RESUMO
Stanozonol (ST) is a synthetic derivative of testosterone; it has anabolic/androgenic activity, increasing both the turnover of trabecular bone and the endocortical apposition of bone. The present study aimed to examine the effects of ST on bone status in rats by bone mineral content, markers of formation and resorption, bone density, and structural and microarchitectural parameters. Twenty male Wistar rats were randomly distributed into two experimental groups corresponding to placebo or ST administration, which consisted of weekly intramuscular injections of 10 mg/kg body weight of ST. Plasma parameters were analyzed by immunoassay. Bone mineral content was determined by spectrophotometry. Bone mineral density (BMD) and structural parameters were measured by peripheral quantitative computed tomography, and trabecular and cortical microarchitecture by micro-computed tomography. Plasma Ca, Mg, and alkaline phosphatase were higher, and urinary Ca excretion, corticosterone, and testosterone concentrations lower in the ST group. Femur Ca content was higher and P content was lower in the ST, whereas osteocalcin, aminoterminal propeptides of type I procollagen, and C-terminal telopeptides of type I collagen were lower. Total cross-sectional, trabecular, and cortical/subcortical areas were lower in the ST. No differences were observed on BMD and area parameters of the diaphysis as well as on trabecular and cortical microarchitecture. The use of ST increases bone mineralization, ash percentage, and Ca and Mg content in femur. In spite of an absence of changes in BMD, geometric metaphyseal changes were observed. We conclude that ST alters bone geometry, leads to low bone turnover, and thus may impair bone quality.
Assuntos
Anabolizantes/toxicidade , Remodelação Óssea/efeitos dos fármacos , Calcificação Fisiológica/efeitos dos fármacos , Estanozolol/toxicidade , Animais , Densidade Óssea/efeitos dos fármacos , Fêmur/efeitos dos fármacos , Masculino , Ratos , Ratos Wistar , Microtomografia por Raio-XRESUMO
Adolescents commonly co-abuse many drugs including anabolic androgenic steroids either they are athletes or non-athletes. Stanozolol is the major anabolic used in recent years and was reported grouped with cannabis. The current study aimed at evaluating the biochemical and histopathological changes related to the hypertrophic effects of stanozolol and/or cannabis whether in condition of exercise practice or sedentary conditions. Adult male Wistar albino rats received either stanozolol (5 mg/kg, s.c), cannabis (10 mg/kg, i.p.), and a combination of both once daily for two months. Swimming exercise protocol was applied as a training model. Relative heart weight, oxidative stress biomarkers, cardiac tissue fibrotic markers were evaluated. Left ventricular morphometric analysis and collagen quantification was done. The combined treatment exhibited serious detrimental effects on the heart tissues. It increased heart tissue fibrotic markers (Masson's trichrome stain (p < 0.001), cardiac COL3 (p < 0.0001), and VEGF-A (p < 0.05)), lowered heart glutathione levels (p < 0.05) and dramatically elevated oxidative stress (increased malondialdehyde (p < 0.0001) and 8-OHDG (p < 0.0001)). Training was not ameliorating for the observed effects. Misuse of cannabis and stanozolol resulted in more hypertrophic consequences of the heart than either drug alone, which were at least largely assigned to oxidative stress, heart tissue fibrotic indicators, histological alterations, and morphometric changes.
