RESUMEN
Two series of novel steroidal[17,16-d]pyrimidines derived from natural epiandrosterone and androsterone were designed and synthesized, and these compounds were screened for their potential anticancer activities. The preliminary bioassay indicated that some of these prepared compounds exhibited significantly good cytotoxic activities against human gastric cancer (SGC-7901), lung cancer (A549), and hepatocellular liver carcinoma (HepG2) cell lines compared with 5-fluorouracil (5-FU), epiandrosterone, and androsterone. Especially the respective pairs from epiandrosterone and androsterone showed significantly different inhibitory activities, and the possible configuration-activity relationships have also been summarized and discussed based on kinase assay and molecular docking, which indicated that the inhibition activities of these steroidal[17,16-d]pyrimidines might obviously be affected by the configuration of the hydroxyl group in the part of the steroidal scaffold.
Asunto(s)
Antineoplásicos , Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Androsterona/farmacología , Pirimidinas/farmacología , Simulación del Acoplamiento Molecular , Proliferación Celular , Línea Celular Tumoral , Antineoplásicos/farmacología , Esteroides/farmacología , Fluorouracilo/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Relación Estructura-ActividadRESUMEN
Tuberculosis (TB) is the leading cause of death from a single bacterial infectious agent and is one of the most relevant issues of public health. Another pandemic disease is type II diabetes mellitus (T2D) that is estimated to affect half a billion people in the world. T2D is directly associated with obesity and a sedentary lifestyle and is frequently associated with immunosuppression. Immune dysfunction induced by hyperglycemia increases infection frequency and severity. Thus, in developing countries the T2D/TB co-morbidity is frequent and represents one of the most significant challenges for the health-care systems. Several immunoendocrine abnormalities are occurring during the chronic phase of both diseases, such as high extra-adrenal production of active glucocorticoids (GCs) by the activity of 11-ß-hydroxysteroid dehydrogenase type 1 (11-ßHSD1). 11-ßHSD1 catalyzes the conversion of inactive cortisone to active cortisol or corticosterone in lungs and liver, while 11-ß-hydroxysteroid dehydrogenase type 2 (11-ßHSD2) has the opposite effect. Active GCs have been related to insulin resistance and suppression of Th1 responses, which are deleterious factors in both T2D and TB. The anabolic adrenal hormone dehydroepiandrosterone (DHEA) exerts antagonistic effects on GC signaling in immune cells and metabolic tissues; however, its anabolic effects prohibit its use to treat immunoendocrine diseases. 16α-bromoepiandrosterone (BEA) is a water miscible synthetic sterol related to DHEA that lacks an anabolic effect while amplifying the immune and metabolic properties with important potential therapeutic uses. In this work, we compared the expression of 11-ßHSD1 and the therapeutic efficacy of BEA in diabetic mice infected with tuberculosis (TB) (T2D/TB) with respect to non-diabetic TB-infected mice (TB). T2D was induced by feeding mice with a high-fat diet and administering a single low-dose of streptozotocin. After 4 weeks of T2D establishment, mice were infected intratracheally with a high-dose of Mycobacterium tuberculosis strain H37Rv. Then, mice were treated with BEA three times a week by subcutaneous and intratracheal routes. Infection with TB increased the expression of 11-ßHSD1 and corticosterone in the lungs and liver of both T2D/TB and TB mice; however, T2D/TB mice developed a more severe lung disease than TB mice. In comparison with untreated animals, BEA decreased GC and 11-ßHSD1 expression while increasing 11-ßHSD2 expression. These molecular effects of BEA were associated with a reduction in hyperglycemia and liver steatosis, lower lung bacillary loads and pneumonia. These results uphold BEA as a promising effective therapy for the T2D/TB co-morbidity.
Asunto(s)
Androsterona/farmacología , Antituberculosos/farmacología , Diabetes Mellitus Experimental/tratamiento farmacológico , Hipoglucemiantes/farmacología , Tuberculosis/tratamiento farmacológico , 11-beta-Hidroxiesteroide Deshidrogenasas/metabolismo , Animales , Comorbilidad , Corticosterona/farmacología , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Modelos Animales de Enfermedad , Hidrocortisona/metabolismo , Pulmón/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Mycobacterium tuberculosis/efectos de los fármacos , Tuberculosis/metabolismoRESUMEN
Glucose 6-phosphate dehydrogenase (G6PDH) fulfills an essential role in cell physiology by catalyzing the production of NADPH+ and of a precursor for the de novo synthesis of ribose 5-phosphate. In trypanosomatids, G6PDH is essential for in vitro proliferation, antioxidant defense and, thereby, drug resistance mechanisms. So far, 16α-brominated epiandrosterone represents the most potent hit targeting trypanosomal G6PDH. Here, we extended the investigations on this important drug target and its inhibition by using a small subset of androstane derivatives. In Trypanosoma cruzi, immunofluorescence revealed a cytoplasmic distribution of G6PDH and the absence of signal in major organelles. Cytochemical assays confirmed parasitic G6PDH as the molecular target of epiandrosterone. Structure-activity analysis for a set of new (dehydro)epiandrosterone derivatives revealed that bromination at position 16α of the cyclopentane moiety yielded more potent T. cruzi G6PDH inhibitors than the corresponding ß-substituted analogues. For the 16α brominated compounds, the inclusion of an acetoxy group at position 3 either proved detrimental or enhanced the activity of the epiandrosterone or the dehydroepiandrosterone derivatives, respectively. Most derivatives presented single digit µM EC50 against infective T. brucei and the killing mechanism involved an early thiol-redox unbalance. This data suggests that infective African trypanosomes lack efficient NADPH+-synthesizing pathways, beyond the Pentose Phosphate, to maintain thiol-redox homeostasis.
