BACKGROUND/AIMS: To evaluate the role of mitochondrial oxidative stress and permeability transition (MPT) in isoniazid (INH) and rifampicin (RMP) induced hepatotoxicity in mice. METHODS: Liver damage was induced by co-treatment of INH (50 mg/kg) and RMP (100 mg/kg). Pre-treatment with either methionine or phorone was done to modulate hepatic GSH level. Liver cell injury was assessed biochemically and histologically. Evidence of apoptosis was sought by TUNEL test, caspase assay and histology. RESULTS: INH and RMP co-treatment caused steatosis and increased apoptosis of the hepatocytes, hepatic oxidative stress, particularly in the mitochondrial fraction with increased mitochondrial permeability transition (MPT). Mitochondrial oxidative stress as well as liver cell injury was increased by prior treatment with phorone. This was attenuated by pretreatment with methionine suggesting a glutathione (GSH) dependent phenomenon. CONCLUSIONS: Oxidative stress in the mitochondria and inappropriate MPT are important in the pathogenesis of apoptotic liver cell injury in INH-RMP hepatotoxicity. The phenomenon is GSH dependent and methionine supplementation might have a protective role.
BACKGROUND/AIMS: To evaluate the role of mitochondrial oxidative stress and permeability transition (MPT) in isoniazid (INH) and rifampicin (RMP) induced hepatotoxicity in mice. METHODS: Liver damage was induced by co-treatment of INH (50 mg/kg) and RMP (100 mg/kg). Pre-treatment with either methionine or phorone was done to modulate hepatic GSH level. Liver cell injury was assessed biochemically and histologically. Evidence of apoptosis was sought by TUNEL test, caspase assay and histology. RESULTS: INH and RMP co-treatment caused steatosis and increased apoptosis of the hepatocytes, hepatic oxidative stress, particularly in the mitochondrial fraction with increased mitochondrial permeability transition (MPT). Mitochondrial oxidative stress as well as liver cell injury was increased by prior treatment with phorone. This was attenuated by pretreatment with methionine suggesting a glutathione (GSH) dependent phenomenon. CONCLUSIONS: Oxidative stress in the mitochondria and inappropriate MPT are important in the pathogenesis of apoptotic liver cell injury in INH-RMP hepatotoxicity. The phenomenon is GSH dependent and methionine supplementation might have a protective role.
Authors: Michael A Joyce; Kathie-Anne Walters; Sue-Ellen Lamb; Mathew M Yeh; Lin-Fu Zhu; Norman Kneteman; Jason S Doyle; Michael G Katze; D Lorne Tyrrell Journal: PLoS Pathog Date: 2009-02-06 Impact factor: 6.823