RESUMEN
Bovine herpesvirus 1 (BoHV-1), a significant viral pathogen, establishes latency in sensory neurons. The viral genome contains more than 100 consensus glucocorticoid receptor (GR) regulatory elements (GREs): consequently, stress stimulates viral replication and reactivation from latency. The immediate early transcription unit 1 (IEtu1) and bICP0 early promoters are transactivated by GR and synthetic corticosteroid dexamethasone. The androgen receptor (AR), like GR, is a Type 1 nuclear hormone receptor that binds and stimulates certain promoters containing GREs. Consequently, we hypothesized AR and 5α-Dihydrotestosterone (DHT) stimulate productive infection and key viral promoters. New studies demonstrated AR, DHT, and Krüppel like transcription factor 4 (KLF4) cooperatively stimulated productive infection and bICP0 E promoter activity in mouse neuroblastoma cells (Neuro-2A). KLF15 also cooperated with AR and DHT to stimulate IEtu1 promoter activity. We suggest AR and testosterone increase the prevalence of virus in semen by stimulating viral gene expression and replication.
Asunto(s)
17-Cetosteroides/metabolismo , Androstanoles/metabolismo , Infecciones por Herpesviridae/virología , Herpesvirus Bovino 1/genética , Herpesvirus Bovino 1/metabolismo , Factores de Transcripción de Tipo Kruppel/metabolismo , Receptores Androgénicos/metabolismo , Receptores de Glucocorticoides/metabolismo , Animales , Bovinos , Línea Celular , Dexametasona/análogos & derivados , Dexametasona/metabolismo , Regulación Viral de la Expresión Génica , Genoma Viral , Factor 4 Similar a Kruppel/metabolismo , Ratones , Regiones Promotoras Genéticas , Replicación ViralRESUMEN
Male rats were exposed to prenatal or postnatal stress, or both. The prenatally stressed males showed low levels of male copulatory behavior and high rates of female lordotic responding. Postnatal stress had no effect. The modifications are attributed to stress-mediated alterations in the ratio of adrenal to gonadal androgens during critical stages of sexual differentiation. Specifically, it appears that stress causes an increase in the weak adrenal androgen, androstenedione, from the maternal or fetal adrenal cortices, or from both, and a concurrent decrease in the potent gonadal androgen, testosterone.
Asunto(s)
Complicaciones del Embarazo , Conducta Sexual Animal , Estrés Fisiológico , 17-Cetosteroides/metabolismo , Androstanos/metabolismo , Animales , Copulación , Trastornos del Desarrollo Sexual , Eyaculación , Ambiente , Femenino , Masculino , Embarazo , Ratas , Factores Sexuales , Estrés Fisiológico/metabolismo , Testosterona/metabolismoRESUMEN
The article presents data on 17-ketosteroid excretion in patients with diabetes mellitus types II depending on age, sex and degree of diabetes mellitus compensation. It was established that 17-ketosteroid excretion and their fractions are considerably increased in men with diabetes mellitus types II in comparison with a control group and it is more evident in patients with insulin resistant diabetes mellitus. Obtained results showed possibility of the participation of changed steroid metabolism in pathogenesis of androgen disorders in aged male patients with diabetes mellitus types II depending on insulin sensitivity.
Asunto(s)
Andrógenos/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Resistencia a la Insulina , 17-Cetosteroides/metabolismo , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Humanos , Hipoglucemiantes/uso terapéutico , MasculinoRESUMEN
The plasma concentration, production rate, and conversion ratio of androstenedione and testosterone were studied in seven children with congenital adrenal hyperplasia (CAH) of the 21-hydroxylase type. Plasma androstenedione and testosterone measured by double isotope derivative assay and estimated blood production rates were manyfold increased in the untreated state, markedly suppressed with glucocorticoid, and increased after the administration of ACTH. The metabolic clearance rate when corrected for body size and the conversion ratio of androstenedione to testosterone were similar to previously determined values in normal adults. Consideration of the androgen concentrations and conversion ratios indicates that in children with CAH, 76% of the plasma testosterone in prepubertal females and 36% in males are derived from peripheral conversion of blood androstenedione. The calculated amount of testosterone unaccounted for by peripheral conversion is similar to normal prepubertal values. This approach indicates that virilization in these children results from increased levels of testosterone but that the major source in CAH of this potent androgen is androstenedione secreted by the adrenal cortex.