Assuntos
Anabolizantes , Cardiomegalia Induzida por Exercícios , Fibrose , Estresse Oxidativo , Ratos Wistar , Estanozolol , Animais , Estanozolol/toxicidade , Masculino , Estresse Oxidativo/efeitos dos fármacos , Anabolizantes/toxicidade , Cardiomegalia Induzida por Exercícios/efeitos dos fármacos , Hipertrofia Ventricular Esquerda/fisiopatologia , Hipertrofia Ventricular Esquerda/induzido quimicamente , Hipertrofia Ventricular Esquerda/metabolismo , Hipertrofia Ventricular Esquerda/patologia , Hipertrofia Ventricular Esquerda/prevenção & controle , Remodelação Ventricular/efeitos dos fármacos , Miocárdio/patologia , Miocárdio/metabolismo , Dopagem Esportivo , Biomarcadores/metabolismo , Natação , Condicionamento Físico Animal/fisiologia , Ratos , Modelos Animais de DoençasRESUMO
Stanozolol (STZ) is a drug used to treat serious disorders like aplastic anemia and hereditary angioedema. It is also indicated as an adjunct therapy for the treatment of vascular disorders and growth failures. Encouraging results obtained using animal models demonstrated that STZ increases bone formation and mineralization, thus improving both density and biomechanical properties. Like natural androgens, such as TST and 5α-dihydrotestosterone (5α-DHT), STZ binds androgen receptor (AR) to activate AR-mediated signaling. Despite its therapeutic effects, this synthetic anabolic-androgenic steroid (AAS), or 5α-DHT derivative, due to its high lipophilicity, is poor soluble in water. Thus, to increase the water solubility and stability of STZ, as well as its bioavailability and efficacy, an innovative PEGylated STZ (STZ conjugated with (MeO-PEG-NH2)10kDa, (MeO-PEG-NH)10kDa-STZ) was synthesized. As confirmed by chromatography (RP-HPLC) and spectrometry (ATR-FTIR, 1H NMR, elemental CHNS(O) analysis, MALDI-TOF/TOF) analyses, a very pure, stable and soluble compound was obtained. Acetylcholinesterase (AChE) competitive ELISA demonstrated that the resulting PEGylated STZ competes against biological TST, especially at lower concentrations. Cytotoxicity of increasing concentrations (1, 10, 25 or 50⯵M) of STZ and/or (MeO-PEG-NH)10kDa-STZ was also evaluated for up 80â¯h by performing the MTT assay on human osteosarcoma Saos-2 cells, which express AR and are responsive to STZ. PEGylation mitigated cytotoxicity of STZ, by increasing the cell viability values, especially at higher drug concentrations. Furthermore, these results suggest that (MeO-PEG-NH)10kDa-STZ is a promising and reliable drug to be used in clinical conditions in which TST is required.
Assuntos
Anabolizantes/farmacocinética , Androgênios/farmacocinética , Composição de Medicamentos/métodos , Desenho de Fármacos , Estanozolol/farmacocinética , Anabolizantes/química , Anabolizantes/uso terapêutico , Anabolizantes/toxicidade , Androgênios/química , Androgênios/uso terapêutico , Androgênios/toxicidade , Disponibilidade Biológica , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Química Farmacêutica , Estabilidade de Medicamentos , Terapia de Reposição Hormonal/métodos , Humanos , Interações Hidrofóbicas e Hidrofílicas , Polietilenoglicóis/química , Receptores Androgênicos/metabolismo , Solubilidade , Estanozolol/química , Estanozolol/uso terapêutico , Estanozolol/toxicidade , Testosterona/deficiência , Testes de Toxicidade , Água/químicaRESUMO
Stanozolol is an anabolic-androgenic steroid which is commonly abused by athletes for improved energy, appearance, and physical size. It has been previously shown to cause changes in behaviour and has various physical effects. Studies have previously been conducted on its neurotoxic effect on the central nervous system (CNS), which are typically psychological in nature. This study was performed to investigate the apoptotic effect of stanozolol on different parts of the rat hippocampus. Sixteen male Wistar rats were divided randomly into two groups (experimental and control). The experimental group received subcutaneous injections of stanozolol (5mg/kg/day) for consecutive 28 days, whereas the control group received saline using the same dosing schedule and administration route. After routine procedures, coronal sections of rat brain were stained with Toluidine blue and TUNEL for pre-apoptotic and apoptotic cell detection, respectively. In order to compare groups, the mean number of TUNEL-positive and pre-apoptotic neurons per unit area were calculated and analysed. Histopathological examination revealed that the mean number of pre-apoptotic and apoptotic neurons in the CA1, CA2, CA3 and DG areas of the hippocampus were significantly increased in the stanozolol treated group. In conclusion, stanozolol abuse may induce pre-apoptotic and apoptotic cell formation in different regions of the hippocampus.
