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At least 19 recordsLinked to original sources
PubMed1989

Conversion of 5 alpha-pregnane-3,20-dione, 3 alpha-hydroxy-5 alpha-pregnan-20-one and 3 beta-hydroxy-5 alpha-pregnan-20-one to delta 16-C19 steroids by the reconstituted delta 16-C19-steroid synthetase system.

The substrate specificity of the reconstituted delta 16-C19-steroid synthetase system, which catalyzes the formation of 5,16-androstadien-3 beta-ol or 4,16-androstadien-3-one from pregnenolone or progesterone, respectively, was studied. The reconstituted system consisted of a partially purified cytochrome P-450, NADPH-cytochrome P-450 reductase, cytochrome b5 and NADH-cytochrome b5 reductase all from pig testicular microsomes. It was found that 5 alpha-reduced C21 steroids such as 5 alpha-pregnane-3,20-dione, 3 alpha-hydroxy-5 alpha-pregnan-20-one and 3 beta-hydroxy-5 alpha-pregnan-20-one can be substrates for the enzyme system, resulting in the formation of 5 alpha-androst-16-en-3-one, 5 alpha-androst-16-en-3 alpha-ol and 5 alpha-androst-16-en-3 beta-ol, respectively. The results suggest that 5 alpha-reduced delta 16-C19 steroids might be synthesized from pregnenolone and progesterone via 5 alpha-reduced C21 steroids as intermediates. The pathways would bypass 5,16-androstadien-3 beta-ol and 4,16-androstadien-3-one which have been assumed as obligatory intermediates in the formation of 5 alpha-reduced delta 16-C19 steroids from pregnenolone and progesterone.

5-alpha-Dihydroprogesterone↗
PubMedDate not supplied

5-Alpha-dihydroprogesterone formation in human placenta from 5alpha-pregnan-3beta/alpha-ol-20-ones and 5-pregnan-3beta-yl-20-one sulfate.

5Alpha-dihydroprogesterone (5alpha-DHP) is the immediate precursor of 5alpha-pregnan-3alpha-ol-20-one, a potent anxiolytic/anesthetic agent in all vertebrate animals tested, including humans. The levels of 5alpha-DHP in the plasma of pregnant women are very high; and during the third trimester of pregnancy, the blood production rate of this steroid may exceed 100 mg/24 h. 5Alpha-DHP in maternal plasma, however, cannot be accounted for totally by the metabolism of maternal plasma progesterone. This study was conducted to evaluate the possibility that 5alpha-DHP is synthesized in placenta from 5alpha-pregnan-3alpha/beta-ol-20-ones delivered to the trophoblast via the fetal umbilical blood. In incubations of placental minces with radiolabelled 5alpha-pregnan-3alpha/beta-ol-20-ones, there is extensive epimerization and the intermediate, 5alpha-DHP, is the major product. In other incubations, 5alpha-pregnan-3beta-ol-20-one-sulfate was hydrolysed and the liberated 5alpha-pregnan-3beta-ol-20-one was converted to 5alpha-DHP by homogenates of placental tissue, but 5alpha-pregnan-3beta-ol-20-one-sulfate was not. The oxidation of 5alpha-pregnan-3alpha/beta-ol-20-ones was concentrated in microsome-enriched preparations of placental tissue and the apparent Kms for 5alpha-pregnan-3alpha-ol-20-one and 5alpha-pregnan-3beta-ol-20-one were 3.6 microM and 78 nM, respectively. The Vmaxs for 5alpha-DHP formation from 5alpha-pregnan-3alpha-ol-20-one and 5alpha-pregnan-3beta-ol-20-one were, respectively, 336 pmol/min/mg protein and 9.7 nmol/min/mg protein. These oxidation reactions were supported by both NAD+ and NADP+. We suggest that progesterone, which enters the umbilical circulation from its site of synthesis in the syncytiotrophoblast, is metabolized in the fetus to 5alpha-pregnan-3alpha/beta-ol-ones and to 5alpha-pregnan-3alpha/beta-yl-20-one sulfates. These metabolites of progesterone, 5alpha-pregnan-3alpha/beta-ol-20-one and 5alpha-pregnan-3beta-yl-20-one sulfate, formed in the fetus, serve as plasma-borne substrates for trophoblast formation of 5alpha-DHP. Because of the hemochorioendothelial nature of human placentation, 5alpha-DHP secreted from the trophoblast will preferentially enter the maternal compartment, thus constituting a maternal plasma progesterone-independent source of 5alpha-DHP.