Asunto(s)
17-Cetosteroides/metabolismo , Enfermedades de las Glándulas Suprarrenales/congénito , Testosterona/biosíntesis , 17-Cetosteroides/sangre , 17-Cetosteroides/orina , Hormona Adrenocorticotrópica , Niño , Preescolar , Femenino , Glucocorticoides , Humanos , Hiperplasia/congénito , Masculino , Testosterona/sangre , Testosterona/orinaRESUMEN
The average plasma testosterone concentration of women with either hirsutism or polycystic ovaries and hirsutism was higher (p < 0.01) than that of normal women although the ranges overlapped. Testosterone blood production rates averaged 830 +/- 120 SE and 1,180 +/- 310 SE mug per day in the two groups of hirsute women and 230 +/- 33 SE mug per day in normal women. The ranges did not overlap. The testosterone metabolic clearance rates of hirsute women (1,090 +/- 140 SE L per day) and of men (1,240 +/- 136 SE L per day) were significantly higher than those of normal women (590 +/- 44 SE L per day). These differences persisted when the metabolic clearance rates were corrected for surface area. We suggest that testosterone metabolic clearance rates vary directly with some function of testosterone production. The mean plasma androstenedione levels (2.8 +/- 0.35 SE and 2.8 +/- 0.30 SE mug per L) and production rates (6,060 +/- 450 SE and 7,360 +/- 345 SE mug per day) of the women with hirsutism or polycystic ovaries, respectively, were significantly higher than those of normal women (1.5 +/- 0.22 SE mug per L; 3,300 +/- 830 SE mug per day). The androstenedione metabolic clearance rates were the same in each group. Plasma androstenedione was the precursor of 49% of plasma testosterone in normal women and of 26% of plasma testosterone in hirsute women. Thus, 74% of the plasma testosterone in these subjects must have been either secreted or derived from a precursor that did not enter the plasma androstenedione pool.
Asunto(s)
17-Cetosteroides/metabolismo , Hirsutismo/metabolismo , Síndrome del Ovario Poliquístico/metabolismo , Testosterona/metabolismo , Adolescente , Adulto , Femenino , Humanos , Persona de Mediana EdadRESUMEN
The metabolic clearance rate (MCR) and blood production rate (BP) of testosterone (T) and dihydrotestosterone (DHT), the conversion of plasma testosterone to plasma dihydrotestosterone, and the renal clearance of androstenedione, testosterone, and dihydrotestosterone have been studied in man. In eight normal men, the MCR(T) (516+/-108 [SD] liters/m(2)/day) was significantly greater than the MCR(DHT) (391+/-71 [SD] liters/m(2)/day). In seven females, the MCR(T) (304+/-53 [SD] liters/m(2)/day) was also greater than the MCR(DHT) (209+/-45 [SD] liters/m(2)/day) and both values were less than their respective values in men (P < 0.001). In men the conversion of testosterone into dihydrotestosterone at 2.8+/-0.3% (SD) was greater than that found in females, 1.56+/-0.5% (SD) (P < 0.001). In five pregnant females the MCR(T) (192+/-36 [SD] liters/m(2)/day), the MCR(DHT) (89+/-30 [SD] liters/m(2)/day) and the conversion of testosterone into dihydrotestosterone (0.72+/-0.15%) (SD) were significantly less than the values found in nonpregnant women. In five females with hyperthyroidism, the MCR for testosterone and dihydrotestosterone were similar to those observed in pregnant females, but the conversion of testosterone into dihydrotestosterone (2.78+/-1.7%) (SD) was greater, and similar to that found in men. In men the production of dihydrotestosterone was 0.39+/-0.1 (SD) mg/day, 50% being derived from the transformation of plasma testosterone. In women the production of DHT was 0.05+/-0.028 (SD) mg/day, only 10% coming from testosterone. During pregnancy, the production of testosterone and dihydrotestosterone are similar to that in normal women. In three patients with testicular feminization syndrome (an adult with hyperthyroidism and two children) these two MCRs were greatly reduced compared to the normal females, but the conversion of testosterone into dihydrotestosterone was in the limits of normal male rangeIn the normal subjects the renal clearance of androstenedione was greater than that of testosterone and dihydrotestosterone. Less than 20% of the dihydrotestosterone and less than 10% of the androstenedione in the urine is derived from the plasma dihydrotestosterone and androstenedione.