Asunto(s)
Glucosafosfato Deshidrogenasa/metabolismo , Estadios del Ciclo de Vida , Esteroides/farmacología , Trypanosoma brucei brucei/enzimología , Trypanosoma brucei brucei/crecimiento & desarrollo , Androsterona/química , Androsterona/farmacología , Sitios de Unión , Citosol/enzimología , Deshidroepiandrosterona/química , Deshidroepiandrosterona/farmacología , Glucosafosfato Deshidrogenasa/antagonistas & inhibidores , Glucosafosfato Deshidrogenasa/química , Humanos , Estadios del Ciclo de Vida/efectos de los fármacos , Modelos Moleculares , Oxidación-Reducción , Reproducibilidad de los Resultados , Trypanosoma brucei brucei/efectos de los fármacosRESUMEN
The synthesis, cytotoxicity and inhibition of CDK8 by thirteen analogs of cortistatin A are reported. These efforts revealed that the analogs with either a 6- or 7-isoquinoline or 5-indole side chain in the 17-position are the most promising anti-proliferative agents. These compounds showed potent cytotoxic effects in CEM, HeLa and HMEC-1 cells. All three compounds exhibited IC50 values < 10µM. The most interesting 10l analog exhibited an IC50 value of 0.59 µM towards the human dermal microvascular endothelial cell line (HMEC-1), significantly lower than the reference standard 2-methoxyestradiol. At a concentration at 50 nM the most potent 10h compound reduced the activity of CDK8 to 35%.
Asunto(s)
Androsterona/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Quinasa 8 Dependiente de Ciclina/antagonistas & inhibidores , Diseño de Fármacos , Leucemia de Células T/tratamiento farmacológico , Androsterona/análogos & derivados , Proliferación Celular , Ensayos de Selección de Medicamentos Antitumorales , Células HeLa , Humanos , Leucemia de Células T/patología , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
Pyridine nucleotides, such as NADPH and NADH, are emerging as critical players in the regulation of heart and vascular function. Glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme in the pentose phosphate pathway, is the primary source and regulator of cellular NADPH. In the current study, we have identified two isoforms of G6PD (slow and fast migrating) and functionally characterized the slow migrating isoform of G6PD (G6PD545) in bovine and human arteries. We found that G6PD545 is eluted in the caveolae fraction of vascular smooth muscle (VSM) and has a higher maximum rate of reaction (Vmax: 1.65-fold) than its fast migrating isoform (G6PD515). Interestingly, caveolae G6PD forms a complex with the pore-forming α1C-subunit of the L-type Ca2+ channel, Cav1.2, as demonstrated by a proximity ligation assay in fixed VSMCs. Additionally, Förster resonance energy transfer (FRET) analysis of HEK293-17T cells cotransfected with red fluorescent protein (RFP)-tagged G6PD545 (C-G6PD545) and green fluorescent protein (GFP)-tagged Cav1.2-(Cav1.2-GFP) demonstrated strong FRET signals as compared with cells cotransfected with Cav1.2-GFP and C-G6PD515. Furthermore, L-type Ca2+ channel conductance was larger and the voltage-independent component of availability (c1) was augmented in C-G6PD545 and Cav1.2-GFP cotransfectants compared with those expressing Cav1.2-GFP alone. Surprisingly, epiandrosterone, a G6PD inhibitor, disrupted the G6PD-Cav1.2 complex, also decreasing the amplitude of L-type Ca2+ currents and window currents, thereby reducing the availability of the c1 component. Moreover, overexpression of adeno-G6PD545-GFP augmented the KCl-induced contraction in coronary arteries compared with control. To determine whether overexpression of G6PD had any clinical implication, we investigated its activity in arteries from patients and rats with metabolic syndrome and found that G6PD activity was high in this disease condition. Interestingly, epiandrosterone treatment reduced elevated mean arterial blood pressure and peripheral vascular resistance in metabolic syndrome rats, suggesting that the increased activity of G6PD augmented vascular contraction and blood pressure in the metabolic syndrome. These data suggest that the novel G6PD-Cav1.2 interaction, in the caveolae fraction, reduces intrinsic voltage-dependent inactivation of the channel and contributes to regulate VSM L-type Ca2+ channel function and Ca2+ signaling, thereby playing a significant role in modulating vascular function in physiological/pathophysiological conditions.NEW & NOTEWORTHY In this study we have identified a novel isozyme of glucose-6-phosphate dehydrogenase (G6PD), a metabolic enzyme, that interacts with and contributes to regulate smooth muscle cell l-type Ca2+ ion channel function, which plays a crucial role in vascular function in physiology and pathophysiology. Furthermore, we demonstrate that expression and activity of this novel G6PD isoform are increased in arteries of individuals with metabolic syndrome and in inhibition of G6PD activity in rats of metabolic syndrome reduced blood pressure.