Assuntos
Anabolizantes/toxicidade , Androgênios/toxicidade , Apoptose , Hipocampo/efeitos dos fármacos , Estanozolol/toxicidade , Animais , Masculino , Ratos , Ratos WistarRESUMO
The aim of the study was to evaluate the effect of an anabolic steroid, stanozolol, in a model of atherosclerosis and to investigate the involvement of the modulation of the inflammatory cytokines and oxidative stress in vascular lipid deposition. Low-density lipid receptor-deficient (LDLr-/-) mice were fed a standard chow diet and were each week injected subcutaneously either saline (control C group) or 20 mg/kg stanozolol (S group). After 8 weeks, the levels of cholesterol, oxidized LDL (OxLDL) and cytokines were measured in plasma, lipid deposition in aorta was evaluated by en face analysis, and thiobarbituric acid-reactive substances and oxidation protein were determined in liver. The S group demonstrated increases in vascular lipid deposition, triglycerides and non-HDL cholesterol levels. Stanozolol increased tumour necrosis factor alpha (TNF-α) and decreased interleukin-10 as well as increased the TNF-α/IL-10 ratio. Furthermore, oxidative stress was observed in the S group, as indicated by an increase in the plasma OxLDL, as well as by lipid peroxidation and oxidation of proteins in the liver. Chronic treatment with stanozolol promoted lipid deposition in the LDLr-/- mice that could be attributed to a modification of the circulating cytokine levels and systemic oxidative stress. Our results suggest that the anabolic steroid stanozolol in the absence of functional LDL receptors by increasing systemic inflammation and oxidative stress may increase the risk of development and progression of atherosclerosis.
Assuntos
Aterosclerose/induzido quimicamente , Metabolismo dos Lipídeos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Estanozolol/toxicidade , Anabolizantes/toxicidade , Animais , Aorta/efeitos dos fármacos , Aorta/patologia , Aterosclerose/patologia , Citocinas/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Inflamação/induzido quimicamente , Inflamação/patologia , Mediadores da Inflamação/metabolismo , Lipoproteínas LDL/metabolismo , Masculino , Camundongos , Camundongos Knockout , Oxirredução/efeitos dos fármacos , Receptores de LDL/genéticaRESUMO
Anabolic androgenic steroid (AAS) abuse is increasing in teenagers. We examined the effects of stacked AAS in adolescent male rats. Stacking, in which multiple AAS are taken simultaneously, is commonly employed by humans. Beginning at puberty gonadally intact male rats received testosterone, nandrolone, or stanozolol. Additional groups received stacked AAS: testosterone + stanozolol, nandrolone + stanozolol, or nandrolone + testosterone. Injections continued during tests for sexual behavior, vocalizations, scent marking, partner preference, aggression and fertility. Body and reproductive tissue weights were taken. Sexual and aggressive behaviors were increased by testosterone yet inhibited by stanozolol; nandrolone had no effect. Stacking testosterone with stanozolol prevented the inhibitory effects of stanozolol. Body weight was decreased by testosterone and all stacked AAS. Cell nuclear androgen receptor binding in brain was significantly increased in nandrolone males and decreased in stanozolol males; testosterone males were slightly higher than controls. Androgen receptors in stacked groups were intermediate between individual AAS suggesting that stanozolol competed with other AAS for androgen receptors despite its low affinity. The results indicate that stacking AAS influences the effects of individual AAS on behavioral and endocrine measures, and levels of androgen receptor occupation are not directly correlated with AAS effects on behavior.
