Isoniazid-induced Hepatotoxicity Research Articles

Isoniazid-induced hepatotoxicity in patients with latent tuberculosis – Experience from a tuberculosis center

BackgroundAlthough the prevalence of isoniazid-induced hepatotoxicity (IIH) has been documented in patients with tuberculosis, its prevalence in latent tuberculosis infection (LTBI) patients is less studied. The aim of this study was to investigate the prevalence of IIH in a group of LTBI patients who received isoniazid monotherapy. MethodsRetrospective cohort study including patients who underwent isoniazid monotherapy for LTBI in an outpatient clinic between January 1st, 2020, and June 30th, 2021. ResultsA total of 274 cases were analyzed. About half (50.4 %) were male; median age was 53 years-old (minimum: six; maximum 89). The most common comorbidities were dyslipidemia (25.5 %), body mass index between 25 and 30 kg/m2 (20.4 %), obesity (14.7 %) and chronic hepatic disease (CHD; 12.8 %). 47.4 % had systemic inflammatory diseases. Significant elevation of liver enzymes was documented in 27 % of patients. IIH was documented in 20.4 % of patients; there was a statistically significant relation with dyslipidemia (p < 0.001), CHD (p = 0.023), psoriasis (p = 0.025), spondyloarthropathies (p = 0.017) and male sex (p = 0.042). Dyslipidemia showed a strong correlation to IIH (adjusted odds ratio: 8.045). ConclusionPatients with dyslipidemia had an adjusted odds ratio of 8.045 to develop IIH. Future multicentric studies should be started to better explore this relation, as well as treatment options.

Quantitative Analysis of Isoniazid and Its Four Primary Metabolites in Plasma of Tuberculosis Patients Using LC-MS/MS

Isoniazid and its metabolites are potentially associated with hepatotoxicity and treatment outcomes in patients who receive antituberculosis (TB) therapy. To further understand the pharmacokinetic profiles of these molecules, a method based on LC-MS/MS was developed to determine the concentration of these compounds in human plasma. Isoniazid, acetylisoniazid, and isonicotinic acid were directly analyzed, whereas hydrazine and acetylhydrazine were determined after derivatization using p-tolualdehyde. Chromatographic separation was conducted on reversed-phase C18 columns with gradient elution, and detection was carried out in multiple reaction monitoring mode. The calibration curves were linear with correlation coefficients (r) greater than 0.9947 for all analytes. The intra- and inter-day precision was less than 13.43%, and the accuracy ranged between 91.63 and 114.00%. The recovery and matrix effect of the analytes were also consistent (coefficient of variation was less than 9.36%). The developed method successfully quantified isoniazid and its metabolites in TB patients. The method has broad applications in clinical research, including isoniazid one-point-based therapeutic drug monitoring, genotype-phenotype association studies of isoniazid metabolic profile and isoniazid-induced hepatotoxicity, and the initial dose prediction of isoniazid using population pharmacokinetic modeling.

Lagerstroemia speciosa (L.) Pers., ethanolic extract attenuates simultaneously administered isoniazid- and dapsone-induced hepatotoxicity in rats.

Herbal tea of Lagerstroemia speciosa Pers., commonly known as banaba, has been traditionally used to treat various ailments including diabetes and obesity due to its antioxidant and anti-inflammatory efficacies. Drug-induced liver injury is a common cause of acute liver failure. Isoniazid (INH) is used as the first-line treatment for tuberculosis; clinical and experimental studies have reported an abnormal liver function after INH therapy. Dapsone (DDS) is used for leprosy and other infections. This study investigates the hepatoprotective effect of ethanolic banaba leaves extract (EBLE) against simultaneously administered INH- and DDS-induced hepatotoxicity in rats. DDS (30mg/kg, i.p.) and INH (50mg/kg. p.o.) were administered simultaneously for 30days. In separate groups, rats were posttreated orally with EBLE (500mg/kg) and silymarin (100mg/kg) for 30days after INH+DDS administration. The marker enzymes of hepatotoxicity, oxidative stress markers, inflammatory markers, and histopathology were done. Simultaneous administration of INH- and DDS-induced significant elevation of marker enzymes of hepatotoxicity in the serum. This treatment also increased lipid peroxidation and pro-inflammatory markers (tumor necrosis factor alpha, transforming growth factor beta, and nuclear factor kappa B) expressions and decreased intracellular antioxidants such as superoxide dismutase, catalase, and glutathione in the liver tissue. All these abnormalities were significantly mitigated after EBLE and SIL posttreatments. The results of this study suggest that EBLE and silymarin can be protective against INH+DDS-induced hepatotoxicity. PRACTICAL APPLICATIONS: Herbal tea contain Lagerstroemia speciosa leaves are used in several Southeast Asian countries due to its rich antioxidant and inflammatory properties. This study showed the hepatoprotective efficacy of L. speciosa ethanolic extract against simultaneously administered dapsone- and isoniazid-induced hepatotoxicity in rats. L. speciosa administration was found to decrease dapsone- and isoniazid-induced oxidative stress and hepatic inflammation. L. speciosa herbal tea can reduce drug-induced hepatic complications as it contains phytochemicals such as corosolic acid, gallic acid, ellagic acid and berberine and are implicated for its hepatoprotective effect. Therefore, L. speciosa extract can be used for drug-induced liver injury.