Asunto(s)
Arterias/metabolismo , Canales de Calcio Tipo L/metabolismo , Glucosafosfato Deshidrogenasa/metabolismo , Potenciales de Acción , Androsterona/farmacología , Animales , Arterias/efectos de los fármacos , Arterias/fisiología , Presión Sanguínea , Bovinos , Caveolas/metabolismo , Células Cultivadas , Inhibidores Enzimáticos/farmacología , Glucosafosfato Deshidrogenasa/antagonistas & inhibidores , Células HEK293 , Humanos , Isoenzimas/antagonistas & inhibidores , Isoenzimas/metabolismo , Masculino , Ratones , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/fisiología , Unión Proteica , Transporte de Proteínas , Ratas , Ratas Sprague-Dawley , VasoconstricciónRESUMEN
Decreasing the intratumoral androgen biosynthesis by using an inhibitor of 17ß-hydroxysteroid dehydrogenase type 3 (17ß-HSD3) is a strategy to treat prostate cancer. The androsterone (ADT) derivative 1 (RM-532-105) has shown strong inhibitory activity on 17ß-HSD3, but needs to be improved. Herein, we describe the chemical synthesis and characterization of two series of analogues to address the impact of A- and D-ring modifications on 17ß-HSD3 inhibitory activity, androgenic effect, and metabolic stability. Structure-activity relationships were generated by adding different groups at C16/C17 (D-ring diversification) or replacing the ADT backbone by a nor-androstane or an estrane backbone (A-ring diversification). D-ring derivatives were less potent inhibitors than lead compound 1, whereas steroidal backbone (A-ring) change led to identifying promising novel estrane derivatives. This culminated with potent 17ß-HSD3 inhibitors 23, 27, 31, and 33 (IC50 = 0.10, 0.02, 0.13, and 0.17 µM, respectively), which did not stimulate LAPC-4 cell proliferation and displayed higher plasma concentration in mice than lead compound 1.
Asunto(s)
17-Hidroxiesteroide Deshidrogenasas/antagonistas & inhibidores , 17-Hidroxiesteroide Deshidrogenasas/química , Androsterona/análogos & derivados , Androsterona/farmacología , Androsterona/uso terapéutico , Animales , Línea Celular Tumoral , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Femenino , Humanos , Masculino , Ratones , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/enzimología , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
This study evaluated the effect of androsterone (AND), a metabolite of testosterone, on the ability of selected classical and novel antiepileptic drugs to prevent seizures caused by maximal electroshock (MES), which may serve as an experimental model of human generalized tonic-clonic seizures in mice. Single intraperitoneal (i.p.) administration of AND (80 mg kg-1) significantly raised the threshold for convulsions in the MES seizure threshold test. Lower doses of AND (5, 10, 20, and 40 mg kg-1) failed to change the threshold. AND at a subthreshold dose of 40 mg kg-1 significantly enhanced the protective activity of carbamazepine, gabapentin, and phenobarbital against MES-induced seizures decreasing their median effective doses (ED50) values ± SEM from 8.59 ± 0.76 to 6.05 ± 0.81 mg kg-1 (p = 0.0308) for carbamazepine, from 419.9 ± 120.6 to 111.5 ± 41.1 mg kg-1 (p = 0.0405) for gabapentin, and from 20.86 ± 1.64 to 10.0 ± 1.21 mg kg-1 (p = 0.0007) for phenobarbital. There were no significant changes in total brain concentrations of carbamazepine, gabapentin, and phenobarbital following AND administration. This suggests that the enhancing effects of AND on the protective activity of these antiepileptic drugs are not related to pharmacokinetic factors. A lower dose of AND (20 mg kg-1) had no effect on the protective activity of carbamazepine, gabapentin, and phenobarbital. AND administered at a dose of 40 mg kg-1 failed to change the anticonvulsant activity of lamotrigine, oxcarbazepine, phenytoin, topiramate, and valproate in the MES test. In the chimney test, AND given at a dose enhancing the protective activity of carbamazepine, gabapentin, and phenobarbital (which alone was without effect on motor performance of mice) did not affect impairment of motor coordination produced by the antiepileptics. Our findings recommend further preclinical and clinical research on AND in respect of its use as adjuvant therapy in the management of epilepsy in men with deficiency of androgens.
Asunto(s)
Androsterona/farmacología , Anticonvulsivantes/metabolismo , Convulsiones/fisiopatología , Andrógenos/metabolismo , Androsterona/metabolismo , Animales , Anticonvulsivantes/farmacología , Reacción de Prevención/efectos de los fármacos , Encéfalo/metabolismo , Carbamazepina , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Electrochoque , Epilepsia/complicaciones , Gabapentina , Masculino , Ratones , Fenobarbital , Desempeño Psicomotor/efectos de los fármacos , Convulsiones/metabolismoRESUMEN
One of the mechanisms of cocaine's actions in the central nervous system is its antidepressant action. This effect might be responsible for increased usage of the drug by individuals with mood disorders. Higher endogenous levels of the excitatory neurosteroid dehydroepiandrosterone sulfate (DHEAS) were reported to correlate with successful abstinence from cocaine use in addicts, but a clinical trial showed that supplementation with a high dose of DHEA increased cocaine usage instead. Such ambiguous effects of DHEA(S) could potentially be linked to its influence on the antidepressant effect of cocaine. In this study we tested DHEAS and its metabolite, androsterone, for interactions with cocaine in animal model of depression (forced swim test) and examined the effects of both steroids and cocaine on serotoninergic neurotransmission. All substances were also tested for influence on locomotor activity. A cocaine dose of 5mg/kg, which had no significant effect on locomotor activity, was chosen for the forced swim test. Neither DHEAS nor androsterone showed any antidepressant action in this test, while cocaine manifested a clear antidepressant effect. Androsterone slightly reduced the antidepressant influence of cocaine while DHEAS markedly, dose-dependently enhanced it. Such an effect might be caused by the influence of DHEAS on serotonin neurotransmission, as this steroid decreased serotonin concentration and turnover in the striatum. When DHEAS and cocaine were administered together, the levels of serotonin in the striatum and hippocampus remained unchanged. This phenomenon may explain the additive antidepressant action of DHEAS and cocaine and why co-administration of DHEAS and cocaine increases drug use.
