RESUMEN
The aim of the present study was to investigate the hypothesis that liver tissue repair induced by exposure to chloroform (CHCl(3))+trichloroethylene binary mixture (BM) is dose-dependent similar to that elicited by exposure to these compounds individually. Male Sprague-Dawley rats (250-300 g) received three dose combinations of binary mixture (74+250, 185+500 and 370+1250 mg CHCl(3)+trichloroethylene/kg, intraperitoneally) in corn oil (maximum of 0.5 ml/kg). Liver injury was assessed by plasma alanine amino transaminase (ALT) activity and histopathology by haematoxylin & eosin. Liver tissue repair was measured by (3)H-thymidine incorporation into hepatonuclear DNA. Blood and liver levels of both the parent compounds and two major metabolites of trichloroethylene (trichloroacetic acid and trichloroethanol) were quantified by gas chromatography. The blood and liver CHCl(3) levels after the administration of binary mixture were similar compared to the administration of CHCl(3) alone. The blood and liver trichloroethylene levels after the binary mixture were significantly lower compared to trichloroethylene alone due to higher elimination in presence of CHCl(3), resulting in decreased production of metabolites. The antagonistic toxicokinetics resulted in lower liver injury than the summation of injury caused by the individual components at all three dose levels. On the other hand, tissue repair elicited by the binary mixture was dose-dependent. The interactive toxicity of this binary mixture of CHCl(3) and trichloroethylene led to subadditive initial liver injury because of a combined effect of higher elimination of TCE and mitigated progression of liver injury was prevented by timely dose-dependent stimulation of compensatory tissue repair. Even though the doses of the toxicants employed in this study are much higher than found in the environment, the results suggest that a mixture of these two compounds at environmental levels is unlikely to cause any exaggerated interactive acute liver toxicity of any biological significance.
Asunto(s)
Cloroformo/antagonistas & inhibidores , Cloroformo/toxicidad , Regeneración Hepática/efectos de los fármacos , Tricloroetileno/antagonistas & inhibidores , Tricloroetileno/toxicidad , Alanina Transaminasa/sangre , Animales , Área Bajo la Curva , Cloroformo/farmacocinética , Hígado/química , Hígado/efectos de los fármacos , Hígado/patología , Masculino , Ratas , Ratas Sprague-Dawley , Ácido Tricloroacético/análisis , Ácido Tricloroacético/sangre , Ácido Tricloroacético/orina , Tricloroetileno/farmacocinéticaRESUMEN
AIM: To study the effect of crocin on intracellular calcium concentration ([Ca2+]i) in cultured bovine aortic smooth muscle cells (BASMCs). METHODS: Cells were loaded with fluorescence probe Fluo-3/AM and [Ca2+]i was measured by laser scanning confocal microscope (LSCM). RESULTS: In the presence or absence of extracellular Ca2+, crocin (1 x 10(-8), 1 x 10(-7), 1 x 10(-6) mol x L(-1)) concentration-dependently inhibited the [Ca2+]i elevation induced by 1 x 10(-2) mol x L(-1) H2O2 (for the former, the inhibition rates were 34.1%, 57.1% and 74.3%, while for the latter were 26.2%, 32.1%, 50.0%). In the absence of extracellular Ca2+, crocin (1 x 10(-8), 1 x 10(-7), 1 x 10(-6) mol x L(-1)) could inhibit the [Ca2+]i elevation induced by 70 mmol x L(-1) CHCl3, the inhibition rates were 27.8%, 27.8% and 50.0% respectively. CONCLUSION: Crocin could inhibit the extracellular Ca2+ influx and release of intracellular Ca2+ stores in endoplasmic reticulum.
