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Aim: To establish an ideal anti-tuberculosis drug induced liver injury model and provide a suitable animal model for its pharmacodynamic evaluation. Methods To explore the contribution rate and interaction of isoniazid (INH) and rifampicin (RIF) on liver injury, mice received intragastric administration of RIF 100 nig · kg-1, 300 mg · kg-1 once, or RIF 300 mg · kg-1, INH 150 mg · kg-1, and RIF 300 mg · kg-1 + INH 150 mg · kg-1 for 1 -3 weeks. Then the biochemical and pathological indexes were determined and analyzed by factorial design ANOVA. Results After single intragastric administration of rifampicin, the serum bilirubin levels gradually increased, but no other indicators were affected in mice. Continuous intragastric administration of RIF 300 mg · kg-1, INH 150 mg · kg-1 or RIF 300 mg · kg-1 +INH 150 mg · kg-1 for 1 ∼3 weeks could significantly increase the liver index of mice. RIF alone or combined with isoniazid could significantly increase the level of ALT, AST and TBIL, resulting in vacuolar lesions in liver tissues in mice. The analysis of variance demonstrated that the combined use of RIF and INH for two weeks or three weeks showed significant antagonism in liver index and the level of ALT, and marked antagonism in TBIL at three weeks. The pathological results were basically consistent with the biochemical indicators. Conclusions RIF is the leading cause of liver injury in mice, and its hepatotoxicity is related to cholestasis. INH has a significant antagonistic effect on liver toxicity of RIF when they are combined, and the deep action mechanisms remains to be further explored.
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OBJECTIVE: To compare the effect on CYP450 isoenzyme in rats with acute liver injury induced by different chemicals. METHODS: Acute liver injury model of rats induced by tetrachloromethane(CCl4), D-aminogalactose(D-GalN)/lipopolysaccharide(LPS), α-naphthyl isothiocyanate(ANIT) respectively whereas the normal Wistar rats were used as controls. After the tail vein injection with Cocktail probe solutions prepared with five CYP450s probe substrates (phenacetin-CYP1A2, omeprazole-CYP2C9, tolbutamide-CYP2C19, dextromethorphan-CYP2D6, midazolam-CYP3A4), the blood samples were collected from the fundus venous plexus of rat at different time point, the blood drug concentration of the five probe substrates were determined by LC-MS/MS, and the pharmacokinetic parameters were calculated by PK Solutions 2™. Compared with normal rats, the changes of the probe drug pharmacokinetics in different rat models were used as the basis for the evaluation of the metabolic activity of CYP450 isoenzyme. RESULTS: Compared with normal rats, the activities of CYP1A2, CYP2C9, CYP2C19, CYP2D6 of CCl4 group rats were significantly inhibited, and the activities of CYP3A4 was slightly inhibited; the activities of CYP2C9, CYP2D6 and CYP3A4 of D-GalN/LPS group rats were significantly induced, and the activity of CYP2D6 and CYP3A4 was slightly induced, and the activity of CYP1A2 was not significantly affected, but the activity of CYP2C19 was significantly inhibited; the activities of CYP2C9, CYP2C19 and CYP3A4 of ANIT group rats were significantly induced, the activity of CYP3A4 were slightly induced, and the activity of CYP2D6 was not significantly affected, but the activity of CYP1A2 was significantly inhibited. CONCLUSION: There are significant differences in the activities of CYP450 isoenzyme in the rat model of acute liver injury induced by different chemicals.
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AIM:To evaluate the therapeutic effects of bisdemethoxycurcumin liposome in mice with CCl4-induced acute liver injury model and its mechanism.METHODS:40 ICR mice were randomly divided into 4 groups:control group,model group,bisdemethoxycurcumin injection group and demethoxycurcumin liposome group(n=10).The liver injury model was made by injecting CCl4 in mouse's abdomen.The activities of ALT,AST in serum,the contents of MDA in liver and the pathological changes of hepatic tissue were investigated.RESULTS:Compared with those in control group,the serum ALT,AST activities and liver MDA contents of model group were highly increased,but those in bisdemethoxycurcumin injection group and bisdemethoxycurcumin liposome group were reduced significantly.The liver lobules were ameliorated obviously too,especially in bisdemethoxycurcumin liposome group.The pharmacodynamic action of liposome was better than that of the injection.CONCLUSION:Bisdemethoxycurcumin liposome has significantly protective effects on CCl4-induced acute chemical liver injury by reducing peroxidation of lipid in endotheliocyte of the liver.