Asunto(s)
Androsterona/farmacología , Antidepresivos/farmacología , Cocaína/farmacología , Sulfato de Deshidroepiandrosterona/farmacología , Serotonina/fisiología , Transmisión Sináptica/efectos de los fármacos , Animales , Química Encefálica/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Masculino , Actividad Motora/efectos de los fármacos , Ratas , Ratas Wistar , Natación/psicologíaRESUMEN
RATIONALE: Animal models suggest that neuroactive steroids contribute to alcohol's acute effects. We previously reported that a common nonsynonymous polymorphism, AKR1C3 2 in the gene encoding the enzyme 3α-HSD2/17ß-HSD5, and a synonymous single nucleotide polymorphism (SNP), rs248793, in SRD5A1, which encodes 5α-reductase, were associated with alcohol dependence (AD). OBJECTIVES: The aim of the study was to investigate whether these polymorphisms moderate subjective effects of alcohol in humans and whether AKR1C3 2 affects neuroactive steroid synthesis. METHODS: Sixty-five Caucasian men (34 lighter and 31 heavier drinkers; mean age 26.2 years) participated in a double-blind laboratory study where they consumed drinks containing no ethanol or 0.8 g/kg of ethanol. Breath alcohol, heart rate (HR), and self-reported alcohol effects were measured at 40-min intervals, and genotype was examined as a moderator of alcohol's effects. Levels of the neuroactive steroid 5α-androstane-3α,17ß-diol and its precursors, 3α,5α-androsterone and dihydrotestosterone, were measured at study entry using GC/MS. RESULTS: Initially, carriers of the AD-protective AKR1C3 2 G allele had higher levels of 5α-androstane-3α,17ß-diol relative to the precursor 3α,5α-androsterone than C allele homozygotes. AKR1C3 2 G allele carriers exhibited greater increases in heart rate and stimulant and sedative effects of alcohol than C allele homozygotes. The genotype effects on sedation were observed only in heavier drinkers. The only effect of the SRD5A1 SNP was to moderate HR. There were no interactive effects of the two SNPs. CONCLUSIONS: The observed effects of variation in a gene encoding a neuroactive steroid biosynthetic enzyme on the rate of 17ß-reduction of androsterone relative to androstanediol and on alcohol's sedative effects may help to explain the association of AKR1C3 2 with AD.
Asunto(s)
3-Hidroxiesteroide Deshidrogenasas/genética , Consumo de Bebidas Alcohólicas/genética , Consumo de Bebidas Alcohólicas/psicología , Depresores del Sistema Nervioso Central/farmacología , Etanol/farmacología , Hidroxiprostaglandina Deshidrogenasas/genética , Inhibidores de 5-alfa-Reductasa/farmacología , Inhibidores de 5-alfa-Reductasa/uso terapéutico , Adulto , Alcoholismo/genética , Alcoholismo/psicología , Miembro C3 de la Familia 1 de las Aldo-Ceto Reductasas , Androsterona/farmacología , Azaesteroides/farmacología , Azaesteroides/uso terapéutico , Método Doble Ciego , Dutasterida , Moduladores del GABA/farmacología , Variación Genética , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple/genética , Receptores de GABA-A/efectos de los fármacos , Adulto JovenRESUMEN
RATIONALE: Androsterone [(3α,5α)-3-hydroxyandrostan-17-one; 5α,3α-A] and its 5ß-epimer etiocholanolone [(3α,5ß)-3-hydroxyandrostan-17-one; 5ß,3α-A)], the major excreted metabolites of testosterone, are neurosteroid positive modulators of GABAA receptors. Such neurosteroids typically show enantioselectivity in which the natural form is more potent than the corresponding unnatural enantiomer. For 5α,3α-A and 5ß,3α-A, the unnatural enantiomers are more potent at GABAA receptors than the natural forms. OBJECTIVES: The aim of this study was to compare the anticonvulsant potencies and time courses of 5α,3α-A and 5ß,3α-A with their enantiomers in mouse seizure models. METHODS: Steroids were administered intraperitoneally to male NIH Swiss mice 15 min (or up to 6 h in time course experiments) prior to administration of an electrical stimulus in the 6-Hz or maximal electroshock (MES) seizure tests or the convulsant pentylenetetrazol (PTZ). RESULTS: In the 6-Hz test, the ED50 values of ent-5α,3α-A was 5.0 mg/kg whereas the value for 5α,3α-A was 12.1 mg/kg; the corresponding values in the PTZ seizure test were 22.8 and 51.8 mg/kg. Neurosteroid GABAA receptor-positive allosteric modulators are generally weak in the MES seizure test and this was confirmed in the present study. However, the atypical relative potency relationship was maintained with ED50 values of 140 and 223 mg/kg for ent-5α,3α-A and 5α,3α-A, respectively. Similar relationships were obtained for the 5ß-isomers, except that the enantioselectivity was accentuated. In the 6-Hz and PTZ tests, the ED50 values of ent-5ß,3α-A were 11.8 and 20.4 mg/kg whereas the values for 5ß,3α-A were 57.6 and 109.1 mg/kg. Protective activity in the 6-Hz test of ent-5α,3α-A persisted for somewhat longer (~5 h) than for 5α,3α-A (~4 h); protection by ent-5ß,3α-A also persisted longer (~3 h) than for 5ß,3α-A (~2 h). CONCLUSIONS: The unnatural enantiomers of 17-keto androgen class neurosteroids have greater in vivo potency and a longer duration of action than their natural counterparts. The more prolonged duration of action of the unnatural enantiomers could reflect reduced susceptibility to metabolism. Unnatural enantiomers of androgen class neurosteroids could have therapeutic utility and may provide advantages over the corresponding natural isomers due to enhanced potency and improved pharmacokinetic characteristics.
