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Pregnenolone ( P5), or pregn-5-en-3β-ol-20-one, is an and precursor/metabolic intermediate in the of most of the , including the , , , , and mineralocorticoids. In addition, pregnenolone is biologically active in its own right, acting as a .

In addition to its role as a natural hormone, pregnenolone has been used as a and supplement; for information on pregnenolone as a medication or supplement, see the pregnenolone (medication) article.


Biological function
Pregnenolone and its 3β-, pregnenolone sulfate, like dehydroepiandrosterone (DHEA), , and , 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 , and enhance . Pregnenolone and its sulfate ester may improve cognitive and function. In addition, they may have protective effects against .


Biological activity

Neurosteroid activity
Pregnenolone is an allosteric , as it is a negative allosteric modulator of the CB1 receptor. Pregnenolone is involved in a natural negative feedback loop against CB1 receptor activation in animals. It prevents CB1 receptor like tetrahydrocannabinol, the main active constituent in cannabis, from fully activating the CB1.Vallée, M., Vitiello, S., Bellocchio, L., Hébert-Chatelain, E., Monlezun, S., Martin-Garcia, E., Kasanetz, F., Baillie, GL., Panin, F., Cathala, A., Roullot-Lacarrière, V., Fabre, S., Hurst, DP., Lynch, DL., Shore, DM., Deroche-Gamonet, V., Spampinato, U., Revest, JM., Maldonado, R., Reggio, PH., Ross, RA., Marsicano, G., Piazza, PV. [1], "Pregnenolone Can Protect the Brain from Cannabis Intoxication", Science, January 2014 Science 343(6166):94-8. A related compound AEF0117 has been derived from pregnenolone and is more specific for this type of activity.

Pregnenolone has been found to bind with high, affinity to microtubule-associated protein 2 (MAP2) in the brain. In contrast to pregnenolone, pregnenolone sulfate did not bind to . However, progesterone did and with similar affinity to pregnenolone, although unlike pregnenolone, it did not increase binding of MAP2 to . Pregnenolone was found to induce tubule polymerization in neuronal cultures and to increase growth in PC12 cells treated with nerve growth factor. As such, pregnenolone may control formation and stabilization of microtubules in neurons and may affect both neural development during prenatal development and neural plasticity during .

Although pregnenolone itself does not possess these activities, its pregnenolone sulfate is a negative allosteric modulator of the as well as a positive allosteric modulator of the . In addition, pregnenolone sulfate has been shown to activate the transient receptor potential M3 (TRPM3) in and pancreatic islets causing entry and subsequent release.


Nuclear receptor activity
Pregnenolone has been found to act as an of the pregnane X receptor.

Pregnenolone has no , , , , or activity.


Biochemistry

Biosynthesis
Pregnenolone is from . This conversion involves of the at the C20 and C22 positions, with of the . The performing this task is cytochrome P450scc, located in the , and controlled by anterior pituitary , such as adrenocorticotropic hormone, follicle-stimulating hormone, and luteinizing hormone, in the and . There are two intermediates in the transformation of cholesterol into pregnenolone, 22 R-hydroxycholesterol and 20α,22 R-dihydroxycholesterol, and all three steps in the transformation are catalyzed by P450scc.
(2025). 9780781768795, Lippincott Williams & Wilkins. .
Pregnenolone is produced mainly in the , the , and the . Although pregnenolone is also produced in the gonads and brain, most circulating pregnenolone is derived from the .

To assay conversion of cholesterol to pregnenolone, radiolabeled cholesterol has been used. Pregnenolone product can be separated from cholesterol substrate using Sephadex LH-20 minicolumns.


Distribution
Pregnenolone is and readily crosses the blood–brain barrier. This is in contrast to pregnenolone sulfate, which does not cross the blood–brain barrier.
(2010). 9781420085600, CRC Press. .
(2008). 9780470513996, John Wiley & Sons. .


Metabolism
Pregnenolone undergoes further steroid in one of several ways:

  • Pregnenolone can be converted into . The critical enzyme step is two-fold using a 3β-hydroxysteroid dehydrogenase and a Δ5-4 isomerase. The latter transfers the from C5 to C4 on the A ring. Progesterone is the entry into the Δ4 pathway, resulting in production of 17α-hydroxyprogesterone and , precursor to and . and are also derived from progesterone or its derivatives.
  • Pregnenolone can be converted to 17α-hydroxypregnenolone by the enzyme 17α-hydroxylase (CYP17A1). Using this pathway, termed Δ5 pathway, the next step is conversion to dehydroepiandrosterone (DHEA) via 17,20-lyase (CYP17A1). DHEA is the precursor of androstenedione.
  • Pregnenolone can be converted to by 16-ene synthase (CYP17A1).
  • Pregnenolone can be converted to pregnenolone sulfate by steroid sulfotransferase, and this conversion can be reversed by steroid sulfatase.


Levels
Normal circulating levels of pregnenolone are as follows:

  • Men: 10 to 200 ng/dL
  • Women: 10 to 230 ng/dL
  • Children: 10 to 48 ng/dL
  • Adolescent boys: 10 to 50 ng/dL
  • Adolescent girls: 15 to 84 ng/dL

Mean levels of pregnenolone have been found not to significantly differ in postmenopausal women and elderly men (40 and 39 ng/dL, respectively).

Studies have found that pregnenolone levels are not significantly changed after surgical or medical castration in men, which is in accordance with the fact that pregnenolone is mainly derived from the adrenal glands.

(2012). 9789400955882, Springer Science & Business Media. .
Conversely, medical castration has been found to partially suppress pregnenolone levels in premenopausal women. Similarly, an premenopausal woman showed incompletely diminished circulating pregnenolone levels.


Chemistry
Pregnenolone is also known chemically as pregn-5-en-3β-ol-20-one.
(2014). 9781475720853, Springer. .
(2025). 9783887630751, Taylor & Francis. .
Like other , it consists of four interconnected cyclic hydrocarbons. The compound contains and , two branches, and a at C5, in the B cyclic hydrocarbon ring. Like many steroid hormones, it is . The derivative, pregnenolone sulfate, is water-soluble.

3β-Dihydroprogesterone (pregn-4-en-3β-ol-20-one) is an of pregnenolone in which the C5 has been replaced with a C4 double bond.


History
Pregnenolone was first synthesized by and colleagues in 1934.

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