Assuntos
Anabolizantes/administração & dosagem , Anabolizantes/toxicidade , Androgênios/administração & dosagem , Androgênios/toxicidade , Comportamento Animal/efeitos dos fármacos , Sistemas Neurossecretores/efeitos dos fármacos , Animais , Comportamento Animal/fisiologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Interações Medicamentosas , Feminino , Fertilidade/efeitos dos fármacos , Humanos , Masculino , Modelos Animais , Nandrolona/administração & dosagem , Nandrolona/toxicidade , Ratos , Ratos Long-Evans , Receptores Androgênicos/efeitos dos fármacos , Receptores Androgênicos/metabolismo , Comportamento Sexual Animal/efeitos dos fármacos , Maturidade Sexual , Estanozolol/administração & dosagem , Estanozolol/toxicidade , Testosterona/administração & dosagem , Testosterona/toxicidadeRESUMO
A busca pelo corpo perfeito pode gerar graves consequências para a população que faz uso indiscriminado de substâncias visando a resultados rápidos. O caso relatado se refere a um pa- ciente de 21 anos, do sexo masculino, na cidade de São Paulo (SP), que apresentou quadro de síndrome colestática 15 dias após uso do anabolizante estanazolol para fins estéticos na ativi- dade física, evoluindo com hepatite medicamentosa grave, com aumento de transaminases, hiperrubilinemia às custas de bilirrubina direta e fatores de coagulação, sem resposta satis- fatória ao tratamento de suporte convencional, com melhora significativa após introdução de corticoterapia.
Searching for the perfect body image can cause severe conse- quences to the population using substances indiscriminately to reach results fast. The case reported refers to a male patient, 21 years old, from the city of São Paulo (SP), who developed choles- tatic syndrome 15 days after the use of the steroid Stanazol for aesthetic purposes during physical activity, progressing with se- vere drug-induced hepatitis, transaminases, bilirubin, and coagu- lation factors increase with no satisfactory response to the con- ventional support treatment, and significant improvement after the introduction of corticotherapy.
Assuntos
Humanos , Masculino , Adulto , Adulto Jovem , Estanozolol/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Glucocorticoides/uso terapêutico , Anabolizantes/toxicidade , Ácido Ursodesoxicólico/administração & dosagem , Bilirrubina/sangue , Biópsia , Colagogos e Coleréticos/uso terapêutico , Prednisona/administração & dosagem , Colestase/diagnóstico , Colestase/patologia , Colesterol/sangue , Resina de Colestiramina/administração & dosagem , Doença Catastrófica , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Doença Hepática Induzida por Substâncias e Drogas/patologia , Transaminases/sangue , Hidroxizina/administração & dosagem , Fígado/patologia , Anticolesterolemiantes/uso terapêutico , Antipruriginosos/uso terapêuticoRESUMO
In this study stanozolol, one of the most abused anabolic steroids, was investigated for tumor initiating and promoting activity in two rat liver foci bioassays, using gamma-glutamyltranspeptidase (GGT) as marker for detection of putative preneoplastic foci. Stanozolol, orally administered for 2 weeks, at a dose level approximately 400-times larger than the human therapeutic dose, in rats initiated with N-nitroso-diethylamine according to the Solt-Farber system assay, did not produce any increase in the number and volume of GGT-positive liver foci. A 6-week oral treatment with stanozolol (430 ppm in the diet) followed by 2 weeks of 2-acetylaminofluorene (AAF) diet (200 ppm), carried out according to the Tatematsu assay system to evaluate the initiating activity, did not provoke any significant modification of the number and volume of GGT-positive foci as compared to the controls. In the rats receiving AAF (200 ppm in the diet for 2 weeks) followed by 6 weeks of stanozolol, to evaluate the promoting activity, an increase in number and volume of the GGT-positive foci was observed at the highest oral dose, but the differences from the corresponding control values which resulted were not statistically significant. Taken as a whole the results of this study do not provide any substantial evidence of carcinogenic activity of stanozolol in rat liver, even when orally administered at high doses.
