A High Dose of Isoniazid Disturbs Endobiotic Homeostasis in Mouse Liver

• Published in: Drug metabolism and disposition 2016-11, Vol.44 (11), p.1742-1751
• Main Authors: Li, Feng, Wang, Pengcheng, Liu, Ke, Tarrago, Mariana G, Lu, Jie, Chini, Eduardo N, Ma, Xiaochao
• Format: Article
• Language: English
• Subjects: Animals; Antitubercular Agents - adverse effects; Antitubercular Agents - metabolism; Carnitine - metabolism; Homeostasis - drug effects; Homeostasis - physiology; Isoniazid - adverse effects; Isoniazid - metabolism; Liver - drug effects; Liver - metabolism; Metabolomics - methods; Mice; Oxidation-Reduction - drug effects; Vitamin B 6 - metabolism
• ISSN: 1521-009X; 0090-9556; 1521-009X
• DOI: 10.1124/dmd.116.070920

Overdose of isoniazid (INH), an antituberculosis drug, can be life-threatening because of neurotoxicity. In clinical practice for management of INH overdose and acute toxicity, the potential of INH-induced hepatotoxicity is also considered. However, the biochemical basis of acute INH toxicity in the liver remains elusive. In the current study, we used an untargeted metabolomic approach to explore the acute effects of INH on endobiotic homeostasis in mouse liver. We found that overdose of INH resulted in accumulation of oleoyl-l-carnitine and linoleoyl-l-carnitine in the liver, indicating mitochondrial dysfunction. We also revealed the interactions between INH and fatty acyl-CoAs by identifying INH-fatty acid amides. In addition, we found that overdose of INH led to the accumulation of heme and oxidized NAD in the liver. We also identified an INH and NAD adduct in the liver. In this adduct, the nicotinamide moiety in NAD was replaced by INH. Furthermore, we illustrated that overdose of INH depleted vitamin B6 in the liver and blocked vitamin B6-dependent cystathionine degradation. These data suggest that INH interacts with multiple biochemical pathways in the liver during acute poisoning caused by INH overdose.