Asunto(s)
Dihidrotestosterona/biosíntesis , Hipertiroidismo/metabolismo , Tasa de Depuración Metabólica , Embarazo , Testosterona/biosíntesis , 17-Cetosteroides/metabolismo , Adulto , Síndrome de Resistencia Androgénica/metabolismo , Androstanos/metabolismo , Isótopos de Carbono , Preescolar , Cromatografía de Gases , Cromatografía en Capa Delgada , Femenino , Humanos , Lactante , Cetosteroides/metabolismo , Riñón/metabolismo , Masculino , Persona de Mediana Edad , Unión Proteica , Testosterona/sangre , Testosterona/metabolismo , Testosterona/orina , TritioRESUMEN
This is the first report of a male with 17alpha-hydroxylase deficiency resulting in male pseudohermaphroditism, ambiguous external genitalia, absence of male secondary sexual characteristics, and gynecomastia at puberty. Diagnosis was based on extensive studies of steroid metabolism including the following: low urinary excretion of 17-ketosteroids and 17-hydroxycorticoids which did not increase after ACTH; no response of very low plasma testosterone and dehydroepiandrosterone to adrenocorticotropin (ACTH) or chorionic gonadotropin; and low urinary aldosterone and plasma renin which increased after dexamethasone. Secretion rates of 17-hydroxylated steroids, cortisol (F) and 11-desoxycortisol (S), were very low while desoxycorticosterone (DOC) and corticosterone (B) secretion rates were increased sevenfold. Results expressed as milligrams per meter squared per day were as follows: F, 1.3; S, 0.023; DOC, 0.35; and B, 16 (mean normal values were F, 7.5; S, 0.26; DOC, 0.055, and B, 2.2). Plasma gonadotropins were markedly increased (FSH, 106; LH, 364 mIU/ml). Testicular biopsies revealed interstitial-cell hyperplasia and early spermatogenesis. Karyotype was 46/XY. Pedigree showed no other affected member. At laparotomy ovaries, uterus, and fallopian tubes were absent, vas deferens was incomplete, and prostate was present. External genitalia consisted of small phallus, bifid scrotum, third-degree hypospadias, and small vagina. At puberty there was no growth of body hair or phallic enlargement. Biopsy of marked gynecomastia showed both ducts and acini. Testosterone administration produced virilization. Sexual ambiguity demonstrates strong dependence of external genitalia on androgens for male differentiation. Suppression of Müllerian structures occurred despite female levels of testosterone indicating this step in male differentiation is not testosterone dependent. Pubertal breast development in this male supports the concept of femaleness during ontogeny unless counteracted by male factors. Diagnosis of other adrenocortical enzymatic deficiencies is excluded by the steroidal studies. The clinical response to testosterone excludes testicular feminization. Deficiency of 17-hydroxylation must be added to the cause of male pseudohermaphroditism.
Asunto(s)
Trastornos del Desarrollo Sexual/etiología , Errores Innatos del Metabolismo/complicaciones , Oxigenasas de Función Mixta , 17-Hidroxicorticoesteroides/metabolismo , 17-Cetosteroides/metabolismo , Adulto , Gonadotropina Coriónica/uso terapéutico , Dexametasona/uso terapéutico , Trastornos del Desarrollo Sexual/tratamiento farmacológico , Trastornos del Desarrollo Sexual/metabolismo , Trastornos del Desarrollo Sexual/cirugía , Humanos , Masculino , Linaje , Testículo/patología , Testosterona/uso terapéuticoRESUMEN
The reduction of 17-oxosteroids to 17ß-hydroxysteroids is one of the important transformations for the preparation of many steroidal drugs and intermediates. The strain Zygowilliopsis sp. WY7905 was found to catalyze the reduction of C-17 carbonyl group of androst-4-ene-3,17-dione (AD) to give testosterone (TS) as the sole product by the constitutive 17ß-hydroxysteroid dehydrogenase (17ß-HSD). The optimal conditions for the reduction were pH 8.0 and 30°C with supplementing 10g/l glucose and 1% Tween 80 (w/v). Under the optimized transformation conditions, 0.75g/l AD was reduced to a single product TS with >90% yield and >99% diastereomeric excess (de) within 24h. This strain also reduced other 17-oxosteroids such as estrone, 3ß-hydroxyandrost-5-en-17-one and norandrostenedione, to give the corresponding 17ß-hydroxysteroids, while the C-3 and C-20 carbonyl groups were intact. The absence of by-products in this microbial 17ß-reduction would facilitate the product purification. As such, the strain might serve as a useful biocatalyst for this important transformation.
