Isoniazid metabolism and hepatotoxicity

Wang, Pengcheng; Pradhan, Komal; Zhong, Xiao Bo; Ma, Xiaochao

doi:10.1016/j.apsb.2016.07.014

Cited by 195 publications

(132 citation statements)

References 120 publications

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“…Acetylation and hydrolysis are two known metabolic pathways of INH [2, 34, 35]. We found that deficiency of NAT1/2 totally abolished INH acetylation in the liver.…”

Section: Discussionmentioning

confidence: 73%

“…In addition to the acetylation pathway, INH can be hydrolyzed by amidases to form Hz and INA [2, 34, 35]. However, no significant difference was found in the hepatic level of INA between Nat1/2(−/−) and WT mice following INH administration (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Hz can be further acetylated to form AcHz and NAT2 is responsible for this metabolic pathway [35]. Therefore, we next measured AcHz in the liver of Nat1/2(−/−) mice.…”

Section: Resultsmentioning

confidence: 99%

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Deficiency of N -acetyltransferase increases the interactions of isoniazid with endobiotics in mouse liver

Wang

Shehu

et al. 2017

Biochemical Pharmacology

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Acetylation is the major metabolic pathway of isoniazid (INH) mediated by N-acetyltransferases (NATs). Previous reports suggest that slow acetylators have higher risks of INH hepatotoxicity than rapid acetylators, but the detailed mechanisms remain elusive. The current study used Nat1/2(−/−) mice to mimic NAT slow metabolizers and to investigate INH metabolism in the liver. We found that INH acetylation is abolished in the liver of Nat1/2(−/−) mice, suggesting that INH acetylation is fully dependent on NAT1/2. In addition to the acetylation pathway, INH can be hydrolyzed to form hydrazine (Hz) and isonicotinic acid (INA). We found that INA level was not altered in the liver of Nat1/2(−/−) mice, indicating that deficiency of NAT1/2 has no effect on INH hydrolysis. Because INH acetylation was abolished and INH hydrolysis was not altered in Nat1/2(−/−) mice, we expected an extremely high level of INH in the liver. However, we only observed a modest accumulation of INH in the liver of Nat1/2(−/−) mice, suggesting that there are alternative pathways in INH metabolism in NAT1/2 deficient condition. Our further studies revealed that the conjugated metabolites of INH with endobiotics, including fatty acids and vitamin B6, were significantly increased in the liver of Nat1/2(−/−) mice. In summary, this study illustrated that deficiency of NAT1/2 decreases INH acetylation, but increases the interactions of INH with endobiotics in the liver. These findings can be used to guide future studies on the mechanisms of INH hepatotoxicity in NAT slow metabolizers.

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“…Acetylation and hydrolysis are two known metabolic pathways of INH [2, 34, 35]. We found that deficiency of NAT1/2 totally abolished INH acetylation in the liver.…”

Section: Discussionmentioning

confidence: 73%

Section: Resultsmentioning

confidence: 99%

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Deficiency of N -acetyltransferase increases the interactions of isoniazid with endobiotics in mouse liver

Wang

Shehu

et al. 2017

Biochemical Pharmacology

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“…With the advantage of genome-wide association studies (GWAS), genetic variants have been identified that are associated with the AT-DILI. Previous reviews have discussed mechanisms and genetic factors that affect isoniazid-induced liver injury [21–23]. However, in a clinical setting, co-treatment with both isoniazid and rifampicin is much more common.…”

Section: Introductionmentioning

confidence: 99%

Genetic Variations Associated with Anti-Tuberculosis Drug-Induced Liver Injury

Bao

Rasmussen

et al. 2018

Curr Pharmacol Rep

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Purpose of this Review In order to combat the development of drug resistance, the clinical treatment of tuberculosis requires the combined use of several anti-tuberculosis (anti-TB) drugs, including isoniazid and rifampicin. Combinational treatment approaches are suggested by the World Health Organization (WHO) and are widely accepted throughout the world. Unfortunately, a major side effect of the treatment is the development of anti-tuberculosis drug-induced liver injury (AT-DILI). Many factors contribute to isoniazid- and rifampicin-mediated AT-DILI and genetic variations are among the most common factors. The purpose of this review is to provide information on genetic variations associated with isoniazid- and rifampicin-mediated AT-DILI. Recent Findings The genetic variations associated with AT-DILI have been identified in the genomic regions within or near genes encoding proteins in the following pathways: drug metabolizing enzymes (NAT2, CYP2E1, and GSTs), accumulation of bile acids, lipids, and heme metabolites (CYP7A1, BSEP, UGTs, and PXR), immune adaptation (HLAs and TNF-α), and oxidant challenge (TXNRD1, SOD1, BACH1, and MAFK). Summary The information summarized in this review considers the genetic bases of risk factors contributing to AT-DILI and provides information that may help for future studies. Some of the implicated genetic variations can be used in the design of genetic tests and serve as biomarkers for the prediction of isoniazid- and rifampicin-mediated AT-DILI risk in personalized medicine.

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“…Isoniazid produces liver injury by producing reactive toxic metabolites (isonicotinic acid, and hydrazine and acetylhydrazine free radical) that interacts with the liver proteins and results into anomaly of the liver anatomy. On the other hand, rifam -picin when given in combination with isoniazid causes cytochrome P450 enzyme-induction and results in the increased metabolism of isoniazid (Gangadharam, 1986;Wang et al, 2016;Pandit et al, 2012). …”

Section: Introductionmentioning

confidence: 99%

Amelioration of isoniazid and rifampicin-induced liver toxicity by Amaranthus graecizans subsp. silvestris in rat

Ishtiaq

Afridi

Masood

2017

Bangladesh J Pharmacol

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Amaranthus graecizans subsp. silvestris, a folk medicine for the treatment of inflammation, was used to evaluate its hepatoprotective potential against rifampicin and isoniazid-induced liver damage. Wistar albino rats were divided into four groups: Group I served as control (distilled water treated), Group II served as hepatotoxic group (isoniazid 50 mg/kg and rifampicin 100 mg/kg, treated), Group III served as positive control (silymarin 100 mg/kg, treated) while Group IV served as A. graecizans subsp. silvestris extract (400 mg/kg) treated group. The results suggest that the liver markers (alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase and total bilirubin) were significantly increased in the animals of Group II. The methanolic extract showed a significant decrease in the raised liver enzymes of Group IV and encountered the liver damage caused by isoniazid and rifampicin. Histopathological examination of liver also revealed the improved architecture in the extract-treated group. Thus, the methanolic extract has potential liver protective action due to its phytochemicals.Video Clip of Methodology:8 min 33 sec: <a href="https://www.youtube.com/v/dUa_1c_S8VY">Full Screen</a> <a href="https://www.youtube.com/watch?v=dUa_1c_S8VY">Alternate</a>

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Isoniazid metabolism and hepatotoxicity

Cited by 195 publications

References 120 publications

Deficiency of N -acetyltransferase increases the interactions of isoniazid with endobiotics in mouse liver

Deficiency of N -acetyltransferase increases the interactions of isoniazid with endobiotics in mouse liver

Genetic Variations Associated with Anti-Tuberculosis Drug-Induced Liver Injury

Amelioration of isoniazid and rifampicin-induced liver toxicity by Amaranthus graecizans subsp. silvestris in rat

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