Asunto(s)
Calcio/metabolismo , Carotenoides/farmacología , Músculo Liso Vascular/metabolismo , Miocitos del Músculo Liso/metabolismo , Animales , Aorta Torácica , Carotenoides/aislamiento & purificación , Bovinos , Células Cultivadas , Cloroformo/antagonistas & inhibidores , Gardenia/química , Peróxido de Hidrógeno/antagonistas & inhibidores , Espacio Intracelular/metabolismo , Músculo Liso Vascular/citología , Plantas Medicinales/químicaRESUMEN
Effects of a single dose of betaine on the chloroform-induced hepatotoxicity were examined in adult male ICR mice. Administration of betaine (1000 mg/kg, ip) 1 to 7 hr prior to a chloroform challenge (0.25 ml/kg, ip) resulted in remarkable enhancement of hepatotoxicity as indicated by increases in serum sorbitol dehydrogenase (SDH), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities. The potentiation of hepatotoxicity was most significant when mice were treated with betaine 4 hr earlier than chloroform. However, a 24 hr prior administration of betaine protected the animals from induction of the chloroform hepatotoxicity. Thus, its effect appeared to be highly dependent on the time lapse from the betaine pretreatment to the challenge of mice with chloroform. Betaine treated either 4 or 24 hr prior to sacrifice did not alter the hepatic contents of cytochrome P-450, cytochrome b5, or NADPH cytochrome P-450 reductase activity. Accordingly the hepatic microsomal p-nitroanisole O-demethylase, aminopyrine N-demethylase, or p-nitrophenol hydroxylase activities were not influenced by the betaine pretreatment. Betaine was shown not to affect any of the enzyme activities associated with glutathione (GSH) conjugation reaction, such as glutathione S-transferases (GSTs), glutathione disulfide (GSSG) reductase and GSH peroxidase irrespective of the time of its administration. When betaine was administered to mice 2-6 hr prior to sacrifice, hepatic GSH level, but not plasma GSH, was decreased significantly. Enhancement of the chloroform hepatotoxicity by betaine correlated well with the reduction in hepatic GSH levels. Both hepatic and plasma GSH levels were elevated in mice 24 hr following the betaine treatment. The results suggest that betaine affects induction of the chloroform hepatotoxicity by modulating the availability of hepatic GSH, which appears to be associated with its role in the transsulfuration pathway in the liver.
Asunto(s)
Betaína/farmacología , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Cloroformo/antagonistas & inhibidores , Fármacos Gastrointestinales/farmacología , Alanina Transaminasa/metabolismo , Animales , Aspartato Aminotransferasas/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/sangre , Enfermedad Hepática Inducida por Sustancias y Drogas/enzimología , Cloroformo/toxicidad , Enzimas/sangre , Glutatión/metabolismo , Masculino , Ratones , Ratones Endogámicos ICR , Tamaño de los Órganos/efectos de los fármacos , Succinato Deshidrogenasa/metabolismoRESUMEN
Racemic tocainide [R,S-T], which is used in the treatment of ventricular arrhythmias, consists of an R(-)-enantiomer [R-T] and an S(+)-enantiomer [S-T]. The present experiments examined these substances for pharmacodynamic differences. The ability of various doses of R-T, S-T, and R,S-T to both induce ataxia (A) and protect against chloroform-induced ventricular arrhythmias (P) in mice were compared at 20 min after subcutaneous treatment. For A effects, the ED50S (95% Fieller Limits) of R-T, S-T, and R,S-T were 125 (78-802), 125 (84-283), and 90 (61-149) mg/kg, respectively. For P effects, the ED50S were 40 (11-71), 116 (82-204), and 86 (55-187) mg/kg. The ratios of A/P, a measure of the margin of safety, were 3.1, 1.1, and 1.0. Effects upon intracardiac conduction in isolated rabbit hearts also exhibited, qualitatively, similar patterns of selectivity. At 1 X 10(-4) M intraatrial, His-Purkinje, intraventricular conduction times, and the QT interval were prolonged with the following order of potency: R-T greater than R,S-T greater than S-T; A-V nodal conduction was unchanged. R-T also evoked the greatest decrease in contractility. With respect to separation of antiarrhythmic action and the production of ataxia, R-T has a greater margin of safety than either S-T or R,S-T.
