RESUMEN
OBJECTIVE: The aim of this study was to investigate whether pretreatment with the Japanese herbal medicine "Hochu-ekki-to" (TJ-41) has an ameliorative effect on carbon tetrachloride (CCl4)-induced hepatotoxicity through anorexia prevention. METHODS: Twenty-four hours before CCl4 injection, TJ-41 or saline solution was intraperitoneally administered. Furthermore, 24 h after TJ-41 injection, mice were intraperitoneally administered 1.6 g/kg CCl4 or olive oil. Moreover, 24 h after CCl4/olive oil injection, mice from each group were euthanized and bled for plasma analysis. RESULTS: Mice injected with CCl4 exhibited severe anorexia. Moreover, CCl4 increased the plasma levels of hepatic injury markers (i.e., alanine aminotransferase and aspartate aminotransferase) as well as lipid peroxidation and hepatic Ca levels. Pretreatment with TJ-41 recovered the CCl4-induced anorexia and plasma levels of the hepatic injury markers. Moreover, CCl4-induced lipid peroxidation and hepatic Ca levels decreased upon TJ-41 pretreatment. In addition, hepatic metallothionein levels in the TJ-41 + CCl4-treated group were decreased by >50 % compared with the levels in the TJ-41-treated group, implying that metallothionein was consumed by CCl4-induced radicals. CONCLUSION: Our results suggest that TJ-41 attenuates CCl4-induced hepatotoxicity, presumably by the induction of metallothionein, which in turn scavenges radicals induced by CCl4 exposure.
Asunto(s)
Intoxicación por Tetracloruro de Carbono/prevención & control , Medicamentos Herbarios Chinos/farmacología , Hígado/efectos de los fármacos , Animales , Inyecciones Intraperitoneales , Masculino , Medicina Kampo , RatonesRESUMEN
The aim of the present study was to investigate whether pretreatment with the Japanese herbal medicine, "Juzen-taiho-to" (JTX), had an ameliorative effect on carbon tetrachloride (CCl4)-induced hepatotoxicity through anorexia prevention. Mice injected with CCl4 exhibited severe anorexia. Moreover, CCl4 increased the plasma levels of hepatic injury markers (i.e., alanine aminotransferase and aspartate aminotransferase), lipid peroxidation, and hepatic Ca(2+) levels. Pretreatment with JTX recovered the CCl4-induced anorexia. In addition, JTX pretreatment decreased CCl4-induced plasma levels of hepatic injury markers. Increased Ca(2+) is a known indicator of the final progression to hepatocyte death, and CCl4-induced hepatotoxicity is mainly caused by oxidative stress. The present study indicated CCl4-induced lipid peroxidation and hepatic Ca(2+) content decreased with JTX pretreatment. Our results suggest that JTX has potential to protect of CCl4-induced anorexia, and the modulation of oxidative stress.
Asunto(s)
Antioxidantes/uso terapéutico , Tetracloruro de Carbono/toxicidad , Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Medicamentos Herbarios Chinos/uso terapéutico , Alanina Transaminasa/sangre , Animales , Antioxidantes/farmacología , Aspartato Aminotransferasas/sangre , Calcio/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/sangre , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Medicamentos Herbarios Chinos/farmacología , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Malondialdehído/metabolismo , Medicina Kampo , Metalotioneína/metabolismo , Ratones , FitoterapiaRESUMEN
Metallothionein (MT) demonstrates strong antioxidant properties, yet the physiological relevance of its antioxidant action is not clear. Injection of mice with ferric nitrilotriacetate (Fe-NTA) caused a dose-dependent increase in hepatic and renal MT. Fe-NTA caused a greater increase in hepatic and renal MT concentration (2.5- and 4-fold) compared with FeCl(3) at the same dose of ferric ion. MT mRNA levels were markedly elevated in both of tissues. Thiobarbituric acid (TBA) values in both tissues reached a maximum after 2-4 h. The MT concentrations were significantly increased after 2-4 h in liver and after 8-16 h in kidneys. Plasma concentrations of cytokines such as IL-6 and TNFalpha were elevated by 4 h; IL-6 levels were 24 times higher after Fe-NTA than that after injection of FeCl(3). Pretreatment of mice with ZnSO(4) attenuated nephrotoxicity induced by Fe-NTA after 2 h, but was not effective 4 h after injection. After a Fe-NTA injection, a loss of Cd-binding properties of preinduced MT was observed only in kidneys of Zn-pretreated mice but not in liver. Treatment with BSO, glutathione (GSH) depletor, intensified a loss of its Cd-binding properties after a Fe-NTA injection. These results indicate that induction of MT synthesis may result from reactive oxygen species (ROS) generated by Fe-NTA, and MT may act in vivo as a complementary antioxidant.
Asunto(s)
Antioxidantes/metabolismo , Compuestos Férricos/toxicidad , Riñón/metabolismo , Hígado/metabolismo , Metalotioneína/metabolismo , Mutágenos/toxicidad , Ácido Nitrilotriacético/análogos & derivados , Ácido Nitrilotriacético/toxicidad , Animales , Bismuto , Nitrógeno de la Urea Sanguínea , Bromatos/toxicidad , Cadmio/metabolismo , Cloruros , Compuestos Férricos/administración & dosificación , Interleucina-6/biosíntesis , Interleucina-6/sangre , Riñón/efectos de los fármacos , Peroxidación de Lípido , Hígado/efectos de los fármacos , Masculino , Metalotioneína/biosíntesis , Ratones , Ratones Endogámicos , Ácido Nitrilotriacético/administración & dosificación , Factores de Tiempo , Factor de Necrosis Tumoral alfa/análisis , Factor de Necrosis Tumoral alfa/biosíntesis , ZincRESUMEN
Cadmium is known to be a potent carcinogenic and mutagenic metal. However, we demonstrated that dietary supplementation with 50 ppm cadmium inhibits spontaneous carcinogenesis in C3H/HeN and spontaneous hepatitis in A/J mice. We found that the frequencies of spontaneous hepatocarcinogenesis in C3H/HeN mice and of spontaneous hepatitis in A/J mice fed low-dose cadmium for 54 weeks were significantly lower than those in the respective control groups. A cadmium-induced increase in metallothionein production itself and/or metallothionein-associated increases in hepatic zinc concentrations may be involved in the observed preventive effects of cadmium. Our results suggest that low doses of cadmium in the diet or environment may play a beneficial role in the prevention of hepatic disease in humans and animals.
Asunto(s)
Cadmio/uso terapéutico , Dieta , Neoplasias Hepáticas Experimentales/prevención & control , Animales , Cadmio/administración & dosificación , Relación Dosis-Respuesta a Droga , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Neoplasias Hepáticas Experimentales/patología , Masculino , Metalotioneína/biosíntesis , Ratones , Ratones Endogámicos C57BL , Especificidad de la Especie , Zinc/metabolismoRESUMEN
Zinc (Zn) is an essential, common metal in animal tissues. Zn levels were elevated in only four tissues after Zn administration, the highest increase being in the pancreas. Zn concentration was increased by metallothionein induction. Metallothionein-bound Zn significantly reduced the toxicity of the metals Cd, Cu and Hg. It should be noted that tissue Zn levels are different in experimental animals and humans. Acute pancreatitis was observed following the injection of a large dose of Zn. Different metals have different target organs. Using metal pathology, treatments may be developed to save patients suffering from hepatic and renal diseases because Zn is used to a model animal of hepatic or renal disease.