Asunto(s)
Androsterona/farmacología , Anticonvulsivantes/farmacología , Etiocolanolona/farmacología , Neurotransmisores/farmacología , Androsterona/química , Animales , Conducta Animal/efectos de los fármacos , Convulsivantes/farmacología , Relación Dosis-Respuesta a Droga , Discinesia Inducida por Medicamentos/psicología , Electrochoque , Etiocolanolona/química , Masculino , Ratones , Neurotransmisores/química , Pentilenotetrazol/antagonistas & inhibidores , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Prohormone supplements (PS) are recognized not to impart anabolic or ergogenic effects in men, but the research supporting these conclusions is dated. The Anabolic Steroid Control Act was amended in 2004 to classify androstenedione and 17 additional anabolic compounds as controlled substances. The viability of PS that entered the market after that time have not been evaluated. Seventeen resistance-trained men (23 ± 1 yr; 13.1 ± 1.5% body fat) were randomly assigned to receive either 330 mg/day of 3ß-hydroxy-5α-androst-1-en-17-one (Prohormone; n = 9) or sugar (Placebo; n = 8) per os and complete a 4-wk (16 session) structured resistance-training program. Body composition, muscular strength, circulating lipids, and markers of liver and kidney dysfunction were assessed at study onset and termination. Prohormone increased lean body mass by 6.3 ± 1.2%, decreased fat body mass by 24.6 ± 7.1%, and increased their back squat one repetition maximum and competition total by 14.3 ± 1.5 and 12.8 ± 1.1%, respectively. These improvements exceeded (P < 0.05) Placebo, which increased lean body mass by 0.5 ± 0.8%, reduced fat body mass by 9.5 ± 3.6%, and increased back squat one repetition maximum and competition total by 5.7 ± 1.7 and 5.9 ± 1.7%, respectively. Prohormone also experienced multiple adverse effects. These included a 38.7 ± 4.0% reduction in HDL (P < 0.01), a 32.8 ± 15.05% elevation in LDL (P < 0.01), and elevations of 120.0 ± 22.6 and 77.4 ± 12.0% in LDL-to-HDL and cholesterol-to-HDL ratios, respectively (both P < 0.01). Prohormone also exhibited elevations in serum creatinine (19.6 ± 4.3%; P < 0.01) and aspartate transaminase (113.8 ± 61.1%; P = 0.05), as well as reductions in serum albumin (5.1 ± 1.9%; P = 0.04), alkaline phosphatase (16.4 ± 4.7%; P = 0.04), and glomerular filtration rate (18.0 ± 3.3%; P = 0.04). None of these values changed (all P > 0.05) in Placebo. The oral PS 3ß-hydroxy-5α-androst-1-en-17-one improves body composition and muscular strength. However, these changes come at a significant cost. Cardiovascular health and liver function are particularly compromised. Given these findings, we feel the harm associated with this particular PS outweighs any potential benefit.
Asunto(s)
Anabolizantes/efectos adversos , Anabolizantes/farmacología , Androsterona/análogos & derivados , Suplementos Dietéticos/efectos adversos , Entrenamiento de Fuerza/métodos , Adolescente , Adulto , Afecto/efectos de los fármacos , Anabolizantes/farmacocinética , Androsterona/efectos adversos , Androsterona/farmacocinética , Androsterona/farmacología , Ira/efectos de los fármacos , Composición Corporal/efectos de los fármacos , Dieta , Método Doble Ciego , Humanos , Pruebas de Función Renal , Lípidos/sangre , Hígado/metabolismo , Pruebas de Función Hepática , Masculino , Fuerza Muscular/efectos de los fármacos , Tamaño de los Órganos/efectos de los fármacos , Educación y Entrenamiento Físico , Profármacos , Encuestas y Cuestionarios , Testosterona/metabolismo , Adulto JovenRESUMEN
OBJECTIVES: The aim of this work was to identify the uridine glucuronosyltransferase (UGT) isoforms involved in the metabolism of the broad-spectrum antiviral drug arbidol. METHODS: A human liver microsome (HLM) incubation system was employed to catalyse the formation of arbidol glucuronide. The glucuronidation activity of commercially recombinant UGT isoforms towards arbidol was screened. A combination of kinetic analysis and chemical inhibition study was used to determine the UGT isoforms involved in arbidol's glucuronidation. KEY FINDINGS: The arbidol glucuronide was detected when arbidol was incubated with HLMs in the presence of UDP-glucuronic acid. The Eadie-Hofstee plot showed that glucuronidation of arbidol was best fit to the Michaelis-Menten kinetic model, and K(m) and apparent V(max) were calculated to be 8.0 ± 0.7 µm and 2.03 ± 0.05 nmol/min/mg protein, respectively. Assessment of a panel of recombinant UGT isoforms revealed that UGT1A1, UGT1A3 and UGT1A9 could catalyse the glucuronidation of arbidol. Kinetic analysis and chemical inhibition study demonstrated that UGT1A9 was the predominant UGT isoform involved in arbidol glucuronidation in HLMs. CONCLUSIONS: The major contribution of UGT1A9 towards arbidol glucuronidation was demonstrated in this study.
