TY - JOUR
T1 - A high dose of isoniazid disturbs endobiotic homeostasis in mouse liver
AU - Li, Feng
AU - Wang, Pengcheng
AU - Liu, Ke
AU - Tarrago, Mariana G.
AU - Lu, Jie
AU - Chini, Eduardo N.
AU - Ma, Xiaochao
N1 - Publisher Copyright:
Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.
PY - 2016/11
Y1 - 2016/11
N2 - Overdose of isoniazid (INH), an antituberculosis drug, can be lifethreatening 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. Wealso identified an INH andNADadduct 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.
AB - Overdose of isoniazid (INH), an antituberculosis drug, can be lifethreatening 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. Wealso identified an INH andNADadduct 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.
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U2 - 10.1124/dmd.116.070920
DO - 10.1124/dmd.116.070920
M3 - Article
C2 - 27531952
AN - SCOPUS:84990849621
SN - 0090-9556
VL - 44
SP - 1742
EP - 1751
JO - Drug Metabolism and Disposition
JF - Drug Metabolism and Disposition
IS - 11
ER -