Protective effects of metallothionein on isoniazid and rifampicin-induced hepatotoxicity in mice.
Protective effects of metallothionein on isoniazid and rifampicin-induced hepatotoxicity in mice.
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DOI：
10.1371/journal.pone.0072058
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Peng S
中科院分区：
文献类型：
--
作者：
Lian Y;Zhao J;Xu P;Wang Y;Zhao J;Jia L;Fu Z;Jing L;Liu G;Peng S
异烟肼（INH）和利福平（RFP）在世界范围内广泛用于治疗结核病，但肝毒性是临床治疗中的一个主要问题。先前的研究表明，这些药物引起肝脏氧化应激，而几种抗氧化剂减轻了这种作用。金属硫蛋白（MT）是富含半胱氨酸的蛋白质中的一员，被认为是一种有效的抗氧化剂。本研究试图确定内源性MT表达是否对小鼠INH和rfp诱导的肝脏氧化应激有保护作用。野生型（MT+/+）和MT-null （MT−/−）小鼠分别灌胃INH （150 mg/kg）、RFP （300 mg/kg）或两者联合（150 mg/kg INH +300 mg/kg RFP） 21天。结果表明，MT−/−小鼠比MT+/+小鼠对INH和rfp诱导的肝损伤更敏感，表现为肝脏组织病理学改变，血清AST水平和肝脏指数升高，肝脏氧化应激增加，表现为MDA生成增加和肝脏抗氧化状态的改变。此外，INH增加了肝脏CYP2E1的蛋白表达，INH/RFP（单独或联合）降低了肝脏CYP1A2的表达。这些发现清楚地表明，基础MT对INH和rfp诱导的肝细胞毒性具有保护作用。CYP2E1和CYP1A2参与了INH和rfp诱导的肝毒性的发病机制。
Isoniazid (INH) and Rifampicin (RFP) are widely used in the world for the treatment of tuberculosis, but the hepatotoxicity is a major concern during clinical therapy. Previous studies showed that these drugs induced oxidative stress in liver, and several antioxidants abated this effect. Metallothionein (MT), a member of cysteine-rich protein, has been proposed as a potent antioxidant. This study attempts to determine whether endogenous expression of MT protects against INH and RFP-induced hepatic oxidative stress in mice. Wild type (MT+/+) and MT-null (MT−/−) mice were treated intragastrically with INH (150 mg/kg), RFP (300 mg/kg), or the combination (150 mg/kg INH +300 mg/kg RFP) for 21 days. The results showed that MT−/− mice were more sensitive than MT+/+ mice to INH and RFP-induced hepatic injuries as evidenced by hepatic histopathological alterations, increased serum AST levels and liver index, and hepatic oxidative stress as evidenced by the increase of MDA production and the change of liver antioxidant status. Furthermore, INH increased the protein expression of hepatic CYP2E1 and INH/RFP (alone or in combination) decreased the expression of hepatic CYP1A2. These findings clearly demonstrate that basal MT provides protection against INH and RFP-induced toxicity in hepatocytes. The CYP2E1 and CYP1A2 were involved in the pathogenesis of INH and RFP-induced hepatotoxicity.
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影响因子：
2.8
作者：
Attri, S;Rana, SV;Singh, K
通讯作者：
Singh, K
DOI：
10.1254/jjp.69.325
发表时间：
1995-12-01
期刊：
JAPANESE JOURNAL OF PHARMACOLOGY
影响因子：
--
作者：
Huang, RB;Okuno, H;Inoue, K
通讯作者：
Inoue, K
影响因子：
3.2
作者：
Ebadi, Manuchair;Sharma, Sushil
通讯作者：
Sharma, Sushil
影响因子：
3.3
作者：
Kumari, MVR;Hiramatsu, M;Ebadi, M
通讯作者：
Ebadi, M
利福平在药物相互作用中的作用：涉及核孕烷 X 受体的潜在分子机制。
影响因子：
5.7
作者：
Chen, Jiezhong;Raymond, Kenneth
通讯作者：
Raymond, Kenneth