5-alpha-Dihydroprogesterone↗
PubMed1992

Effects in vitro of progesterone and two 5 alpha-reduced progestins, 5 alpha-pregnane-3,20-dione and 5 alpha-pregnane-3 alpha-ol-20-one, on contracting human myometrium at term.

Progesterone is known to prevent labour at term in domestic animals, but its effect in primates is uncertain. 5 alpha-reduced progesterone metabolites are more potent central nervous system depressants than progesterone is itself. Progesterone and its 5 alpha-reduced metabolites also relax pregnant rat myometrium in vitro. The serum concentration of the initial 5 alpha-reduced metabolite, 5 alpha-pregnane-3,20-dione, is high during pregnancy, but decreases significantly prior to parturition. The next metabolite, 5 alpha-pregnane-3 alpha-ol-20-one, has anaesthetic properties in human beings. The purpose of this study was to ascertain whether these progesterone metabolites also suppress contracting human uterine muscle at term. An in vitro model was devised. Strips of human myometrial muscle were mounted in organ chambers and after regular contractions had become established, the strips were superfused with progestin solutions. The progestins were dissolved in the buffer using an ultrasound bath. Progesterone, used as reference substance, slightly reduced the measured amount of muscular work performed per contraction, recordable after 18 min of exposure (p less than 0.05). Similar results have been reported previously in the literature; 5 alpha-pregnane-3 alpha-ol-20-one showed the same tendency though not significant at the 5% level. 5 alpha-pregnane-3,20-dione evidently reduced the contraction frequency after 10 min of exposure (p less than 0.05). None of the substances affected the duration of the contraction. These 5 alpha-reduced progesterone metabolites are thus not potent inhibitors of contracting human term myometrium in vitro.

5-alpha-Dihydroprogesterone↗
PubMed1993

Synthesis and structure-activity relationships of 14 beta-hydroxy-5 alpha-pregnanes: pregnanes that bind to the cardiac glycoside receptor.

5 alpha-pregnane-3 beta,14 beta,20 beta-triol 3-alpha-L-rhamnopyranoside (8) and 3 beta-(alpha-L-rhamnopyranosyloxy)-5 alpha-pregn-14-en-20-one (14) were prepared from uzarigenin by ozonolysis followed by zinc and acetic acid reduction and glycosidation. During the glycosidation reaction leading to (8) the corresponding ortho ester (9) was also obtained. Uzarigenin alpha-L-rhamnopyranoside (15) also was prepared. Synthesis of 5 alpha-pregnane-3 beta,14 beta,20 beta-triol (20) is described. Structures were established by analysis of their NMR spectra. The binding affinity of 5 alpha and 5 beta cardenolide and pregnane derivatives as measured in a radioligand binding assay was determined and their structure-activity relationships compared. The receptor binding affinity of the 5 alpha derivatives is less than that of the corresponding 5 beta derivatives.

Acetates↗
PubMed1993

Synthesis of 20-hydroxy-, 20-amino-, and 20-nitro-14-hydroxy-21-nor-5 beta,14 beta-pregnane C-3 glycosides and related derivatives: structure-activity relationships of pregnanes that bind to the digitalis receptor.

The preparation of derivatives of 14-hydroxy-21-nor-5 beta,14 beta-pregnane and 5 beta,14 beta-pregnane C-3 alpha-L-rhamnosides and tris-beta-D-digitoxosides is described. These derivatives, possessing a C-17 beta COCH2OH, CH2OH, CO2H, CO2Me, CH2NH2, or CH2NO2 group, bind to the digitalis receptor recognition site of heart muscle as measured in a radioligand binding assay. The 21-norpregnane derivatives consistently show greater binding affinity than the corresponding 20 alpha- and 20 beta-pregnane analogs. The C-20 nitro rhamnoside is comparable to digitoxin in binding affinity. The 17 beta-CH2NO2 group is the most effective replacement for the unsaturated lactone in the binding assay found so far, showing binding affinity comparable to that of the cardiac glycosides.