Influence of the Acetylation Type on the Incidence of Isoniazid-Induced Hepatotoxicity in Patients with Newly Diagnosed Pulmonary Tuberculosis

Introduction. Liver damage can be a dangerous side effect of using isoniazid. Individual susceptibility to isoniazid in humans is dependent on the presence of N-acetyltransferase 2 allelic variants in genome. It was imperative to assess the effect of genetically determined isoniazid acetylation rate in terms of risk of developing isoniazid-induced hepatotoxicity, as well as prevention of potential hepatopathy, and improvement of tuberculosis chemotherapy safety. Aim. To study the effect of acetylation type on the incidence of isoniazid hepatotoxicity in residents of the Sakha Republic (Yakutia) with newly diagnosed pulmonary tuberculosis. Methods. The study included 112 patients with newly diagnosed pulmonary tuberculosis. Genotyping was performed using real-time polymerase chain reaction. The following single nucleotide polymorphisms were studied: rs1801280, rs1799930, rs1799931, rs1799929, rs1208, rs1041983. Hepatotoxicity was determined based on the results of clinical laboratory monitoring and using the criteria developed by the European Association for the Study of the Liver (2019). Results. Hepatotoxic reactions developed more often in slow acetylators (43.2%), compared to fast acetylators (20.7%) and intermediate acetylators (10.9%); p=0.002. Serum alanine aminotransferase activity was 5 or more times above the upper limit of normal activity in 37.8% of slow acetylators, and in 8.7% of intermediate acetylators; p=0.001. Clinical manifestations of isoniazid hepatotoxicity were observed more often in slow acetylators (29.7%), than in fast acetylators (3.4%); p=0.000. Conclusion. Slow acetylation type ought to be considered an important risk factor for developing isoniazid hepatotoxicity in patients with pulmonary tuberculosis.

Hepatoprotective effect of rutin and N-acetyl cysteine against isoniazid induced hepatotoxicity

This study was carried to evaluate the protective effect of rutin and N-acetyl cysteine (NAC) against isoniazid-induced (INH) hepatotoxicity. In this study, Seventy two adult male rats were divided into six equal groups as follow: control group: 1 ml saline /Kg b.wt I/P. INH group: 100 mg INH /kg b.wt I/P. INH + Rutin group: 100 mg INH /kg b.wt I/P with 200 mg rutin /kg orally. INH + NAC group: 100 mg INH /kg b.wt I/P with 300 mg NAC /kg orally. Rutin group: 200 mg rutin /kg/day orally. NAC group: 300 mg NAC /kg b.wt orally. Serum and tissue specimens were collected at 7th, 14th and 21th day. IP injection of Isoniazid induced significant increase in values of ALT, AST, ALP, GGT and total bilirubin, while significant decrease in total protein and albumin was recorded. INH + Rutin showed significant decreases in the levels of ALT, AST, ALP and GGT with significant increase in albumin values and significant increase in total protein however significant decrease in the level of total bilirubin was recorded only at 21 days. INH + NAC induced significant decreases in the levels of ALT, AST, ALP and GGT with significant increase in albumin and total protein at 14 and 21 days and significant decrease in total bilirubin at 21 days. Rutin and NAC have potent protective effect against INH induced hepatotoxicity.