Asunto(s)
Antivirales/metabolismo , Glucurónidos/metabolismo , Glucuronosiltransferasa/metabolismo , Indoles/metabolismo , Fase II de la Desintoxicación Metabólica , Microsomas Hepáticos/enzimología , Androsterona/farmacología , Antivirales/química , Inhibidores Enzimáticos/farmacología , Clorhidrato de Erlotinib , Glucurónidos/química , Glucuronosiltransferasa/antagonistas & inhibidores , Glucuronosiltransferasa/genética , Humanos , Indoles/química , Isoenzimas/antagonistas & inhibidores , Isoenzimas/genética , Isoenzimas/metabolismo , Cinética , Ácido Mefenámico/farmacología , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Quinazolinas/farmacología , Proteínas Recombinantes/antagonistas & inhibidores , Proteínas Recombinantes/metabolismo , Espectrometría de Masas en Tándem , UDP Glucuronosiltransferasa 1A9 , Uridina Difosfato Ácido Glucurónico/metabolismoRESUMEN
The effect of 16α-bromoepiandrosterone (EpiBr), a dehydroepiandrosterone (DHEA) analogue, was tested on the cysticerci of Taenia solium, both in vitro and in vivo. In vitro treatment of T. solium cultures with EpiBr reduced scolex evagination, growth, motility, and viability in dose- and time-dependent fashions. Administration of EpiBr prior to infection with T. solium cysticerci in hamsters reduced the number and size of developed taenias in the intestine, compared with controls. These effects were associated to an increase in splenocyte proliferation in infected hamsters. These results leave open the possibility of assessing the potential of this hormonal analogue as a possible antiparasite drug, particularly in cysticercosis and taeniosis.
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Androsterona/análogos & derivados , Antiparasitarios/farmacología , Cisticercosis/tratamiento farmacológico , Taenia solium/efectos de los fármacos , Androsterona/farmacología , Animales , Proliferación Celular/efectos de los fármacos , Cricetinae , Deshidroepiandrosterona/análogos & derivados , Deshidroepiandrosterona/química , Entamoeba histolytica/efectos de los fármacos , Intestinos/parasitología , Masculino , Mesocricetus , Músculos/parasitología , Bazo/citología , Bazo/parasitología , PorcinosRESUMEN
The title compounds, (3R,5S,5'R,8R,9S,10S,13S,14S)-10,13-dimethyl-5'-(2-methylpropyl)tetradecahydro-6'H-spiro[cyclopenta[a]phenanthrene-3,2'-[1,4]oxazinane]-6',17(2H)-dione, C(26)H(41)NO(3), (I), and methyl (2R)-2-[(3R,5S,8R,9S,10S,13S,14S)-10,13-dimethyl-2',17-dioxohexadecahydro-3'H-spiro[cyclopenta[a]phenanthrene-3,5'-[1,3]oxazolidin-3'-yl]]-4-methylpentanoate, C(28)H(43)NO(5), (II), possess the typical steroid shape (A-D rings), but they differ in their extra E ring. The azalactone E ring in (I) shows a half-chair conformation, while the carbamate E ring of (II) is planar. The orientation of the E-ring substituent is clearly established and allows a rationalization of the biological results obtained with such androsterone derivatives.
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Antagonistas de Andrógenos/química , Antagonistas de Andrógenos/farmacología , Andrógenos/biosíntesis , Andrógenos/química , Androsterona/química , Androsterona/farmacología , Androsterona/análogos & derivados , Cristalografía por Rayos X , Modelos MolecularesRESUMEN
Although odour perception impacts food preferences, the effect of genotypic variation of odorant receptors (ORs) on the sensory perception of food is unclear. Human OR7D4 responds to androstenone, and genotypic variation in OR7D4 predicts variation in the perception of androstenone. Since androstenone is naturally present in meat derived from male pigs, we asked whether OR7D4 genotype correlates with either the ability to detect androstenone or the evaluation of cooked pork tainted with varying levels of androstenone within the naturally-occurring range. Consistent with previous findings, subjects with two copies of the functional OR7D4 RT variant were more sensitive to androstenone than subjects carrying a non-functional OR7D4 WM variant. When pork containing varying levels of androstenone was cooked and tested by sniffing and tasting, subjects with two copies of the RT variant tended to rate the androstenone-containing meat as less favourable than subjects carrying the WM variant. Our data is consistent with the idea that OR7D4 genotype predicts the sensory perception of meat containing androstenone and that genetic variation in an odorant receptor can alter food preferences.