Binding Sites↗
PubMed1999

Pregnanes and pregnane glycosides from Hoya carnosa.

Eleven pregnanes were isolated from the hydrolysate of the CHCl3 extract fractionated from the caules of Hoya carnosa. Among these, six pregnanes, including 19-acetoxydigipurpurogenin II, were new, and their structures were elucidated. The structures of twenty new pregnane tetraosides and pentaosides, named hoyacarnosides A-T, besides three known ones from the CHCl3 extract, were determined.

Carbohydrate Sequence↗
PubMed1995

Comparative behavioral characterization of the neuroactive steroids 3 alpha-OH,5 alpha-pregnan-20-one and 3 alpha-OH,5 beta-pregnan-20-one in rodents.

Pregnan steroids have been shown to possess anesthetic, hypnotic, anticonvulsant and anxiolytic properties. In this study, two endogenous neuroactive steroid isomers, 3 alpha-hydroxy-5 alpha-pregnan-20-one (3 alpha,5 alpha-P) and 3 alpha-hydroxy-5 beta-pregnan-20-one 3 alpha,5 beta-P), were studied for differences in their pharmacological properties using behavioral assays. 3 alpha,5 alpha-P and 3 alpha,5 beta-P were similar in their potencies and efficacies in blocking pentylenetetrazol-induced seizures in mice (ED50: 3 alpha, 5 alpha-P = 2.8 mg/kg and 3 alpha,5 beta-P = 3.0 mg/kg). Similarly, both neuroactive steroids produced roto-rod deficits within the same range of potency (TD50: 3 alpha,5 alpha-P = 18.8 mg/kg and 3 alpha,5 beta-P = 21.2 mg/kg). However, in animal models of anxiety, subtle differences were observed between the two isomers. In both the light/dark transition test and elevated plus-maze, 3 alpha,5 beta-P was more efficacious than 3 alpha,5 alpha-P, though both compounds had similar potencies. In the Geller-Seifter test, 3 alpha,5 beta-P was more potent and efficacious than 3 alpha,5 alpha-P. Neither compound had significant effects on unpunished responding within the dose range tested. Both compounds produced similar biphasic curves in the locomotor test. All together, the data indicate that 3 alpha,5 alpha-P and 3 alpha,5 beta-P have similar anticonvulsant activity, but the 5 beta-isomer possesses more potent and efficacious anxiolytic properties than the 5 alpha-isomer.

Animals↗
PubMed1975

Steroidal anaesthetics: synthesis of 3alpha-hydroxy-5alpha-pregnane-11,20-dione-(21-14C) and 3alpha,21-dihydroxy-5alpha-pregnane-11,20-dione-(21-14C) 21-acetate.

3alpha-Hydroxy-5alpha-pregnane-11,20-dione-[21-14C] and 3alpha,21-dihydroxy-5alpha-pregnane-11,20-dione-[21-14C] 21-acetate were prepared from a common radio-labelled intermediate, 21-diazo-3alpha-hydroxy-5alpha-pregnane-11,20-dione-[21-14C] 3-nitrate, obtained by the reaction of 17beta-chlorocarbonyl-3alpha-hydroxy-5alpha-androstan-11-one 3-nitrate with diazomethane-[14C].

Alfaxalone Alfadolone Mixture↗
PubMed1989

Identification of 20 alpha-hydroxy-5 alpha-pregnan-3-one and 20 beta-hydroxy-5 alpha-pregnan-3-one in human pregnancy urine.

20 beta-Hydroxy-5 alpha-pregnan-3-one and 20 alpha-hydroxy-5 alpha-pregnan-3-one were isolated and identified from a pool of urine collected from women in the third trimester of pregnancy. Following isolation by Sephadex LH-20 and HPLC, the identity of each compound was established by comparison of GC-MS data for the methyloxime-trimethylsilyl ethers with those for authentic standards.

Chromatography, High Pressure Liquid↗
PubMed2003

Pregnanes and pregnane glycosides from Marsdenia roylei.