Adherence to nine-month isoniazid for latent tuberculosis infection in healthcare workers: a prospective study in a tertiary hospital

Poor adherence to medication can lead to treatment failure in healthcare workers (HWCs) with latent tuberculosis infection (LTBI) who are at high risk of developing active tuberculosis. However, the factors associated with non-completion of nine-month LTBI treatment with isoniazid (9 H) have not been well studied. We investigated the completion rate and factors affecting adherence to LTBI treatment with 9 H among HCWs. A prospective cohort study of 114 HCWs who were diagnosed with LTBI by QuantiFERON-TB Gold In-Tube tests were performed in a single university hospital between June 2016 and December 2017. All patients received the 9 H LTBI treatment. At each visit, treatment adherence and development of adverse reactions to isoniazid were evaluated via a standard questionnaire. To evaluate the impact of the severity of hepatotoxicity on non-completion of LTBI treatment, we classified hepatotoxicity into two groups: severe hepatotoxicity was defined as alanine aminotransferase >3.0 times the upper normal limit (UNL) with symptoms or = 5.0 times the UNL. Mild hepatotoxicity was defined as alanine aminotransferase>UNL, but not meet the definition of severe hepatotoxicity. Overall, 71 HCWs (62.3%) completed LTBI treatment with 9 H while 43 HCWs (37.7%) discontinued their treatment. Most discontinuation (81.4%, 35/43) occurred during the first three months of treatment. There were no significant differences in age, sex, occupation, or comorbidities between the HCWs who completed and those who discontinued LTBI treatment. However, HCWs who discontinued LTBI treatment had more hepatotoxicity than those who completed treatment (44.2% vs. 11.3%, P < 0.001). Cox proportional hazard analysis revealed that hepatotoxicity is the only factor significantly associated with discontinuation of 9 H LTBI treatment (unadjusted HR = 2.89, 95% CI = 1.62–5.46). In multivariable analysis, not only severe hepatotoxicity (adjusted HR = 7.99, 95% CI = 3.05–20.94) but also mild hepatotoxicity was significantly associated with discontinuation of LTBI treatment (adjusted HR = 2.34, 95% CI = 1.05–5.21). The completion rate of 9 H LTBI treatment was 62.3% among HCWs. While age, sex, occupation, and pretreatment comorbidities were not associated with treatment completion, isoniazid-induced hepatotoxicity significantly affected adherence.

Challenges of Hepatotoxicity Associated with Isoniazid Preventive Therapy among People Living with HIV in Eritrea

Background Isoniazid preventive therapy (IPT) is an intervention recommended by the WHO for prophylaxis of Tuberculosis (TB) in people living with HIV (PLWH) and reported as generally safe with little risk of hepatotoxicity. Following its introduction in Eritrea in 2014, IPT related hepatotoxicity and fatality have been frequently reported to the Eritrean Pharmacovigilance Centre. The aim of this study is, therefore, to quantify the risk of hepatotoxicity, evaluate the effectiveness of close laboratory monitoring, assess the causal relationship of IPT and hepatotoxicity, identify possible risk factors and assess preventability of Isoniazid-induced hepatotoxicity in PLWH. Methods This was an observational cohort study of PLWH on IPT enrolled from three Antiretroviral therapy (ART) Clinics in Asmara, Eritrea, between August 2016 and February 2017. Causality and preventability of the cases was assessed using Naranjo probability scale and P-method respectively. Results Of the 360 eligible patients, 56 were identified with hepatotoxicity with an incidence rate of cases per 1000 person-months with a median time to reaction onset of 34 days. About 41% of the cases developed severe or very severe hepatotoxicity following initiation of IPT. INH was terminated in 78.6% of the cases and reaction abated in 84.1% (37/44) following withdrawal of INH. Besides, ART was discontinued in 42.5% of the cases due to hepatotoxicity. In majority of the cases (87.5%), the causal relationship was found to be ‘probable’ and in 82.1% hepatotoxicity was not preventable. Conclusion The incidence rate of INH-related hepatotoxicity is very high with a short time to reaction onset and the occurrence of severe/ very severe hepatotoxicity was unavoidable in substantial number of patients; making risk minimization plan and IPT deployment challenging.

