title: Protective effects of metallothionein on isoniazid and rifampicin-induced hepatotoxicity in mice.
abstract: 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.
authors: Evaluation and Research Centre for Toxicology, Institute of Disease Control and Prevention, Academy of Military Medical Sciences, Beijing, China.
authors: Yong
authors: Y
authors: Lian
authors: Jing
authors: J
authors: Zhao
authors: Peiyu
authors: P
authors: Xu
authors: Yimei
authors: Y
authors: Wang
authors: Jun
authors: J
authors: Zhao
authors: Li
authors: L
authors: Jia
authors: Ze
authors: Z
authors: Fu
authors: Li
authors: L
authors: Jing
authors: Gang
authors: G
authors: Liu
authors: Shuangqing
authors: S
authors: Peng
mesh_terms: D000410:Alanine Transaminase / Q000097:blood / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D000995:Antitubercular Agents / Q000633:toxicity*; D001219:Aspartate Aminotransferases / Q000097:blood / Q000378:metabolism; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000378:metabolism; D007538:Isoniazid / Q000633:toxicity*; D015227:Lipid Peroxidation; D008099:Liver / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008668:Metallothionein / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D012293:Rifampin / Q000633:toxicity*; D013482:Superoxide Dismutase / Q000378:metabolism
chemical_list: D000975:Antioxidants; D000995:Antitubercular Agents; D008668:Metallothionein; D005979:Glutathione Peroxidase; D019392:Cytochrome P-450 CYP2E1; D019388:Cytochrome P-450 CYP1A2; D013482:Superoxide Dismutase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D005978:Glutathione; D007538:Isoniazid; D012293:Rifampin
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