Two pregnanes namely desacylkondurangogenin C (1) and deniagenin (3, new) and two new pregnane glycosides designated as denin (5) and marsin (12) have been isolated from chloroform soluble extract of dried stem of Marsdenia roylei. Chemical and spectroscopic evidences are consistent with the structures of deniagenin, denin and marsin as 3beta, 11alpha, l2beta, 14beta, 17beta, 20-hexahydroxy pregn-5-ene; desacylkondurangogenin C-3-O-alpha-D-glucopyranosyl-(1-->4)-O-alpha-L-fucopyranoside and ketocalogenin-3-O-alpha-L-fucopyranoside, respectively.

Glycosides↗
PubMed1991

Pregnanes that bind to the digitalis receptor: synthesis of 14-hydroxy-5 beta,14 beta-pregnane glycosides from digitoxin and digitoxigenin.

The preparation of the mono-, bis-, and trisdigitoxosides of 14-hydroxy-5 beta,14 beta-pregnan-20-one and 14,20 beta-dihydroxy-5 beta,14 beta-pregnane by two routes, based on the conversion of the alpha,beta-unsaturated gamma-lactone in digitoxin to the 20-ketone and 20 beta-alcohol by ozonolysis and zinc-acetic acid treatment followed by lithium tri-tert-butoxyaluminum hydride reduction, are described. Synthesis of the alpha-L-rhamnoside derivatives is described also. Structures were confirmed by 1H and 13C NMR spectra. These derivatives show strong interaction with the cardiac glycoside receptor of heart muscle in an [3H]ouabain radioligand binding assay. Structure-activity relationships which are reported for glycosides and genins show that the alpha-L-rhamnoside derivatives are more potent than the beta-D-digitoxoside or the beta-D-glucoside and that the beta-D-glucosides are more potent than the mono-, bis-, and trisdigitoxosides. Potency is not increased by the addition of the second and third digitoxose units.

Digitalis↗
PubMed1987

The anaesthetic potency of 3 alpha-hydroxy-5 alpha-pregnan-20-one and 3 alpha-hydroxy-5 beta-pregnan-20-one determined with an intravenous EEG-threshold method in male rats.

Two progesterone metabolites 3 alpha-hydroxy-5 alpha-pregnan-20-one (5-alpha) and 3 alpha-hydroxy-5 beta-pregnan-20-one (5-beta) were investigated for anaesthetic potency in male rats with an EEG-threshold method. Dose rate curves were obtained by infusing 5-alpha and 5 beta intravenously with different rates until an EEG-criterion (a burst suppression of one sec. or more, the "silent second") was seen in the EEG. The potency of the investigated drugs has been estimated by comparing threshold doses at optimal infusion rates. 5-alpha and 5-beta were tested on both young (44 to 46 days) and adult (109 to 118 days) rats. The relation between age and the anaesthetic sensitivity of 5-beta was tested by weekly threshold determinations. 5-alpha and 5-beta infused separately with different infusion rates gave almost V-shaped dose rate curves. The optimal infusion rate was in all age groups 2 mg/kg/min. In young rats 5-alpha (6.7 mg/kg) was more potent than 5-beta (8.9 mg/kg). In adult rats the sensitivity was increased but the relation in potency between 5-alpha (5.1 mg/kg) and 5-beta (6.6 mg/kg) was unchanged. With 5-beta the main change in this age-related increase in anaesthetic sensitivity was seen between 49 and 70 days of age. Both 5-alpha and 5-beta exhibited an excitatory action seen as jerks during induction of the EEG-criterion.

Aging↗
PubMed1982

The conversion of progesterone into 5 alpha-pregnane-3,20-dione, 3 beta-hydroxy-5 alpha-pregnan-20-one, and its fatty acid esters by preparations of bovine corpora lutea.