Mechanism of isoniazid-induced hepatotoxicity in zebrafish larvae: Activation of ROS-mediated ERS, apoptosis and the Nrf2 pathway

Isoniazid (INH) is a first-line anti-tuberculosis drug. INH has been detected in surface waters which may create a risk to aquatic organisms. In this study, the hepatotoxicity of INH was elucidated using zebrafish. The liver morphology, transaminase level, redox-related enzyme activity, reactive oxygen species (ROS) content and mRNA levels of liver injury-related genes were measured. The results showed that INH (4, 6 mM) significantly caused liver atrophy and increased levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in zebrafish. INH (6 mM) led to decreased catalase (CAT) activity, glutathione peroxidase (GPx) activity and glutathione (GSH) content but increased ROS and malondialdehyde (MDA) levels. Moreover, INH (6 mM) decreased expression levels of miR-122 and pparα but increased mRNA levels of ap-1 and c-jun. Furthermore, mRNA levels of factors related to endoplasmic reticulum stress (ERS) (grp78, atf6, perk, ire1, xbp1s and chop), apoptosis (bax, cyt, caspase-3, caspase-8 and caspase-9) and the Nrf2 signalling pathway (nrf2, ho-1, nqo1, gclm and gclc) were significantly upregulated. INH may act on hepatotoxicity in zebrafish by increasing ROS content, which weakens the antioxidant capacity, leading to ERS, cell apoptosis and liver injury. In addition, the Nrf2 signalling pathway is activated as a stress compensation mechanism during INH-induced liver injury, but it is not sufficient to counteract INH-induced hepatotoxicity.

Pharmacogenetic association between NAT2 gene polymorphisms and isoniazid induced hepatotoxicity: trial sequence meta-analysis as evidence.

Hepatotoxicity is a severe problem generally faced by tuberculosis (TB) patients. It is a well-known adverse reaction due to anti-TB drugs in TB patients undergoing long-term treatment. The studies published previously have explored the connection of N-acetyltransferase 2 (NAT2) gene polymorphisms with isoniazid-induced hepatotoxicity, but the results obtained were inconsistent and inconclusive. A comprehensive trial sequence meta-analysis was conducted employing 12 studies comprising 3613 controls and 933 confirmed TB cases using the databases namely, EMBASE, PubMed (Medline) and Google Scholar till December 2017. A significant association was observed with individuals carrying variant allele at position 481C>T (T vs. C: P = 0.001; OR = 1.278, 95% CI = 1.1100–1.484), at position 590G>A (A vs. G: P = 0.002; OR = 1.421, 95% CI = 1.137–1.776) and at position 857G>A (A vs. G: P = 0.0022; OR = 1.411, 95% CI = 1.052–1.894) to higher risk of hepatotoxicity vis-à-vis wild-type allele. Likewise, the other genetic models of NAT2 gene polymorphisms have also shown increased risk of hepatotoxicity. No evidence of publication bias was observed. These results suggest that genetic variants of NAT2 gene have significant role in isoniazid induced hepatotoxicity. Thus, NAT2 genotyping has the potential to improve the understanding of the drug–enzyme metabolic capacity and help in early predisposition of isoniazid-induced hepatotoxicity.

Isoniazid-induced hepatotoxicity and neurotoxicity in rats investigated by 1H NMR based metabolomics approach

Isoniazid (INH) is a well-known therapeutic and preventive agent against tuberculosis. However, high rates of side effects with various symptoms concerning hepatotoxicity and neurotoxicity have been reported, hindering its wide and safe application in clinic. In this investigation, rats were intoxicated with INH by gavage at doses of 200 and 400 mg/kg for 7 consecutive days to develop a rat model of acute INH-induced toxicity, which was investigated by a 1H NMR-based metabolomics complemented with clinical assays, histopathological inspection and western blotting. INH decreased the weights of dosed rats and induced seizure and hepatic steatosis dose-dependently. Orthogonal signal correction partial least-squares discriminant analysis (OSC-PLS-DA) of the NMR profiles of rat livers, brains and serum revealed that INH dose-dependently induced oxidative stress, disorders of excitatory and inhibitory amino acid neurotransmitters, and disturbances of energy metabolism and osmotic balance, which could help clarify the mechanisms of INH-induced hepatotoxicity and neurotoxicity. This integrated metabolomics approach showcased its ability to characterize the global metabolic status of organism, providing a powerful and feasible tool to probe drug induced toxicity or side effects.

