Pregnenolone, 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.
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. Pregnenolone product can
be separated from cholesterol substrate using Sephadex LH-20 minicolumns.
= 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. Using this pathway, termed delta-5 pathway, the next step is
conversion to dehydroepiandrosterone 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. Pregnenolone is also being considered as a potential treatment for
schizophrenia. Interestingly, unlike pregnenolone,
pregnenolone sulfate is a negative allosteric modulator of the GABAA
receptor as well as a positive allosteric modulator of the NMDA
receptor. In addition, it has been shown to activate the transient receptor
potential M3 ion channel in hepatocytes and pancreatic islets causing calcium
entry and subsequent insulin release. Pregnenolone, a molecule produced by the
brain, acts as a natural defense mechanism against effects of
cannabis/marijuana in animals. 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
References