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Androsterona/farmacología , Variación Genética/genética , Carne , Receptores Odorantes/genética , Sensación/efectos de los fármacos , Sensación/genética , Animales , Genotipo , Masculino , Olfato/genética , Porcinos , Gusto/genéticaRESUMEN
The aim of study was to elucidate the influence of foliar sprays of androsterone in alleviating detrimental effects of chilling stress in maize seedlings. Eleven-days-old maize seedlings were treated with 10(-9) mol L(-1) androsterone and then transferred to a chamber with temperature of 10/7 °C (day/night) for 3 days. The stress injury was measured in terms of increase in electrolyte leakage, superoxide production and hydrogen peroxide level, and decrease in chlorophyll content. Androsterone application mitigated significantly the chilling-induced stress injury. Under chilling stress, the oxidative damage which was measured as malondialdehyde content was lesser in androsterone-applied seedlings that were associated with greater activities of superoxide dismutase (SOD), catalase (CAT), guaiacol peroxidase (POX), ascorbate peroxidase (APX) and glutathione reductase (GR). Moreover, SOD, POX and APX isozymes exhibited a strong correlation with changes in their activities. Androsterone application enhanced the level of antioxidant compounds like ascorbic acid, glutathione, proline and carotenoid as well as activities of antioxidant enzymes. Similarly, while androsterone treatment increased total antioxidant status, it reduced total oxidant status relative to chilling-stressed seedlings alone. Soluble protein profile was significantly changed by only chilling stress and chilling stress plus androsterone treatment, as well. According to these findings, it is possible to say that androsterone could be used to alleviate the damaging effects of chilling stress by improving antioxidative system in maize seedlings. This is the first study elucidating the effects of androsterone on resistance to chilling stress of plants.
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Androsterona/farmacología , Frío , Plantones/efectos de los fármacos , Plantones/metabolismo , Zea mays/efectos de los fármacos , Zea mays/metabolismo , Antioxidantes/metabolismo , Ascorbato Peroxidasas/metabolismo , Catalasa/metabolismo , Regulación de la Expresión Génica de las Plantas/efectos de los fármacos , Glutatión/metabolismo , Glutatión Reductasa/metabolismo , Peróxido de Hidrógeno/metabolismo , Isoenzimas/metabolismo , Malondialdehído/metabolismo , Peroxidasa/metabolismo , Plantones/fisiología , Superóxido Dismutasa/metabolismo , Zea mays/fisiologíaRESUMEN
The neurosteroids, dehydroepiandrosterone sulfate (DHEAS) and androsterone, are implicated in drug addictions. We examined their influence on locomotor activity and reward in male Wistar rats, and on steroid and monoamine metabolism in the hippocampus and striatum. In the open field test, DHEAS injections (10, 40, 80 mg/kg, i.p.) 30 min prior the test had no significant effect on ambulation, but androsterone (10 mg/kg) increased general locomotion and at doses 1-10 mg/kg, increased central field activity, suggestive of an anxiolytic action. In the conditioned place preference test, both steroids had a biphasic effect: DHEAS was rewarding at doses of 10 and 40 mg/kg, but not at 80 mg/kg, while androsterone was rewarding at doses of 1 and 10 mg/kg, but aversive at 40 mg/kg. Monoamine and steroid concentrations were analyzed in homogenates from the hippocampus and striatum of DHEAS and androsterone injected rats. DHEAS reduced the hippocampal dopamine level, increased striatal homovanilic acid (HVA) and decreased the striatal serotonin concentrations. Androsterone did not affect dopamine levels or turnover, but increased noradrenaline concentration and serotonin turnover in the hippocampus. DHEAS administration augmented concentrations of DHEA, pregnenolone, androstendiol and androstentriol in both brain structures, while androsterone injections increased brain levels of androsterone, epiandrosterone, 5α-dihydrotestosterone, and androstandiol. Present data document that although psychobehavioral and neurochemical effects of DHEAS and androsterone differ in several aspects; both neurosteroids have rewarding properties at certain dose ranges, suggesting their likely involvement in addictions, which entail different mechanisms.
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Androsterona/farmacología , Sulfato de Deshidroepiandrosterona/farmacología , Desempeño Psicomotor , Recompensa , Esteroides/metabolismo , Animales , Ganglios Basales/efectos de los fármacos , Ganglios Basales/metabolismo , Aminas Biogénicas/metabolismo , Dopamina/metabolismo , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Masculino , Pregnenolona/metabolismo , Ratas , Ratas Wistar , Serotonina/metabolismoRESUMEN
7ß-Hydroxy-epiandrosterone (7ß-OH-EpiA), an endogenous androgenic derivative of dehydroepiandrosterone, has previously been shown to exert anti-inflammatory action in vitro and in vivo via a shift from prostaglandin E2 (PGE2) to 15-deoxy-Δ(12,14)-PGJ2 production. This modulation in prostaglandin production was obtained with low concentrations of 7ß-OH-EpiA (1-100nM) and suggested that it might act through a specific receptor. Inflammation and prostaglandin synthesis is important in the development and survival of estrogen-dependent mammary cancers. Estrogen induced PGE2 production and cell proliferation via its binding to estrogen receptors (ERs) in these tumors. Our objective was to test the effects of 7ß-OH-EpiA on the proliferation (by counting with trypan blue exclusion), cell cycle and cell apoptosis (by flow cytometry) of breast cancer cell lines MCF-7 (ERα+, ERß+, G-protein coupled receptor 30: GPR30+) and MDA-MB-231 (ERα-, ERß+, GPR30+) and to identify a potential target of this steroid in these cell lineages (by transactivations) and in the nuclear ER-negative SKBr3 cells (GPR30+) (by proliferation assays). 7ß-OH-EpiA exerted anti-estrogenic effects in MCF-7 and MDA-MB-231 cells associated with cell proliferation inhibition and cell cycle arrest. Moreover, transactivation and proliferation with ER agonists assays indicated that 7ß-OH-EpiA interacted with ERß. Data from proliferation assays on the MCF-7, MDA-MB-231 and SKBr3 cell lines suggested that 7ß-OH-EpiA may also act through the membrane GPR30 receptor. These results support that this androgenic steroid acts as an anti-estrogenic compound. Moreover, this is the first evidence that low doses of androgenic steroid exert antiproliferative effects in these mammary cancer cells. Further investigations are needed to improve understanding of the observed actions of endogenous 7ß-OH-EpiA.
