Topic
Pregnenolone
About: Pregnenolone is a research topic. Over the lifetime, 3539 publications have been published within this topic receiving 126444 citations. The topic is also known as: (3b)-3-hydroxy-Pregn-5-en-20-one & 3-Hydroxypregn-5-en-20-one.
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TL;DR: The different pathways of biosynthesis are described, by which steroid hormones are produced in vivo in the gonads, the adrenal cortex and the placenta, or in vitro by corresponding tissue preparations, and compounds which block one or other of the biosynthetic steps are discussed.
Abstract: The different pathways of biosynthesis are described, by which steroid hormones are producedin vivo in the gonads, the adrenal cortex and the placenta, orin vitro by corresponding tissue preparations. First of all a short outline of the origin of cholesterol from acetyl coenzyme A through the ‘biological isoprene unit’, the pyrophosphate of Δ3-iso-pentenol, through squalene, lanosterol and zymosterol is given. Partial side-chain degradation of cholesterol, where ACTH plays an important role, leads to pregnenolone and further to progesterone. The latter compounds are the starting material for the other steroid hormones. On the one hand, they are converted in the gonads and adrenals into 17α-hydroxy derivatives, in which the side chain is completely removed by enzymes of the said and also of non-endocrine tissues, to form the androgens. Furthermore the adrenals produce their own typical androgens. After hydroxylation of the angular 19-methyl group, androgens are aromatised to estrogens. On the other hand, the adrenal converts progesterone by hydroxylation in 21- and, depending on the case, also in 11- and/or 17-position into the classical adrenocortical hormones. The special feature of an 18-hydroxylation and -dehydrogenation forms part of the biogenesis of aldosterone; a new example is given for the methods used towards its elucidation, consisting in the biosynthetic conversion of progesterone into two virtual intermediates, 18-oxo-progesterone and 21-desoxyaldosterone, which already contain the 18-aldehyde group, characteristic for aldosterone. The regulation of the biogenesis of the different hormones is mentioned and compounds are discussed which block one or other of the biosynthetic steps.
55 citations
TL;DR: Results indicate that the Leydig cell enzyme activities responsible for converting PREG to PROG are distributed in the Leydenig cell SER fraction which remains in Leydigs cell cytoplasm 10 days after LH withdrawal, and thus, the bulk of these enzyme activities are sequested in a SER compartment that is resistant to LH withdrawal.
Abstract: Depletion of endogenous LH with sc implants of testosterone-17β-estradiol (T-E) caused a reduction in the Leydig cell smooth endoplasmic reticulum (SER) over a 10-day treatment period. Decreases also occurred in some, but not all, of the testicular steroidogenic reactions responsible for the conversion of pregnenolone (PREG) to testosterone. The conversions of progesterone (PROG) to 17α-hydroxyprogesterone, 17α hydroxyprogesterone to androstenedione, and androstenedione to testosterone were significantly correlated (P < 0.05) with the loss of Leydig cell SER. In contrast, the testicular conversion of PREG to PROG in rats deprived of endogenous LH for up to 10 days was identical to that in intact controls. Similar results were obtained when rats were hypophysectomized for 10 days. These results indicate that the Leydig cell enzyme activities responsible for converting PREG to PROG are distributed in the Leydig cell SER fraction which remains in Leydig cell cytoplasm 10 days after LH withdrawal, and thus, t...
55 citations
TL;DR: It is concluded that early ACTH-induced effects on cellular steroidogenesis result from changes in mitochondrial free cholesterol, and that changes from 4 to 24 h result from a progressive stimulation by ACTH of 17 alpha-hydroxylase activity that is maintained even when stimulation of total steroidogenesis has stopped.
55 citations
TL;DR: Evidence was obtained that phosphorylation or sulphation are obligatory steps in cholesterol oxidation by adrenal-cortex mitochondria and that the 3beta-hydroxyl group was necessary for inhibitory activity.
Abstract: 1. Cholesteryl 3beta-sulphate is oxidized in vitro by preparations of bovine adrenal-cortex mitochondria to pregnenolone sulphate and isocaproic acid (4-methyl-pentanoic acid) without hydrolysis of the ester linkage. 2. Free cholesterol is the preferred substrate for adrenal-cortex cholesterol oxidase; the apparent K(m) for cholesteryl sulphate is 500mum and for free cholesterol 50mum under the same conditions. 3. Cholesteryl 3beta-acetate is hydrolysed by bovine adrenal-cortex mitochondria in vitro to free cholesterol, which is subsequently oxidized to more polar steroids and isocaproic acid. Evidence was obtained that other cholesterol esters behave similarly. Cholesterol esters may thus act as precursors of steroid hormones. 4. Cholest-4-en-3-one is only poorly oxidized to isocaproic acid and more polar steroids and thus is probably not a significant precursor of steroid hormones. 5. Cholesteryl esters inhibit the oxidation of cholesterol competitively (K(i) for cholesteryl phosphate 28mum, for cholesteryl sulphate 110mum, for cholesteryl acetate 65mum) but pregnenolone esters do not inhibit this system. 6. Pregnenolone and 20alpha-hydroxycholesterol (both metabolites of cholesterol in this system) inhibit the oxidation of cholesterol non-competitively. K(i) for pregnenolone is 130mum and K(i) for 20alpha-hydroxycholesterol is 17mum. 7. 25-Oxo-27-norcholesterol inhibits cholesterol oxidation non-competitively (K(i)16mum). A number of other Delta(5)-3beta-hydroxy steroids inhibit cholesterol oxidation and evidence was obtained that the 3beta-hydroxyl group was necessary for inhibitory activity. 8. Pregnenolone, 20alpha-hydroxycholesterol and 25-oxo-27-norcholesterol inhibit oxidation of cholesteryl sulphate by this system but their sulphates do not. 9. 3beta-Hydroxychol-5-enoic acid, 3alpha-hydroxy-5beta-cholanic acid and 3beta-hydroxy-22,23-bisnorchol-5-enoic acid stimulated formation of isocaproic acid from cholesterol. 10. No evidence was obtained that phosphorylation or sulphation are obligatory steps in cholesterol oxidation by adrenal-cortex mitochondria. 11. The cholesteryl 3beta-sulphate sulphatase of bovine adrenal cortex was found mostly in the microsomal fraction and was inhibited by inorganic phosphate.
55 citations
TL;DR: A marked lack of mitochondrial specificity towards the steroid side chains is in direct contrast with the rat liver microsomal cholesterol 7alpha-hydroxylase, which has a high specificity for the side chain.
Abstract: The rate of oxidation of cholesterol and its analogues to pregnenolone (3beta-hydroxypregn-5-en-20-one) by various mitochondrial preparations was measured. Sterols with the cholest-5-en-3beta-ol ring system and saturated side chains of different lengths were converted into pregnenolone rat rates similar to that of cholesterol. This marked lack of mitochondrial specificity towards the steroid side chains is in direct contrast with the rat liver microsomal cholesterol 7alpha-hydroxylase, which has a high specificity for the side chain. Steroids that retain the ring system, but contain hydroxyl groups at various points in the side chain, are converted into pregnenolone at rates three to eight times higher than in cholesterol. The results are discussed with reference to current ideas on the mechanism of the side-chain cleavage of cholesterol. The results are discussed with reference to current ideas on the mechanism of the side-chain cleavage of cholesterol.
55 citations