Asunto(s)
17-Cetosteroides/química , 17-Cetosteroides/metabolismo , Hidroxiesteroides/química , Hidroxiesteroides/metabolismo , Saccharomycetales/metabolismo , Espectroscopía de Resonancia Magnética , Nandrolona/química , Nandrolona/metabolismo , Oxidación-Reducción , Testosterona/química , Testosterona/metabolismoRESUMEN
Suppression of androgen receptor (AR) activity in prostate cancer by androgen depletion or direct AR antagonist treatment, although initially effective, leads to incurable castration-resistant prostate cancer (CRPC) via compensatory mechanisms including resurgence of AR and AR splice variant (ARV) signaling. Emerging evidence suggests that Sigma1 (also known as sigma-1 receptor) is a unique chaperone or scaffolding protein that contributes to cellular protein homeostasis. We reported previously that some Sigma1-selective small molecules can be used to pharmacologically modulate protein homeostasis pathways. We hypothesized that these Sigma1-mediated responses could be exploited to suppress AR protein levels and activity. Here we demonstrate that treatment with a small-molecule Sigma1 inhibitor prevented 5α- dihydrotestosterone-mediated nuclear translocation of AR and induced proteasomal degradation of AR and ARV, suppressing the transcriptional activity and protein levels of both full-length and splice-variant AR. Consistent with these data, RNAi knockdown of Sigma1 resulted in decreased AR levels and transcriptional activity. Furthermore, Sigma1 physically associated with ARV7 and ARv567es as well as full-length AR. Treatment of mice xenografted with ARV-driven CRPC tumors with a drug-like small-molecule Sigma1 inhibitor significantly inhibited tumor growth associated with elimination of AR and ARV7 in responsive tumors. Together, our data show that Sigma1 modulators can be used to suppress AR/ARV-driven prostate cancer cells via regulation of pharmacologically responsive Sigma1-AR/ARV interactions, both in vitro and in vivoCancer Res; 77(9); 2439-52. ©2017 AACR.
Asunto(s)
Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Isoformas de Proteínas/genética , Receptores Androgénicos/genética , Receptores sigma/genética , 17-Cetosteroides/metabolismo , Antagonistas de Andrógenos/administración & dosificación , Andrógenos/metabolismo , Androstanoles/metabolismo , Animales , Línea Celular Tumoral , Humanos , Masculino , Ratones , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/patología , Receptores sigma/antagonistas & inhibidores , Ensayos Antitumor por Modelo de Xenoinjerto , Receptor Sigma-1RESUMEN
Seven metabolites were obtained from the microbial transformation of anabolic-androgenic steroid mibolerone (1) with Cunninghamella blakesleeana, C. echinulata, and Macrophomina phaseolina. Their structures were determined as 10ß,17ß-dihydroxy-7α,17α-dimethylestr-4-en-3-one (2), 6ß,17ß-dihydroxy-7α,17α-dimethylestr-4-en-3-one (3), 6ß,10ß,17ß-trihydroxy-7α,17α-dimethylestr-4-en-3-one (4), 11ß,17ß-dihydroxy-(20-hydroxymethyl)-7α,17α-dimethylestr-4-en-3-one (5), 1α,17ß-dihydroxy-7α,17α-dimethylestr-4-en-3-one (6), 1α,11ß,17ß-trihydroxy-7α,17α-dimethylestr-4-en-3-one (7), and 11ß,17ß-dihydroxy-7α,17α-dimethylestr-4-en-3-one (8), on the basis of spectroscopic studies. All metabolites, except 8, were identified as new compounds. This study indicates that C. blakesleeana, and C. echinulata are able to catalyze hydroxylation at allylic positions, while M. phaseolina can catalyze hydroxylation of CH2 and CH3 groups of substrate 1. Mibolerone (1) was found to be a moderate inhibitor of ß-glucuronidase enzyme (IC50 = 42.98 ± 1.24 µM) during random biological screening, while its metabolites 2-4, and 8 were found to be inactive. Mibolerone (1) was also found to be significantly active against Leishmania major promastigotes (IC50 = 29.64 ± 0.88 µM). Its transformed products 3 (IC50 = 79.09 ± 0.06 µM), and 8 (IC50 = 70.09 ± 0.05 µM) showed a weak leishmanicidal activity, while 2 and 4 were found to be inactive. In addition, substrate 1 (IC50 = 35.7 ± 4.46 µM), and its metabolite 8 (IC50 = 34.16 ± 5.3 µM) exhibited potent cytotoxicity against HeLa cancer cell line (human cervical carcinoma). Metabolite 2 (IC50 = 46.5 ± 5.4 µM) also showed a significant cytotoxicity, while 3 (IC50 = 107.8 ± 4.0 µM) and 4 (IC50 = 152.5 ± 2.15 µM) showed weak cytotoxicity against HeLa cancer cell line. Compound 1 (IC50 = 46.3 ± 11.7 µM), and its transformed products 2 (IC50 = 43.3 ± 7.7 µM), 3 (IC50 = 65.6 ± 2.5 µM), and 4 (IC50 = 89.4 ± 2.7 µM) were also found to be moderately toxic to 3T3 cell line (mouse fibroblast). Interestingly, metabolite 8 showed no cytotoxicity against 3T3 cell line. Compounds 1-4, and 8 were also evaluated for inhibition of tyrosinase, carbonic anhydrase, and α-glucosidase enzymes, and all were found to be inactive.
