Role of Inflammatory and Oxidative Stress, Cytochrome P450 2E1, and Bile Acid Disturbance in Rat Liver Injury Induced by Isoniazid and Lipopolysaccharide Cotreatment.
Isoniazid (INH) remains the core drug in tuberculosis management, but serious hepatotoxicity and potentially fatal liver injury continue to accompany INH consumption. Among numerous theories that have been established to explain INH-induced liver injury, an inflammatory stress theory has recently been widely used to explain the idiosyncrasy. Inflammatory stress usually sensitizes tissues to a drug's toxic consequences. Therefore, the present study was conducted to verify whether bacterial lipopolysaccharide (LPS)-induced inflammation may have a role in enhancing INH hepatotoxicity. While single INH or LPS administration showed no major toxicity signs, INH-LPS cotreatment intensified liver toxicity. Both blood biomarkers and histological evaluations clearly showed positive signs of severe liver damage accompanied by massive necrosis, inflammatory infiltration, and hepatic steatosis. Furthermore, elevated serum levels of bile acid associated with the repression of bile acid synthesis and transport regulatory parameters were observed. Moreover, the principal impact of cytochrome P450 2E1 (CYP2E1) on INH toxicity could be anticipated, as its protein expression showed enormous increases in INH-LPS-cotreated animals. Furthermore, the crucial role of CYP2E1 in the production of reactive oxygen species (ROS) was clearly obvious in the repression of hepatic antioxidant parameters. In summary, these results confirmed that this LPS-induced inflammation model might prove valuable in revealing the hepatotoxic mechanisms of INH and the crucial role played by CYP2E1 in the initiation and propagation of INH-induced liver damage, information which could be very useful to clinicians in understanding the pathogenesis of drug-induced liver injury.
Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, China Department of Pharmacology, Faculty of Pharmacy, University of Gezira, Wad-Medani, Sudan.
Hozeifa Mohamed
HM
Hassan
Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, China.
Hongli
H
Guo
Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, China.
Bashir Alsiddig
BA
Yousef
Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, China.
Mounia
M
Guerram
Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, China.
Aida Mejda
AM
Hamdi
Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, China Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, China Jiangsu Key Laboratory of TCM Evaluation and Translational Research, China Pharmaceutical University, Nanjing, China lyzhang@cpu.edu.cn beaglejiang@cpu.edu.cn.
Luyong
L
Zhang
Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, China Key Laboratory of Drug Quality Control and Pharmacovigilance, China Pharmaceutical University, Ministry of Education, Nanjing, China lyzhang@cpu.edu.cn beaglejiang@cpu.edu.cn.
Zhenzhou
Z
Jiang
D000818:Animals; D000995:Antitubercular Agents / Q000009:adverse effects*; D001647:Bile Acids and Salts / Q000097:blood; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics* / Q000378:metabolism; D004338:Drug Combinations; D005234:Fatty Liver / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D015870:Gene Expression; D007249:Inflammation; D007538:Isoniazid / Q000009:adverse effects*; D008070:Lipopolysaccharides / Q000633:toxicity*; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000819:agonists / Q000378:metabolism; D015854:Up-Regulation
D000995:Antitubercular Agents; D001647:Bile Acids and Salts; D004338:Drug Combinations; D008070:Lipopolysaccharides; D017382:Reactive Oxygen Species; D019392:Cytochrome P-450 CYP2E1; D007538:Isoniazid