Assuntos
Fígado/efeitos dos fármacos , Estanozolol/toxicidade , gama-Glutamiltransferase/metabolismo , Animais , Peso Corporal/efeitos dos fármacos , Neoplasias Hepáticas/induzido quimicamente , Neoplasias Hepáticas Experimentais/induzido quimicamente , Tamanho do Órgão/efeitos dos fármacos , Lesões Pré-Cancerosas , RatosRESUMO
Hepatic complications in athletes and bodybuilders after abusing anabolic-androgenic steroids (AAS) have been reported. Hepatic injury, including cholestasis, peliosis hepatis, hyperplasia, and tumors, have been attributed to abuse of the 17 alpha-alkylated AAS. Some of these pathological conditions have been reversed when individuals were converted to nonalkylated AAS regimens. The purpose of this study was to determine and compare the direct toxic effects of commonly abused AAS (both 17 alpha-alkylated and nonalkylated) in primary hepatic cell cultures. Primary cultures, established from 60-day-old Sprague-Dawley rats, were exposed to doses of 1 x 10(-8), 1 x 10(-6), and 1 x 10(-4)M 19-nortestosterone, fluoxymesterone, testosterone cypionate, stanozolol, danazol, oxymetholone, testosterone, estradiol, and methyltestosterone for 1, 4, and 24 hr. Lactate dehydrogenase (LDH) release, neutral red (NR) retention, and glutathione (GSH) depletion were evaluated to determine plasma membrane damage, cell viability, and possible oxidative injury, respectively. Those cultures exposed to the 17 alpha-alkylated AAS, methyltestosterone and stanozolol, at doses of 1 x 10(-4) M for 24 hr and the 17 alpha-alkylated AAS, oxymetholone, at 1 x 10(-4) M for 4 and 24 hr showed significant increased in LDH release and decreases in NR retention while there were no significant differences with the nonalkylated steroids (testosterone cypionate, 19-nortestosterone, testosterone, and estradiol). GSH depletion was evaluated in cultures treated with 1 x 10(-8), 1 x 10(-6), and 1 x 10(-4) M concentrations of methyltestosterone, stanozolol, and oxymetholone for 1, 2, 4, and 6 hr. Cultures exposed to 1 x 10(-4) M oxymetholone were significantly depleted of GSH at 2, 4, and 6 hr; cultures exposed to 1 x 10(-4) M methyltestosterone were significantly depleted of GSH at 4 and 6 hr; and cultures exposed to stanozolol were not significantly depleted of GSH at any of the time periods tested. These data indicate that the 17 alpha-alkylated steroids (methyltestosterone, oxymetholone, and stanozolol) are directly toxic to hepatocytes, whereas the nonalkylated steroids (testosterone cypionate, 19-nortestosterone, testosterone, and estradiol) show no effects at similar doses. These data demonstrate a trend toward a structural-activity relationship to AAS-induced toxicity in primary cultures of rat hepatocytes.
Assuntos
Anabolizantes/toxicidade , Fígado/efeitos dos fármacos , Análise de Variância , Animais , Células Cultivadas , Estradiol/toxicidade , Fluoximesterona/toxicidade , Glutationa/metabolismo , L-Lactato Desidrogenase/metabolismo , Fígado/citologia , Metiltestosterona/toxicidade , Nandrolona/toxicidade , Vermelho Neutro/metabolismo , Oximetolona/toxicidade , Ratos , Ratos Sprague-Dawley , Estanozolol/toxicidade , Testosterona/análogos & derivados , Testosterona/toxicidadeRESUMO
Twenty-four male rats were divided into four groups, with anabolic steroids and exercise as variables. Biomechanical tests and histological evaluations were performed. The results of the biomechanical tests suggested that anabolic steroids produce a stiffer tendon, which fails with less elongation. The energy at the time when the tendon failed, the toe-limit elongation, and the elongation at the time of the first failure were all affected significantly. Changes in the force at failure were not statistically significant. No alterations of structure were noted when the specimens were viewed with light microscopy. Alterations of the sizes of the collagen fibrils were noted on electron microscopy.