Evaluation of ameliorative ability of Silibinin against zidovudine and isoniazid-induced hepatotoxicity and hyperlipidaemia in rats: Role of Silibinin in Phase I and II drug metabolism

HIV/AIDS patients have suppressed immune system, making them vulnerable to many opportunistic infections including tuberculosis (TB). The patients who are co-infected with TB undergo combined regimens with anti-retroviral drugs such as zidovudine (AZT) and anti-tubercular drug such as isoniazid (INH) for therapy leading to hepatotoxicty. Silibinin (SBN), extracted from Silybum marianum commonly called as “Milk thistle” is used against several drugs-induced hepatotoxicity. The present study evaluates the ameliorative effect of SBN against AZT alone, INH alone, and INH + AZT-induced toxic insults to liver of rats. Wistar albino rats (n = 6/groups) were given INH and AZT (25 and 50 mg mg/kg b.w.) respectively either alone or in combination for a sub-chronic period of 45 days orally. Another group of rats received SBN (100 mg/kg b.w.) along with INH and AZT. The group that received propylene glycol served as control. AZT alone, INH alone and INH + AZT treatments showed parenchymal cell injury and cholestasis by highly significant increase in the activities of marker enzymes (aspartate and alanine transaminase, alkaline phosphatase, argino succinic acid lyase), bilirubin and protein. The presence of hyperlipidaemia was observed by analyzing lipid profiles in serum/liver/adipose tissue, gene expression (RT-PCR) of Phase-I and II metabolizing enzymes and western blot. Transmission electron microscopy study also revealed large vacuoles with membraneous debri, pleomorphic mitochondria, disruption of endoplasmic reticulum, presence of lipid droplets, breakage in cellular and nuclear membrane. SBN simultaneous treatment showed ameliorative effect against INH + AZT-induced hepatotoxicity and hyperlipidemia in rats.

Risk factors of isoniazid-induced hepatotoxicity in Tunisian tuberculosis patients.

Previous studies have shown controversial results on whether acetylator status causes isoniazid-induced hepatotoxicity (IIH). Moreover, the contribution of CYP2E1, a hepatic enzyme implicated in the formation of hepatotoxins, to the risk of developing IIH remains unclear. The objectives of this study were (i) to assess the quantitative relationship between the level of isoniazid serum concentration and the incidence of IIH and (ii) to evaluate the extent of implication of the N-acetyltransferase-2 (NAT2) and CYP2E1 polymorphisms genes to induce this disorder. Seventy-one patients with tuberculosis receiving a conventional antituberculosis regimen were included. NAT2 and CYP2E1 genotypes were determined using polymerase chain reaction. Three restriction enzymes, RsaI, PstI and DraI were used to detect CYP2E1 RFLP and four different restriction enzymes, KpnI, TaqI, BamHI and Ddel were used to determine NAT2 acetylator status. Therapeutic drug monitoring (TDM) of isoniazid (serum concentration performed 3 h after the morning dose: C3) was performed. Cases of isoniazid-induced hepatotoxicity were diagnosed according to Benichou et al. Receiver Operating Characteristics curve analysis was used to evaluate the relationship between risk factors and the incidence of IIH. Eleven (15.4%) patients have developed IIH. Demographic factors, including age, weight and gender were not associated with the incidence of hepatotoxicity. High serum concentration of isoniazid (C3) was found to be a risk factor of IIH (area under the curve: 0.74, P=0.007, 95% confidence interval (95% CI): 0.56-0.93), with a cutoff value at 3.69 mg l-1 (odds ratio (OR): 13.2, P=0.0007, 95% CI: 2.9-59). Multivariate analysis showed that only a C3 over 3.69 mg l-1 remains a risk factor of IIH. NAT2 and CYP2E1 variants were not found to increase the risk of IIH when analyzed separately. However, combined analysis of the NAT2/CYP2E1 gene polymorphisms showed that patients with both DraI C/D and slow acetylator have an increased risk of IIH compared with other combined NAT2/CYP2E1 genotype profiles (OR: 8.41, P=0.01, 95% CI: 1.54-45.76). Our results suggest that a serum concentration of isoniazid over 3.69 mg l-1 and a combined genotype CYP2E1 DraI(C/D)/slow acetylator are major risk factors for IIH. Therefore, TDM of isoniazid and the determination of both NAT2 and CYP2E1 genotypes could be useful for the prediction and prevention of IIH in Tunisian tuberculosis patients.