Asunto(s)
17-Cetosteroides/metabolismo , Antineoplásicos/metabolismo , Antiprotozoarios/metabolismo , Cunninghamella/metabolismo , Nandrolona/análogos & derivados , Saccharomycetales/metabolismo , Congéneres de la Testosterona/metabolismo , 17-Cetosteroides/química , 17-Cetosteroides/aislamiento & purificación , 17-Cetosteroides/farmacología , Animales , Antineoplásicos/química , Antineoplásicos/aislamiento & purificación , Antineoplásicos/farmacología , Antiprotozoarios/química , Antiprotozoarios/aislamiento & purificación , Antiprotozoarios/farmacología , Biotransformación , Anhidrasas Carbónicas/química , Supervivencia Celular/efectos de los fármacos , Cromatografía Líquida de Alta Presión , Cunninghamella/química , Cunninghamella/efectos de los fármacos , Glucuronidasa/antagonistas & inhibidores , Glucuronidasa/química , Células HeLa , Humanos , Hidroxilación , Leishmania major/efectos de los fármacos , Leishmania major/crecimiento & desarrollo , Ratones , Estructura Molecular , Monofenol Monooxigenasa/química , Células 3T3 NIH , Nandrolona/química , Nandrolona/metabolismo , Nandrolona/farmacología , Saccharomycetales/química , Saccharomycetales/efectos de los fármacos , Congéneres de la Testosterona/química , Congéneres de la Testosterona/aislamiento & purificación , Congéneres de la Testosterona/farmacología , alfa-Glucosidasas/químicaRESUMEN
Specimens of ventral prostate from 37- to 46-month-old Andradurin-treated A X C rats demonstrated three primary morphologic patterns, each being divisible into two sub-groups based upon the extent of glandular alteration. The principal groups were: group 1, hyperplasia; group 2, atypical hyperplasia; and group 3, adenocarcinoma. The secondary classifications were: subgroup (+), few glands involved; and subgroup (++), most glands involved. Multiple parameters of ventral prostate testosterone metabolic potential failed to distinguish the morphologically diverse prostate specimens of groups (1+). 1(++), 2(+), 2(++), and 3(+) which predominantly metabolized testosterone to 5alpha-reduced 17beta-hydroxysteroids. By contrast, testosterone metabolism by ventral prostate specimens predominantly composed of neoplastic epithelium, group 3(++), was distinct from all other prostate specimens. The distinguishing feature was a shift to more prominent elaboration of 17-ketosteroids, principally delta4-androstenedione, and a cteroids. The change in this biochemical parameter of prostate epithelial cell function was indicated to be an early manifestation of the neoplastic transformation.
Asunto(s)
Adenocarcinoma/metabolismo , Neoplasias de la Próstata/metabolismo , Testosterona/metabolismo , 17-Cetosteroides/metabolismo , Adenocarcinoma/patología , Androstenodiona/metabolismo , Animales , Dihidrotestosterona/metabolismo , Hidroxiesteroides/metabolismo , Hiperplasia , Masculino , Neoplasias Experimentales/metabolismo , Neoplasias Experimentales/patología , Neoplasias de la Próstata/patología , RatasRESUMEN
Humans are significantly exposed to phthalates via food packaging, cosmetics and medical devices such as tubings and catheters. Testicular Leydig cells (LCs) are suggested to be among the main targets of phthalate toxicity in the body. However, their sensitivity to phthalates is species-dependent. This paper describes the response of the LCs from different species (mouse, rat and human) to phthalate exposure in different experimental paradigms (in vivo, ex vivo and in vitro), with particular focus on mechanisms of phthalate action on LC steroidogenesis. A comprehensive analysis of the impact of phthalate diesters and phthalate monoesters on LCs in different stages of their development is presented and possible mechanisms of phthalates action are discussed. Finally novel, not yet fully elucidated sites of action of phthalate monoesters on the backdoor pathway of 5α-dihydrotestosterone biosynthesis in immature mouse LCs and their effects on steroidogenesis and redox state in adult mouse LCs are reported.
