Abstract
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.
Footnotes
- Received April 9, 2016.
- Accepted August 15, 2016.
F.L. and P.W. contributed equally to this work.
This work was supported in part by the National Institute of Diabetes and Digestive and Kidney Diseases [Grant number DK090305]. The authors declare that there are no conflicts of interest.
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- Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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