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.

Comparison of the induction profile for drug disposition proteins by typical nuclear receptor activators in human hepatic and intestinal cells.

Abstract: Background and purpose: Certain nuclear receptors (NRs) such as the constitutive androstane receptor (CAR), pregnane X receptor (PXR) and farnesoid X receptor (FXR) mediate induction of some cytochrome P450 enzymes and ABC transporters but conflicting reports exist. The purpose of this study was to assess the reasons for these discrepancies and use a standardized approach to compare activators of NRs. Experimental approach: Dexamethasone, pregnenolone 16α-carbonitrile, rifampicin, phenobarbital and chenodeoxycholic acid were incubated with HepG2, Caco-2 and cryopreserved human hepatocytes prior to analysis of mRNA and protein for CYP2B6, CYP3A4, CYP3A5, ABCB1, ABCC1, ABCC2, PXR, CAR and FXR. Key results: Dexamethasone significantly up-regulated PXR, CYP3A4 and ABCB1 expression in HepG2 and Caco-2 cells. As a result, including dexamethasone as a media supplement masked the induction of these genes by pregnenolone 16α-carbonitrile, which may explain discrepancies between previous reports. In the absence of dexamethasone, significant activator-dependent induction was observed in all cell types. Significant correlations were observed between the fold increase in mRNA and in protein, which were, for most instances, logarithmic. Changes in mRNA expression were greater in cell lines than primary cells but for most transcripts correlations were observed between fold increases in HepG2 and hepatocytes. Conclusions and implications: Clearly, no in vitro system can imitate the physiology of a hepatocyte or intestinal cell within an intact organ in vivo, but these data explain some of the discrepancies reported between laboratories and have important implications for study design. British Journal of Pharmacology (2008) 153, 805–819; doi:10.1038/sj.bjp.0707601; published online 26 November 2007

Serum Pregnenolone, Progesterone, 17-Hydroxyprogesterone, Testosterone and 5α-Dihydrotestosterone During Female Puberty

Abstract: Serum pregnenolone, progesterone, 17-hydroxyprogesterone, testosterone and 5α-dihydrotestosterone concentrations were measured radio-immunologically from a group of 200 normal girls 7–17 years of age. Samples from postmenarcheal girls were taken on days 6–9 and 20–23 of the menstrual cycle. Steroid concentrations were related to bone age, breast and pubic hair developmental stages, and gynecological age. When the premenarcheal values and the values from postmenarcheal samples taken on days 6–9 were related to bone age, the concentrations of all the five steroids increased with advancing age. The first steroid to exhibit a significant rise was pregnenolone. This rise was first seen between the bone age groups 7.5 and 8.5 years. Testosterone was quite unchanged until 9.5 years of bone age, after which a steep increase took place until 12.5 years, the concentrations reached being 3.5-fold the initial level. Following menarche, which took place at 13.4 years of bone age in this series, a plateau was visible i...

Chemistry, binding affinities, and behavioral properties of a new class of "antineophobic" mitochondrial DBI receptor complex (mDRC) ligands

Abstract: The mitochondrial DBI receptor complex (mDRC; previously called the peripheral benzodiazepine receptors) is linked to the production of neurosteroids such as pregnenolone sulfate, dehydroepiandrosterone sulfate, and others. In order to gain further information as to the function of the mDRC in the brain, we have constructed and tested both in vitro and in vivo a novel series of ligands, 2-arylindole-3-acetamides. The SAR studies detailed herein delineate some of the structural features required for high affinity binding to the mDRCs. In most cases the new ligands were prepared by use of the Fischer indole synthesis. Variations in the length and number of the alkyl groups on the amide nitrogen were probed together with the effects of halogen substituents on one or both of the aryl rings. Some ligands were also synthesized for study which represent conformationally constrained versions of the parent structure. Broad screening studies revealed these indoleacetamides to be highly selective for the mDRC, since they failed to bind with any significant affinity to other receptor systems. Some of the ligands were found to exhibit Ki values in the low nanomolar range for the mDRC as measured by the displacement of [3H]4'-chlorodiazepam. A subset of these ligands was also shown to stimulate pregnenolone formation from the mitochondria of C6-2B glioma cells with an EC50 of about 3 nM. In animal experiments ligands selected for further study were found to exhibit antineophobic effects, in spite of the fact that they exhibit no direct action on GABAA receptors. Consequently, it is postulated that these ligands owe their action to an indirect modulation of GABAA receptor function, presumably by stimulation of neurosteroid production and release from glial cells, followed by neurosteroid modulation of GABA's action on the chloride ion channel conductance of GABAA receptors.