Asunto(s)
17-Cetosteroides/metabolismo , Androstanoles/metabolismo , Células Intersticiales del Testículo/metabolismo , Ácidos Ftálicos/toxicidad , Animales , Humanos , Células Intersticiales del Testículo/patología , Masculino , Ratones , Oxidación-Reducción/efectos de los fármacos , RatasRESUMEN
Two steroids were identified in a supplement named D-2 following the detection of unknown compounds during the routine testing of an athlete's sample. The main glucuroconjugated metabolites were isolated from this urine by high performance liquid chromatography (HPLC) following enzymatic hydrolysis and identified by gas chromatography-mass spectrometry (GC-MS) and nuclear magnetic resonance (NMR) analyses as being 2α-hydroxy-5α-androst-3-en-17-one (M1) and 2ß,3α-dihydroxy-5α-androstan-17-one (M2). A third metabolite, 3α,4ß-dihydroxy-5α-androstan-17-one (M3) was also detected, however in lower amounts. The precursor steroids, 5α-androst-2-en-17-one (1) and 5α-androst-3-en-17-one (2) were present in the first D-2 products offered on the Internet. Later, the corresponding 17-hydroxyl compounds were offered as such or as esters (acetate, cypionate) in different relative ratios. Both M2 and M3 were synthesized from the trans-diaxial hydrolysis of the corresponding 2α,3α- and 3α,4α-epoxides (3). These were excreted in the hours following the controlled administration of the commercial product called D-2 R to a male volunteer and were also produced from the incubation of 1 and 2 with S9 liver fractions. Some preparations contain predominantly the alkene in C-2 and, therefore, an efficient detection method must include both primary metabolites M1 and M2. The latter was found equally in the fractions extracted following the enzymatic hydrolysis with ß-glucuronidase and the chemical solvolysis, which may ease its identification. Copyright © 2016 John Wiley & Sons, Ltd.
Asunto(s)
17-Cetosteroides/análisis , 17-Cetosteroides/orina , Androstenos/análisis , Androstenos/orina , Cromatografía Líquida de Alta Presión/métodos , Compuestos Epoxi/química , Esteroides/química , 17-Cetosteroides/química , 17-Cetosteroides/metabolismo , Androstenos/química , Androstenos/metabolismo , Doping en los Deportes , Cromatografía de Gases y Espectrometría de Masas/métodos , Humanos , Espectroscopía de Resonancia Magnética , Esteroides/metabolismoRESUMEN
The Wobbler mouse is an animal model for human motoneuron diseases, especially amyotrophic lateral sclerosis (ALS), used in the investigation of both pathology and therapeutic treatment. ALS is a fatal neurodegenerative disease, characterized by the selective and progressive death of motoneurons, leading to progressive paralysis. Previous limited studies have reported steroidal hormone dysregulation in Wobbler mouse and in ALS patients, suggesting endocrine dysfunctions which may be involved in the pathogenesis of the disease. In this study, we established a steroid profiling in brain, spinal cord, plasma, adrenal glands, and testes in 2-month-old male Wobbler mice and their littermates by gas chromatography coupled to mass spectrometry. Our results show in Wobbler mice the following: 1) a marked up-regulation of corticosterone levels in adrenal glands, plasma, spinal cord regions (cervical, thoracic, lumbar) and brain; 2) a strong decrease in T levels in the testis, plasma, spinal cord, and brain; and 3) increased levels of progesterone and especially of its reduced metabolites 5α-dihydroprogesterone, allopregnanolone, and 20α-dihydroprogesterone in the brain, spinal cord, and adrenal glands. Furthermore, Wobbler mice showed a hypothalamic-pituitary-gonadal hypoactivity. Interestingly, plasma concentrations of corticosterone and T correlate well with their respective levels in cervical spinal cord in both control and Wobbler mice. T down-regulation is probably the consequence of adrenal hyperactivity, and the up-regulation of progesterone and its reduced metabolites may correspond to an endogenous protective mechanism in response to motoneuron degeneration. Our findings suggest that increased levels of corticosterone and decreased levels of T in plasma could be a signature of motoneuron degeneration.