Monoammonium glycyrrhizinate protects rifampicin- and isoniazid-induced hepatotoxicity via regulating the expression of transporter Mrp2, Ntcp, and Oatp1a4 in liver

Context: Drug-induced liver injury (DILI) is associated with altering expression of hepatobiliary membrane transporters. Monoammonium glycyrrhizin (MAG) is commonly used for hepatic protection and may have a correlation with the inhibition effect of multidrug resistance-associated protein 2 (Mrp2). Objective: This study evaluates the dynamic protective effect of MAG on rifampicin (RIF)- and isoniazid (INH)-induced hepatotoxicity in rats. Materials and methods: Male Wistar rats were randomly divided into four groups of 15 rats. Liver injury was induced by co-treatment with RIF (60 mg/kg) and INH (60 mg/kg) by gavage administration; MAG was orally pretreated at the doses of 45 or 90 mg/kg 3 h before RIF and INH. Rats in each group were sacrificed at 7, 14, and 21 d time points after drug administration. Results: Liver function, histopathological analysis, and oxidative stress factors were significantly altered in each group. The expression of Mrp2 was significantly increased 230, 760, and 990% at 7, 14, and 21 time points, respectively, in RIF- and INH-treated rats. Compared with the RIF and INH groups, Mrp2 was reduced and Ntcp was significantly elevated by 180, 140, and 160% in the MAG high-dose group at the three time points, respectively. The immunoreaction intensity of Oatp1a4 was increased 170, 190, and 370% in the MAG low-dose group and 160, 290, and 420% in the MAG high-dose group at the three time points, respectively, compared with the RIF and INH groups. Discussion and conclusion: These results indicated that MAG has a protective effects against RIF- and INH-induced hepatotoxicity. The underlying mechanism may have correlation with its effect on regulating the expression of hepatobiliary membrane transporters.

Acute and Fatal Isoniazid-Induced Hepatotoxicity: A Case Report and Review of the Literature

This paper describes a case of an acute and fatal isoniazid-induced hepatotoxicity and provides a review of the literature. A 65-year-old female diagnosed with latent Mycobacterium tuberculosis infection was receiving oral isoniazid 300 mg daily. She was admitted to the hospital for epigastric and right sided flank pain of one-week duration. Laboratory results and imaging confirmed hepatitis. After ruling out all other possible causes, she was diagnosed with isoniazid-induced acute hepatitis (probable association by the Naranjo scale). After discharge, the patient was readmitted and suffered from severe coagulopathy, metabolic acidosis, acute kidney injury, hepatic encephalopathy, and cardiorespiratory arrest necessitating two rounds of cardiopulmonary resuscitation. Despite maximal hemodynamic support, the patient did not survive. A review of the literature, from several European countries and the United States of America, revealed a low incidence of mortality due to isoniazid-induced hepatotoxicity when used as a single agent for latent Mycobacterium tuberculosis infection. As for the management, the first step consists of withdrawing isoniazid and rechallenge is usually discouraged. Few treatment modalities have been proposed; however there is no robust evidence to support any of them. Routine monitoring for hepatotoxicity in patients receiving isoniazid is warranted to prevent morbidity and mortality.

Isoniazid-induced hepatotoxicity in children with latent tuberculosis infection.

We aimed to determine overall incidence of severe and mild isoniazid (INH) hepatotoxicity and outcome of hepatotoxicity in children who were receiving INH for latent tuberculosis. Patients who had received isoniazid for treatment of latent tuberculosis were included in the study. Hepatotoxicity was classified according to the World Health Organization Toxicity Classification Standards. Among 1038 patients, overall hepatotoxicity was observed in 22 patients (2.2%), while 5 patients (0.48%) had moderate-severe hepatotoxicity; while other 17 patients had grade I-II hepatotoxicity (1.63%). Age and gender did not appear to be risk factors for hepatotoxicity. The median time for therapy rechallenge in patients with grade III-IV hepatotoxicity was 21 days (ranging from 14 to 25 days). Isoniazid hepatotoxicity is lower and generally reversible after cessation of INH in children. The grade of hepatotoxicity affects the duration for recovery of hepatotoxicity and restarting of INH therapy.

