Role of CYP3A in Isoniazid Metabolism In Vivo

Liu, Ke; Li, Feng; Lu, Jie; Gao, Zhiwei; Klaassen, Curtis D.; Ma, Xiaochao

doi:10.2133/dmpk.dmpk-13-nt-089

Cited by 17 publications

(17 citation statements)

References 21 publications

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“…4-nitrophenol was used as a probe for CYP2E1 activity assay [30]. CYP2E1 expression was analyzed by Western-blot (n = 3) [31]. The primary antibody against CYP2E1 was purchased from EMD Millipore (Billerica, MA; cat# AB1252).…”

Section: Methodsmentioning

confidence: 99%

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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Section: Methodsmentioning

confidence: 99%

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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“…However, this study concluded that no association of these SNPs correlated with development of AT-DILI in the Chinese population. A study with Cyp3a -null mice also concludes that CYP3A enzymes have no effect on the systemic pharmacokinetics of isoniazid in mice and are not involved in bioactivation of isoniazid and development of AT-DILI [63]. …”

Section: Specific Molecular Mechanisms Of Isoniazid/rifampicin-inducementioning

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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“…Despite the fact that INH has been widely used as a first-line antitubercular agent (2,3), its therapeutic value is usually accompanied by severe hepatotoxicity and lethal hepatic injury (4,5). Although the pathophysiology of INH-induced liver injury might vary, the toxicity features of the drug, including hepatocellular steatosis, necrosis, and inflammatory infiltration, are nearly consistent (6,7).…”

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Role of Inflammatory and Oxidative Stress, Cytochrome P450 2E1, and Bile Acid Disturbance in Rat Liver Injury Induced by Isoniazid and Lipopolysaccharide Cotreatment

Hassan

Guo

Yousef

et al. 2016

Antimicrob Agents Chemother

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Isoniazid (INH), since its introduction in the year 1952, still serves as a frontline drug in tuberculosis treatment (1). Despite the fact that INH has been widely used as a first-line antitubercular agent (2, 3), its therapeutic value is usually accompanied by severe hepatotoxicity and lethal hepatic injury (4, 5). Although the pathophysiology of INH-induced liver injury might vary, the toxicity features of the drug, including hepatocellular steatosis, necrosis, and inflammatory infiltration, are nearly consistent (6, 7).Even though extensive studies expounding INH toxicity have been carried out, the exact mechanism of INH hepatotoxicity remains controversial. Among numerous established theories, an inflammatory stress theory has recently been widely used to explain the idiosyncrasy. One hypothesis is that inflammatory stress increases sensitivity to drug-induced liver injury (DILI) (8, 9). In this theory, an incidence of systemic inflammation might reduce the xenobiotic toxicity threshold, which could be easily accomplished by coadministration with an inflammatory agent (10), thus promoting drug toxicity. Lipopolysaccharide (LPS) is an outer cell wall membrane constituent of Gram-negative bacteria that has been comprehensively studied as an inflammatory agent with a major role in bacterial infections (11,12). Previous studies have suggested that LPS might intensify DILI (13-15), and, hence, a possible cornerstone role for LPS in INH-induced hepatotoxicity might be assumed.Oxidative stress, generated from the accumulation of reactive oxygen species (ROS), may be potentiated by different factors, including drugs and inflammation (16,17). In addition, oxidative stress plays a major role in several types of hepatic injury (18). Furthermore, with cytochrome P450 2E1 (CYP2E1) playing a major role in drug metabolism and the pathophysiology of DILI (19) and being considered a principal element in human susceptibility to chemical toxins (20), it plays a central part in oxidative stress, production of ROS, and hepatotoxic injury. Moreover, a previous report proposed that hepatic CYP2E1 plays a fundamental role in the propagation of INH-induced hepatotoxicity, mainly throughout ROS generation (21). Nevertheless, a full understanding of CYP2E1 as a major hepatotoxin-forming, catalyzing enzyme and its influence on INH-induced liver damage has not been completely achieved.Studies of the hepatotoxic mechanisms of INH were previously conducted using different animal models; however, results were accompanied by the absence of certain features of INH toxicity, i.e., delayed onset or inconsistency in severity compared to that in hu-

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Role of CYP3A in Isoniazid Metabolism In Vivo

Cited by 17 publications

References 21 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

Role of Inflammatory and Oxidative Stress, Cytochrome P450 2E1, and Bile Acid Disturbance in Rat Liver Injury Induced by Isoniazid and Lipopolysaccharide Cotreatment

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