Asunto(s)
Esclerosis Amiotrófica Lateral/metabolismo , 17-Cetosteroides/sangre , 17-Cetosteroides/metabolismo , Glándulas Suprarrenales/metabolismo , Esclerosis Amiotrófica Lateral/sangre , Androstanoles/sangre , Androstanoles/metabolismo , Animales , Encéfalo/metabolismo , Corticosterona/sangre , Corticosterona/metabolismo , Modelos Animales de Enfermedad , Femenino , Cromatografía de Gases y Espectrometría de Masas , Hormona Liberadora de Gonadotropina/metabolismo , Hormona Luteinizante/sangre , Masculino , Ratones , Neuronas Motoras/metabolismo , Neuronas Motoras/fisiología , Pregnanolona/sangre , Pregnanolona/metabolismo , Progesterona/sangre , Progesterona/metabolismo , Médula Espinal/metabolismo , Testículo/metabolismo , Testosterona/sangre , Testosterona/metabolismoRESUMEN
The 17-keto function of phenolic steroids is reduced by the following intestinal bacteria: Eubacterium lentum, Clostridium paraputrificum, Clostridium J-1 and Clostridium innocuum. The 17-keto group of androstenedione is reduced solely by Bacteroides fragilis.
Asunto(s)
17-Cetosteroides/metabolismo , Bacterias Anaerobias/metabolismo , Heces/microbiología , Bacteroides fragilis/metabolismo , Bifidobacterium/metabolismo , Clostridium/metabolismo , Eubacterium/metabolismo , Humanos , Hidroxiesteroides/aislamiento & purificación , Oxidación-ReducciónRESUMEN
The culture of human male foreskin fibroblasts was incubated with various concentrations of testosterone in the medium. It has been shown that the minimum formation of 17beta-oestradiol and 5alpha-dihydrotestosterone occurs at physiological testosterone concentrations. Any deviation of testosterone concentration, both up and down, was accompanied by an increase in the formation of 17beta-oestradiol and 5alpha-dihydrotestosterone.
Asunto(s)
17-Cetosteroides/metabolismo , Androstanoles/metabolismo , Estradiol/biosíntesis , Testosterona/farmacología , Línea Celular , Relación Dosis-Respuesta a Droga , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Humanos , Masculino , PielRESUMEN
Rubrosterone, possessing various remarkable bioactivities, is an insect-molting C19-steroid. However, only very small amounts are available for biological tests due to its limited content from plant sources. Fungi of genus Fusarium have been reported to have the ability to convert C27-steroids into C19-steroids. In this study, Asparagus filicinus, containing a high content of 20-hydroxyecdysone, was utilized to accumulate rubrosterone through solid fermentation by Fusarium oxysporum. The results showed that F. oxysporum had the ability to facilitate the complete biotransformation of 20-hydroxyecdysone to rubrosterone by solid-state fermentation. The present method could be an innovative and efficient approach to accumulate rubrosterone with an outstanding conversion ratio.
Asunto(s)
17-Cetosteroides/metabolismo , Androstanoles/metabolismo , Asparagus/metabolismo , Ecdisterona/metabolismo , Fermentación , Fusarium/metabolismo , Asparagus/microbiologíaRESUMEN
[3H]Equilin [3H-labeled 3-hydroxy-1,3,5(10), 7-estratetraen-17-one] was administered iv to a pregnant mare in the 10th month of gestation. Maternal urine was collected for 3 days, and blood samples were taken 35 min and 3, 6, 12, and 24 h after the injection. The half-life of the disappearance of radioactivity from the blood was approximately 2.5 h. Over 90% of the administered dose was excreted in the first 24 h. The urine was extracted, hydrolyzed, and fractionated. The bulk of the radioactive material (75%) was present in the phenolic sulfate fraction from which radiochemically pure equilin, equilenin [3-hydroxy-1,3,5(10),6,8-estrapentaen-17-one], 17 alpha-dihydroequilin [1,3,5(10), 7-estratetraen-3,17 alpha-diol], 17 beta-dihydroequilin [1,3,5-(10,7-estratetraen-3,17 beta-diol], 17 alpha-dihydroequilenin [1,3,5(10),6,8-estrapentaen-3,17 alpha-diol], and 17 beta-dihydroequilenin [1,3,5(10),6,8-estrapentaen-3,17 beta-diol] were isolated and identified. Except for equilenin, the above-named steroids were also isolated and identified from the glucuronide fraction. Along with these estrogens, the two classical estrogens, estrone and 17 alpha-estradiol, were also isolated, but both of these estrogens were devoid of any radioactivity. These results indicate that 1) the B ring unsaturated estrogens are not metabolized to the B ring saturated estrogens (classical estrogens), 2) all of the B ring unsaturated estrogens isolated and identified from the pregnant mare's urine are metabolites of equilin, 3) the major metabolite of equilin excreted in the urine was equilin sulfate, 4) from the specific activity of the isolated equilin sulfate and the amount of [3H]equilin injected, the secretion rate of equilin was calculated to be 96 mg/24 h, and 5) the major reduced metabolites of equilin are the biologically less active 17 alpha-reduced products.