Homogenates obtained from bovine corpora luteal tissue were found to catalyze the synthesis of 3 beta-hydroxy-5 alpha-pregnan-20-one (allopregnanolone) from progesterone but not from pregnenolone. The major metabolites of progesterone included allopregnanolone, 5 alpha-pregnane-3,20-dione, and fatty acid esters of allopregnanolone. Incubation with labeled pregnenolone resulted in the formation of pregnenolone esters; however, neither allopregnanolone nor esterified derivatives of it were detected. The esterifying enzyme(s) leading to the formation of allopregnanolone esters was associated primarily with the microsome-enriched subcellular fraction and was stimulated by the addition of ATP and coenzyme A. With these added cofactors, the pH optimum was 6.0-6.5. The rate of steroid ester formation was enhanced by the addition to the homogenate fraction of oleic acid, which was incorporated into the steroid ester fraction. Thus, enzymatic activity, with characteristics similar to either cholesteryl ester hydrolase (EC 3.1.1.13) or acyl cholesterol acyltransferase (EC 2.3.1.26), catalyzed the esterification of allopregnanolone. The data suggest that the allopregnanolone esters found in vivo are derived from progesterone rather than from pregnenolone.

5-alpha-Dihydroprogesterone↗
PubMed1997

Effect of age on synthesis of the GABAergic steroids 5-alpha-pregnane-3,20-dione and 5-alpha-pregnane-3-alpha-ol-20-one in rat cortex in vitro.

Progesterone 5-alpha-reductase activity and 3-alpha-hydroxysteroid dehydrogenase activity were determined in the cortex of male and female rats in vitro. Age effects were investigated. The age of the male rats was 3-23 months, and that of the female rats 4-23 months. On addition, we investigated the enzyme 3 beta-hydroxysteroid oxidoreductase, 5-ene-isomerase in rat cortex in order to estimate the local synthesis of progesterone from pregnenolone. We found age-related increases in progesterone 5-alpha-reductase activity in the female rats (r = 0.64, p < 0.01, n = 6) and in the male rats (r = 0.5, p < 0.05, n = 18). 3-alpha-HSDH activity remained constant with age in female and male rats. The ratio of 3-alpha-hydroxysteroid dehydrogenase activity to 5-alpha-reductase activity tended to decrease with age (not significantly) in both male rats (r = -0.45, p = 0.06, n = 19) and the female rats (r = -0.36, p = 0.17, n = 16). We could not detect significant metabolism of pregnenolone to progesterone in rat cortex in vitro. The sensitivity of the assays of 3 beta-hydroxysteroid oxidoreductase, 5-ene-isomerase was calculated from the mean of the blank values + 3SD; the sensitivity of the assay was calculated as 0.103 fmol/mg protein/min. No significant metabolism of pregnenolone could be detected in cortex pooled from several male rats. The mean metabolism of progesterone was 1,200 times higher than the detection threshold of the assay for 3 beta-hydroxysteroid oxidoreductase, 5-ene-isomerase. We conclude that modifications of the inhibitory effects of the GABAergic steroids 5-alpha-pregnane-3,20-dione and 5-alpha-pregnane-3-alpha-ol-20-one via altered progesterone metabolism in rat cortex are possible with aging. A connection with the age-related increase in incidence of epileptic attacks, and with age-related changes in the effects of anticonvulsant and GABAA-active drugs, appears possible.

3-Hydroxysteroid Dehydrogenases↗
PubMed1988

5 beta-pregnane-3 alpha,6 alpha,17 alpha,20 beta-tetrol and 5 beta-pregnane-3 alpha,6 alpha,17 alpha-triol-20-one: steroids of ovarian origin in the African catfish, Clarias gariepinus, during oocyte maturation.

At the stage of oocyte maturation, three very polar steroids were demonstrated by in vitro incubations with tritiated pregnenolone in the ovaries of the African catfish, Clarias gariepinus. Two of these compounds could be identified by chromatography, derivatization, and oxidation as 5 beta-pregnane-3 alpha,6 alpha,17 alpha,20 beta-tetrol and 5 beta-pregnane-3 alpha,6 alpha,-17 alpha-triol-20-one. Blood plasma analysis by means of gas chromatography followed by mass spectrometry confirmed the presence of these steroids with selected ion monitoring. The occurrence of the five most characteristic ions of each steroid was demonstrated at the proper retention times and with the correct abundance ratios. These very polar steroids, which were identified in vitro and in vivo, might have a function in maturation and ovulation induction.

Animals↗
PubMed1997

Progesterone, 5alpha-pregnane-3,20-dione and 3alpha-hydroxy-5alpha-pregnane-20-one in specific regions of the human female brain in different endocrine states.