Assuntos
Anabolizantes/toxicidade , Tendões/efeitos dos fármacos , Análise de Variância , Animais , Fenômenos Biomecânicos , Colágeno/ultraestrutura , Elasticidade , Análise dos Mínimos Quadrados , Modelos Lineares , Masculino , Nandrolona/análogos & derivados , Nandrolona/toxicidade , Decanoato de Nandrolona , Esforço Físico , Ratos , Ratos Endogâmicos , Estanozolol/toxicidade , Estresse Mecânico , Propriedades de Superfície , Tendões/ultraestrutura , Resistência à TraçãoRESUMO
The aim of the present study was to evaluate DNA damage (micronucleus) and cellular death (pyknosis, karyolysis and karyorrhexis) in exfoliated buccal mucosa cells from anabolic steroid users after 2 months of exposure. Two experimental groups consisting of 15 adult males who practise weight lifting and are anabolic steroid users or 15 adult males who practise weight lifting, but are non-anabolic steroid users, were recruited. In addition, 20 sedentary males, who do not practise any physical activity regularly, were matched by age with experimental groups. No significant statistical differences (p>0.05) were noticed in individuals who practise physical activity only. On the other hand, an increase of micronucleated cells (MNCs) in anabolic steroid (decadurabulin and Winstrol) users was observed. Regarding cytotoxic parameters, the same observation has occurred, that is, significant statistical differences (p<0.05) were noticed in the group exposed to anabolic steroids when compared with other controls, as depicted by high frequencies of pyknosis, karyolysis and karyorrhexis. Taken together, our results suggest that genomic instability and cytotoxicity are induced by anabolic steroid administration in oral mucosa cells as assessed by the micronucleus test.
Assuntos
Transtornos Cromossômicos/induzido quimicamente , Dano ao DNA , Mucosa Bucal/efeitos dos fármacos , Mucosa Bucal/patologia , Nandrolona/análogos & derivados , Estanozolol/toxicidade , Levantamento de Peso , Adulto , Morte Celular/efeitos dos fármacos , Morte Celular/genética , Transtornos Cromossômicos/genética , Transtornos Cromossômicos/patologia , Humanos , Masculino , Testes para Micronúcleos , Mucosa Bucal/metabolismo , Nandrolona/toxicidade , Decanoato de Nandrolona , Fatores de Tempo , Adulto JovemAssuntos
Genes Precoces/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Estanozolol/toxicidade , Animais , Corticosterona/farmacologia , Creatina Quinase/metabolismo , Proteínas de Ligação a DNA/genética , Expressão Gênica/efeitos dos fármacos , Músculo Esquelético/lesões , Músculo Esquelético/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores Androgênicos/metabolismo , Receptores de Glucocorticoides/metabolismo , Fatores de Transcrição/genéticaRESUMO
The survival and growth rate of the Indian freshwater mussel, Lamellidens marginalis, (Lamarck) was ascertained in cultivation by using certain drugs in CIFA, fish farm, BBSR (India) during June 1998 to February 1999. Two sets of experiments were carried out to evaluate the effects of drugs like Betamethasone, Calcium, Azathioprine, Stanazolol, and Folic acid. Chloramphenicol was added with each treatment as prophylaxis to prevent the bacterial growth. In the first set, the inactiveness and mortality of the mussels in different drugs were studied through two different dosages and in subsequent tests the fixation of dosage was employed. The study in the second set was regarding the survival, increment of shell length, its thickness, and wet weight in response to different drugs therapy. The drugs were administered parenterally in "fixed dosage" at a regular interval of 21-23 days. The survival rate was good with Betamethasone and Azathioprine that is 75%, whereas it was 16.66% in Folic acid treatment. But the mussels originating from the control site had the significant survival rate though the growth rate was average. Calcium treatment had shown a marked increment of shell thickness and luster. The culture was lasted for 160 days. The wet weight gain of mussels in all the treatments were significant, p<0.0001 whereas increment of shell thickness was significant only in treatment B (Calcium) and treatment D (Azathioprine), p<0.0001 but with regard to the increment of length of mussel, treatment E (Stanazolol) was not significant, p>0.05. The regression analysis was adopted to find out the coefficient of determination (R(2)=0.90, being the best) from the relationship between length and weight of mussels and to establish the LWR equation with condition factor k=W/L(b).