Asunto(s)
Antiarrítmicos/farmacología , Arritmias Cardíacas/prevención & control , Lidocaína/análogos & derivados , Animales , Arritmias Cardíacas/inducido químicamente , Cloroformo/antagonistas & inhibidores , Electrocardiografía , Femenino , Sistema de Conducción Cardíaco/efectos de los fármacos , Técnicas In Vitro , Inyecciones Subcutáneas , Lidocaína/farmacología , Ratones , Contracción Miocárdica/efectos de los fármacos , Conejos , Estereoisomerismo , TocainidaRESUMEN
Carbon tetrachloride, chloroform, dimethylnitrosamine, thioacetamide or acetaminophen was each administered to rats in a single hepatotoxic dose. Nifedipine, verapamil or chlorpromazine was administered in association with the hepatotoxic agents to determine if calcium channel blocking agents would prevent an increase in liver cell calcium associated with hepatotoxicity and to determine if these agents would protect against the development of centrilobular necrosis. Following a latent period different for each toxic agent, a 4- to 18-fold increase in liver cell calcium content had occurred by 24 hr. The calcium increase and the centrilobular necrosis (mean histologic score) were correlated. A relatively high calcium to necrosis ratio was obtained with dimethylnitrosamine, thioacetamide and acetaminophen. A lesser calcium to necrosis ratio was obtained with chloroform and carbon tetrachloride, the two toxic agents that destroyed the intracellular calcium sequestration activity of the liver endoplasmic reticulum. Nifedipine or chlorpromazine, administered prior to and 7 hr after the toxic agent, completely prevented the centrilobular necrosis caused by thioacetamide, carbon tetrachloride and acetaminophen; almost completely prevented necrosis with dimethylnitrosamine; and provided partial protection against chloroform toxicity. Two doses of verapamil provided partial protection against necrosis when carbon tetrachloride was the toxic agent and provided almost complete protection with dimethylnitrosamine. A reduction in liver cell calcium was associated with the protective action of the three calcium channel blocking agents. These findings are compared with earlier studies of the protective effects of calcium channel blocking agents in cardiac ischemia.
Asunto(s)
Bloqueadores de los Canales de Calcio/farmacología , Calcio/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Hígado/efectos de los fármacos , Acetaminofén/antagonistas & inhibidores , Animales , Tetracloruro de Carbono/antagonistas & inhibidores , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Cloroformo/antagonistas & inhibidores , Dimetilnitrosamina/antagonistas & inhibidores , Hígado/metabolismo , Masculino , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Necrosis/inducido químicamente , Necrosis/prevención & control , Ratas , Ratas Endogámicas , Tioacetamida/antagonistas & inhibidoresRESUMEN
Oral administration of diethyldithiocarbamate (DTC) and carbon disulfide (CS2) protected mice against CHCl3-induced kidney injury, as evidenced by normalization of delayed plasma phenolsulfonphthalein clearance, suppression of increased kidney calcium content and prevention of renal tubular necrosis. In CCl4-treated mice, in which liver microsomal monooxygenase activities were decreased markedly, and kidney microsomal aniline hydroxylase and p-nitroanisole demethylase activities were increased to about twice those of the untreated mice, renal toxicity of CHCl3 was greatly potentiated, and the latter effect was also blocked by both agents. DTC and CS2 per se markedly decreased kidney microsomal aniline hydroxylase and p-nitroanisole demethylase activities at 1 hr after oral administration, accompanying a moderate loss of cytochrome P-450 content, in both normal and CCl4-treated mice. The protection was not due to hypothermia, because pretreatment with DTC or CS2 (p.o.) also prevented the hypothermia induced by CHCl3. The mechanism of the protection may have involved inhibition of metabolic activation of CHCl3 in the kidney rather than in the liver.