Post-mortem concentrations of progesterone, 5alpha-pregnane-3,20-dione (5alpha-DHP) and 3alpha-hydroxy-5alpha-pregnane-20-one (allopregnanolone) were measured in 17 brain areas and serum in five fertile and five postmenopausal women. Steroid concentrations were measured with radioimmunoassay after extraction of brain tissue with ethanol and purification with celite chromatography. There were regional differences in brain concentrations of all three steroids. The highest progesterone levels were noted in the amygdala, cerebellum and hypothalamus and the highest levels of 5alpha-DHP and allopregnanolone were seen in the substantia nigra and basal hypothalamus. Brain concentrations of all three steroids were significantly higher in the fertile women in luteal phase compared to their postmenopausal controls (P < 0.01). In general, the study showed that there is a variation in brain concentrations depending on ovarian steroid production, indicating that the secretion pattern during the menstrual cycle is reflected in the brain. However, regional differences in brain steroid levels imply local mechanisms for steroid uptake and binding as well. Investigations of gonadal steroid distributions in the human brain might be of importance considering the actions of these steroids in the central nervous system. Such studies could provide information about physiological mechanisms, such as the ovulation, and also form a baseline for comparative studies of normal and pathological conditions involving steroids, for instance, catamenial epilepsy and the premenstrual tension syndrome.

5-alpha-Dihydroprogesterone↗
PubMed1997

Concentrations of progesterone and the 5 alpha-reduced progestins, 5 alpha-pregnane-3,20-dione and 3 alpha-hydroxy-5 alpha-pregnan-20-one, in luteal tissue and circulating blood and their relationship to luteal function in the African elephant, Loxodonta africana.

The 5 alpha-reduced metabolites 5 alpha-pregnane-3,20-dione (5 alpha-DHP) and 3 alpha-hydroxy-5 alpha-pregnan-20-one (5 alpha-P-3 alpha-OH) are the principal progestins biosynthesized by the African elephant corpus luteum. The aim of the present study was to determine luteal and circulating concentrations of these 5 alpha-reduced progestins in relation to progesterone (P4) and to examine whether their measurement reflects corpus luteum function. Ovarian (luteal) tissue (30 corpora lutea and 3 corpora rubra from 8 animals) and plasma samples (30 animals) were collected from pregnant and nonpregnant adult elephants shot in the Kruger National Park. Specific immunological measurement for both 5 alpha-reduced progestins and P4 was achieved by enzymeimmunoassay of tissue and plasma extracts following purification by HPLC. Mean (+/- SEM) luteal concentrations of 5 alpha-DHP and 5 alpha-P-3 alpha-OH were 79.5 +/- 9.4 micrograms/g and 196.5 +/- 24.8 micrograms/g, respectively, approximately 2-3 orders of magnitude higher than those of P4 (mean +/- SEM, 0.16 +/- 0.01 microgram/g). Whereas 5 alpha-reduced progestin concentrations tended to be lower in corpora lutea from late pregnancy compared with earlier stages and were lowest in corpora rubra, P4 levels were similar in all tissues/stages examined. The 5 alpha-reduced progestins also predominated over P4 in plasma (mean 5 alpha-DHP:P4 and 5 alpha-P-3 alpha-OH:P4 ratios 20.3 and 13.4, respectively). Similar to results for luteal tissue, plasma concentrations of 5 alpha-reduced progestins, but not of P4, were lower in late pregnancy than in earlier gestation stages and in nonpregnant animals. Moreover, plasma levels of both 5 alpha-reduced metabolites were negatively correlated with gestation age, whereas those of P4 were not. Levels of 5 alpha-reduced metabolites (without chromatography) were also measured in weekly blood samples throughout two complete ovarian cycles in one captive female. Both measurements showed a cyclic profile (similar to that of P4) with a luteal-phase elevation of 10- to 15-fold. The results indicate that 5 alpha-reduced compounds are the predominant progestins contained within and secreted by the corpus luteum of the African elephant, both during the ovarian cycle and throughout pregnancy. They also provide preliminary evidence to suggest that measurements of 5 alpha-reduced metabolites may reflect corpus luteum function more closely than those of P4.

5-alpha-Dihydroprogesterone↗