量 (mg/day)
糖質コルチコイド	コルチゾール	40～180	15～20
糖質コルチコイド	コルチコステロン	2～6	2～5
鉱質コルチコイド	アルドステロン	0.05～0.20	0.05～0.15
鉱質コルチコイド	11-DOC	0.05～0.30	0.10～0.20
副腎アンドロジェン	DHEA	2～8	7～15
	DHEA-S	1～4
	アンドロステンジオン	1～2	2～3