Asunto(s)
17-Cetosteroides/metabolismo , Equilina/metabolismo , Caballos/metabolismo , Preñez , Animales , Equilina/análogos & derivados , Estradiol/metabolismo , Estrona/metabolismo , Femenino , Glucuronatos/metabolismo , EmbarazoRESUMEN
The MCRs of equilin sulfate and equilin were determined in normal postmenopausal women and a normal man by single iv injections of either [3H]equilin sulfate or [3H] equilin. After the administration of [3H]equilin sulfate, blood was drawn at various time intervals, and the plasma obtained was fractionated into the unconjugated, sulfate, and glucuronide fractions. The bulk of radioactivity was present in the sulfate fraction, and from this, [3H]equilin sulfate, [3H]17 beta-dihydro-equilin sulfate, [3H]equilenin sulfate, and [3H]17 beta-dihydroequilenin sulfate were isolated and purified, and their concentrations were measured. The disappearance of radioactivity from plasma as equilin sulfate can be described as a function that is the sum of two exponentials. The initial fast component (half-life, 5.2 +/- 1.2 min) represents distribution and transfer from a space, with a mean volume of 12.4 +/- 1.6 liters. The mean value for the rate constant of total removal from the initial volume is 163 +/- 19 U/day, of which 15.8 +/- 2% is irreversible. The mean half-life of the slower component of equilin sulfate is 190 +/- 23 min, and the mean MCR is 176 +/- 44 liters/day . m2. Similarly, after the administration of [3H]equilin to a normal postmenopausal woman and a man, the disappearance of radio-activity from plasma as equilin could be fitted by a single straight line, consistent with a one-compartment system. The half-life of equilin was approximately 19-27 min, and the MCR of equilin was calculated to be 1982 liters/day/m2 in the normal man and 3300 liters/day/m2 in the normal postmenopausal woman. The bulk of [3H]equilin was very rapidly metabolized to mainly equilin sulfate. Small amounts of 17 beta-dihydroequilin sulfate and 17 beta-dihydroequilin were also isolated from the plasma. The in vivo formation of 17 beta-dihydroequilin and its sulfate may be of importance, as this estrogen is approximately 8 times more potent as a uterotropic agent than equilin sulfate.
Asunto(s)
17-Cetosteroides/metabolismo , Equilina/metabolismo , Estrógenos Conjugados (USP)/sangre , Menopausia , Adulto , Equilenina/análogos & derivados , Equilenina/sangre , Equilina/análogos & derivados , Equilina/sangre , Femenino , Humanos , Cinética , Masculino , Tasa de Depuración Metabólica , Persona de Mediana EdadRESUMEN
The absorption of equilin sulfate and equilin from the gastrointestinal tract was determined in normal men after the ingestion of [3H]equilin-[35S]sulfate or a mixture of [3H]equilin and equilin-[35S]sulfate, while the metabolism of equilin sulfate was investigated after iv administration of [3H]equilin sulfate to postmenopausal women. After the oral administration of [3H]equilin-[35S]sulfate, equilin sulfate containing both 3H and 35S was isolated from plasma; however, only in the first sample taken at 10 min was the 3H/35S ratio the same as that of the [3H]equilin-[35S]sulfate ingested. The 3H/35S ratio then increased, and by 12 h only traces of equilin-[35S]sulfate were detectable. Similarly, after the ingestion of [3H]equilin and equilin-[35S]sulfate, [3H]equilin-[35S]sulfate was isolated from plasma. The 3H/35S ratio was at all time points greater than the 3H/35S ratio of the ingested mixture. Analysis of urine indicated that over 98% of 35S was not associated with any steroid and was most likely inorganic sulfate. After iv administration of [3H] equilin sulfate to postmenopausal women, equilin, equilenin, 17 beta-dihydroequilin, and 17 beta-dihydroequilenin were isolated from the urine. These results indicate that 1) some of the orally administered equilin sulfate was absorbed from the gut without prior hydrolysis, 2) some equilin sulfate was hydrolyzed in the gut before absorption; 3) equilin was absorbed more efficiently than equilin sulfate; 4) equilin absorbed was readily sulfated and circulated in this form; and 5) equilin sulfate was extensively metabolized, and the metabolites were excreted in the urine mainly conjugated with glucuronic acid.