Assuntos
Azatioprina/toxicidade , Betametasona/toxicidade , Cálcio/toxicidade , Ácido Fólico/toxicidade , Estanozolol/toxicidade , Unionidae/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Animais , Tamanho Corporal/efeitos dos fármacos , Unionidae/crescimento & desenvolvimentoRESUMO
Apoptosis is an active form of cellular death, or suicide, which plays an important physiologic role during organ development and in cellular turnover in differentiated tissues. Apoptosis has also been demonstrated to occur in several organs in response to hypoxic/ischemic, oxidative, or drug-induced injury and is thus involved in disease pathogenesis. However, it is generally assumed that apoptosis does not occur in differentiated skeletal muscle. Apoptosis has been demonstrated in differentiated myocardial muscle, neonatal skeletal muscle, and skeletal myoblasts in response to injury. We therefore studied differentiated murine C2 skeletal muscle cells that have been injured by supraphysiologic doses (>10 microM) of an anabolic steroid, stanozolol. Stanozolol-injured muscle cells exhibited pathologic features suggestive of apoptosis: cytoplasmic shrinkage and chromatin condensation. Muscle cells also showed positive in situ nick-end labeling of nuclear chromatin, indicating DNA strand breakage. Staining with the DNA-binding dye 33342 (bisbenzimide) also showed chromatin changes characteristic of apoptotic nuclei. Total protein levels measured at 4 and 24 hr post-stanozolol injury was not significantly decreased, indicating absence of cell lysis. Cellular ATP levels (nmol ATP/mg protein) of stanozolol-injured muscle cells, measured 4 and 24 hr postinjury, also did not change significantly. In contrast, necrotic muscle cells, injured by the calcium ionophore A23187 (2 microM), showed a progressive decline in total protein and ATP levels. This study supports two other histologic studies that showed evidence of apoptosis in differentiated skeletal muscle fibers. Our data further suggest that during the early stages of apoptosis, but not necrosis, cellular energy metabolism is preserved.
Assuntos
Anabolizantes/toxicidade , Apoptose/efeitos dos fármacos , Calcimicina/toxicidade , Ionóforos/toxicidade , Músculo Esquelético/efeitos dos fármacos , Estanozolol/toxicidade , Trifosfato de Adenosina/metabolismo , Animais , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Fragmentação do DNA , Avaliação Pré-Clínica de Medicamentos , Cinética , Camundongos , Músculo Esquelético/patologia , Necrose , Nucleossomos/efeitos dos fármacosRESUMO
Stanozolol (ST) is a 17alpha-alkyl anabolic-androgenic steroid (17alpha-AAS) often misused by athletes and bodybuilders. The use of anabolic-steroids by sportsmen and teenagers has increased dramatically, thus raising the question about their hepatotoxicity, specially those such as ST which are orally administered. Previously, we have reported diverse in vivo effects exerted by this steroid and published the existence of a highly specific ST-binding site in male rat liver microsomes. The existence of this binding site, the reported hepatic effects exerted in humans, and the very limited information about its potential hepatotoxicity led us to treat adult male rats acutely and chronically with ST and study different parameters that could indicate liver damage: serum levels of transaminases, concentration of monooxygenase enzymes in liver, liver membrane lipid peroxidation products, liver histopathology, and cell cycle/ploidy status of liver cells. In our study, no changes in serum transaminases or lipid peroxidation levels were obtained. However, acute stanozolol treatment significantly decreased the levels of cytochrome P450 (Cyt. P450) and cytochrome b5 (Cyt. b5) during the first 48 h of treatment, while subsequently, at 72 and 96 h, these microsomal enzymes underwent a significant increase in their levels. In sharp contrast with this response to acute treatment, the content of these two enzymes during chronic treatment showed an important decrease. Interestingly, acutely and chronically ST-treated livers showed slight to moderate inflammatory or degenerative lesions in centrilobular hepatocytes. Flow cytometric analysis demonstrated that both acute and chronic ST treatment were capable of increasing the percentage of S-phase fraction (%SPF) of liver cells. These findings taken together clearly show that this steroid is capable of altering the liver capacity for metabolizing xenobiotics and indicate that high doses of ST could exert a proliferative effect on liver cells. Such data should be considered in risk evaluations for this compound.