Asunto(s)
Lesión Renal Aguda/prevención & control , Disulfuro de Carbono/farmacología , Cloroformo/antagonistas & inhibidores , Ditiocarba/farmacología , Necrosis Tubular Aguda/prevención & control , Tiocarbamatos/farmacología , Animales , Temperatura Corporal/efectos de los fármacos , Intoxicación por Tetracloruro de Carbono/metabolismo , Riñón/metabolismo , Masculino , Ratones , Microsomas/metabolismoAsunto(s)
Cloroformo/toxicidad , Enfermedades Renales/inducido químicamente , Maleatos/farmacología , Butóxido de Piperonilo/farmacología , Animales , Cloroformo/antagonistas & inhibidores , Sinergismo Farmacológico , Glutatión/metabolismo , Corteza Renal/metabolismo , Masculino , Ratones , Ratones Endogámicos ICR , Microsomas Hepáticos/enzimología , Proadifeno/farmacologíaRESUMEN
Renal and hepatic microsomal enzyme activities were measured in ICR male mice treated with phenobarbital (PB), 3-methylcholanthrene (3MC), 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or polychlorinated biphenyls (PCB). The effect of these agents on subsequently administered single doses of chloroform (CHCI3) were also determined. 3MC, TCDD and PCB increased renal as well as hepatic microsomal enzyme activities. PB increased hepatic but not renal microsomal enzyme activities. The hepatotoxicity of CHCI3 was increased by pretreatment with PB but decreased by pretreatment with TCDD. 3MC and PCB were without effect on CHCI3-induced liver damage. Pretreatment with 3MC, TCDD or PCB reduced the renal toxicity of CHCI3, but PB had no effect on CHCI3-induced kidney damage. Since at least one product of enzymatic metabolism of CHCI3 is believed to be a toxic, reactive intermediate the differential effects of inducers of microsomal drug-metabolizing enzyme activities on the renal and hepatic toxicities of CHCI3 strongly suggest that the CHCI3 metabolite(s) ultimately responsible for renal and hepatic damage are not generated at a common site. That is the metabolite responsible for hepatic is probably generated in the liver and the metabolite responsible for renal damage is probably generated in the kidney.
Asunto(s)
Cloroformo/toxicidad , Riñón/efectos de los fármacos , Hígado/efectos de los fármacos , Animales , Hidrocarburo de Aril Hidroxilasas/biosíntesis , Cloroformo/antagonistas & inhibidores , Inducción Enzimática/efectos de los fármacos , Inactivación Metabólica , Riñón/enzimología , Hígado/enzimología , Masculino , Metilcolantreno/farmacología , Ratones , Oxidorreductasas/biosíntesis , Fenobarbital/farmacología , Bifenilos Policlorados/farmacología , Dibenzodioxinas Policloradas/farmacologíaRESUMEN
In the course of routine screening of beta-adrenoceptor blocking compounds, it was found that a number of compounds did not block the vascular and cardiac effects of isoprenaline in proportion. Moreover, it was also found that the anti-arrhythmic action was not wholly related to the beta-adrenoceptor blocking potency. In particular, the anti-ouabain arrhythmia properties were not dependent upon beta-blocking potency. It was, therefore, possible to select a compound which had both cardioselective beta-adrenoceptor blocking and anti-ouabain arrhythmic activities. The chosen compound was acebutolol. Acebutolol is a cardioselective beta-adrenoceptor blocking agent which has marked anti-arrhythmic against arrhythmia induced by methylchloroform and adrenalin in the cat, and also arrhythmia induced by ouabain in dogs and rabbits. It has less pronounced membrane stabilising properties than propranolol and has no demonstrable sympathomimetic action in normal anaesthetised cats or dogs. Bronchial beta-adrenoceptor blockade has been investigated in anaesthetised cats in which bronchoconstriction is evoked by PGF2 alpha. Isoprenaline prevents the effect of PGF2 alpha and this is restored by pre-treatment with propranolol. Acebutolol is 100 times less active than propranolol in these experiments.