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Androsterona/análogos & derivados , Proliferación Celular/efectos de los fármacos , Deshidroepiandrosterona/metabolismo , Antagonistas de Estrógenos/farmacología , Androsterona/química , Androsterona/metabolismo , Androsterona/farmacología , Apoptosis/efectos de los fármacos , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Ciclooxigenasa 2/genética , Relación Dosis-Respuesta a Droga , Antagonistas de Estrógenos/química , Antagonistas de Estrógenos/metabolismo , Receptor alfa de Estrógeno/metabolismo , Receptor beta de Estrógeno/metabolismo , Femenino , Citometría de Flujo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Oxidorreductasas Intramoleculares/genética , Lipocalinas/genética , Redes y Vías Metabólicas , Estructura Molecular , PPAR gamma/genética , Prostaglandina-E Sintasas , Receptores de Estrógenos/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factores de TiempoRESUMEN
Twin pairs and their siblings rated the intensity of the odorants amyl acetate, androstenone, eugenol, Galaxolide, mercaptans, and rose (N = 1573). Heritability was established for ratings of androstenone (h (2) = 0.30) and Galaxolide (h(2) = 0.34) but not for the other odorants. Genome-wide association analysis using 2.3 million single nucleotide polymorphisms indicated that the most significant association was between androstenone and a region without known olfactory receptor genes (rs10966900, P = 1.2 × 10(-7)). A previously reported association between the olfactory receptor OR7D4 and the androstenone was not detected until we specifically typed this gene (P = 1.1 × 10(-4)). We also tested these 2 associations in a second independent sample of subjects and replicated the results either fully (OR7D4, P = 0.00002) or partially (rs10966900, P = 0.010; N = 266). These findings suggest that 1) the perceived intensity of some but not all odorants is a heritable trait, 2) use of a current genome-wide marker panel did not detect a known olfactory genotype-phenotype association, and 3) person-to-person differences in androstenone perception are influenced by OR7D4 genotype and perhaps by variants of other genes.
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Androsterona/farmacología , Benzopiranos/farmacología , Estudio de Asociación del Genoma Completo , Odorantes/análisis , Receptores Odorantes/genética , Olfato/efectos de los fármacos , Olfato/genética , Adolescente , Adulto , Niño , Femenino , Genotipo , Humanos , Masculino , Polimorfismo Genético/genética , Receptores Odorantes/metabolismo , Hermanos , Olfato/fisiología , Estimulación Química , Adulto JovenRESUMEN
Edaravone was launched in Japan in 2001 and was the first neuroprotectant developed for the treatment of acute cerebral infarction. Edaravone is mainly eliminated as glucuronide conjugate in human urine (approximately 70%), but the mechanism involved in the elimination pathway remains unidentified. We investigated the glucuronidation of edaravone in human liver microsomes (HLM) and human kidney microsomes (HKM) and identified the major hepatic and renal UDP-glucuronosyltransferases (UGTs) involved. As we observed, edaravone glucuronidation in HLM and HKM exhibited biphasic kinetics. The intrinsic clearance of glucuronidation at high-affinity phase (CL(int1)) and low-affinity phase (CL(int2)) were 8.4 ± 3.3 and 1.3 ± 0.2 µl · min(-1) · mg(-1), respectively, for HLM and were 45.3 ± 8.2 and 1.8 ± 0.1 µl · min(-1) · mg(-1), respectively, for HKM. However, in microsomal incubations contained with 2% bovine serum albumin, CL(int1) and CL(int2) were 16.4 ± 1.2 and 3.7 ± 0.3 µl · min(-1) · mg(-1), respectively, for HLM and were 78.5 ± 3.9 and 3.6 ± 0.5 µl · min(-1) · mg(-1), respectively, for HKM. Screening with 12 recombinant UGTs indicated that eight UGTs (UGT1A1, UGT1A6, UGT1A7, UGT1A8, UGT1A9, UGT1A10, UGT2B7, and UGT2B17) produced a significant amount of glucuronide metabolite. Thus, six UGTs (UGT1A1, UGT1A6, UGT1A7, UGT1A9, UGT2B7, and UGT2B17) expressed in human liver or kidney were selected for kinetic studies. Among them, UGT1A9 exhibited the highest activity (CL(int1) = 42.4 ± 9.5 µl · min(-1) · mg(-1)), followed by UGT2B17 (CL(int) = 3.3 ± 0.4 µl · min(-1) · mg(-1)) and UGT1A7 (CL(int) = 1.7 ± 0.2 µl · min(-1) · mg(-1)). Inhibition study found that inhibitor of UGT1A9 (propofol) attenuated edaravone glucuronidation in HLM and HKM. In addition, edaravone glucuronidation in a panel of seven HLM was significantly correlated (r = 0.9340, p = 0.0021) with propofol glucuronidation. Results indicated that UGT1A9 was the main UGT isoform involved in edaravone glucuronidation in HLM and HKM.