The association of genetic polymorphisms of N-acetyltransferase 2 gene with hepatotoxicity and efficacy in Chinese Han patients with tuberculosis

Objective To investigate the association of the polymorphism of the N-acetyltransferase 2 (NAT2) gene with isoniazid-induced hepatotoxicity and anti-tuberculous treatment efficacy in Chinese Han patients with tuberculosis(TB). Methods A total of 108 TB patients who received initial anti-TB treatment were followed up prospectively. A polymerase chain reaction direct sequencing approach was used to detect genetic polymorphisms of the NAT2 gene. Associations between NAT2 genotype and isoniazid-induced hepatitis/early treatment were analyzed. Chi-square test was used for statistical analysis. Results Among the 108 TB patients, intermediate-acetylators(IA) was the most frequent NAT2 genotype with the proportion of 54.63%(59/108). The proportion of rapid-acetylators(RA) was 33.33%(36/108), slow-acetylators (SA) was 10.19%(11/108) and super-rapid acetylators was 1.85% (2/108). Among the 20 patients who developed drug-induced hepatitis, 2 were RA, 5 were SA and 13 were IA. Regarding NAT2 genotype, RA patients had a lower incidence of hepatotoxicity (OR=0.176, 95%CI: 0.038-0.809, P=0.014) and SA patients were more likely to developed drug-induced hepatic injury (OR=4.556, 95%CI: 1.231-16.854, P=0.044). Statistical analysis revealed that the frequency of variant diplotypes, NAT2*4/*6A (OR=7.741, 95%CI: 2.653-22.586, P<0.01) and NAT2*6A/*6A (OR=15.353, 95%CI: 1.506-156.552, P=0.020) were significantly increased in TB patients with hepatotoxicity. NAT2*4/*4 was less likely to developed hepatic injury (OR=0.176, 95%CI: 0.038-0.809, P=0.014). Among the 58 culture-positive patients, 12(31.03%) were persistent culture positive after 2 months standard therapy. Early treatment failure was observed with significantly higher incidence rate in RA than other genotypes (OR=7.200, 95%CI: 1.794-28.900, P=0.008). Conclusions In Chinese Han TB patients, IA is the most frequent NAT2 genotype. The SA status of NAT2 is a risk factor of isoniazid-induced hepatotoxicity. The diplotype of NAT2*6A has clearly high risk of isoniazid-induced hepatotoxicity. In contrast, NAT2*4/*4 is protective diplotype. RA is associated with early treatment failure in culture-positive patients. Key words: N-acetyltransferase 2; Isoniazid; Genetic polymorphism; Drug-induced liver injury; Efficacy; Han population

&lt;I&gt;N&lt;/I&gt;-acetyl transferase 2 and cytochrome P450 2E1 genes and isoniazid-induced hepatotoxicity in Brazilian patients

Isoniazid (INH) is related to the development of hepatotoxicity in some patients. To investigate the role of N-acetyl transferase 2 (NAT2) and cytochrome P450 2E1 (CYP2E1) in the hepatotoxicity of patients treated with INH in an Amazonian Brazilian population. Patients undergoing anti-tuberculosis treatment were investigated. Hepatotoxicity was defined as an increase of more than three times the upper limit of normal in serum alanine aminotransferase levels after treatment. NAT2 genotypes were identified by sequencing, whereas CYP2E1 alleles were detected using polymerase chain reaction based methods. Of the 270 individuals included in the study, 18 (6.7%) developed drug-related hepatotoxicity. A high association was found between slow acetylators and hepatotoxicity, particularly with regard to allele *5. The adjusted risk of developing hepatotoxicity was significant in individuals carrying two slow acetylation alleles (P = 0.036, OR 3.05, 95%CI 1.07-8.64). In all of the CYP2E1 markers examined, wild homozygous genotypes were more prevalent in subjects with hepatotoxicity than in controls; however, the difference was not statistically significant. Joint evaluation of the genes revealed a high risk of developing hepatotoxicity in slow acetylators with CYP2E1 wild alleles (adjusted OR 4.26; 95%CI 1.47-12.37, P = 0.008). Large-scale screening for NAT2 and CYP2E1 genotypes can prove useful in predicting the risk of adverse effects.

CYP2E1-dependent elevation of serum cholesterol, triglycerides, and hepatic bile acids by isoniazid

Isoniazid is the first-line medication in the prevention and treatment of tuberculosis. Isoniazid is known to have a biphasic effect on the inhibition–induction of CYP2E1 and is also considered to be involved in isoniazid-induced hepatotoxicity. However, the full extent and mechanism of involvement of CYP2E1 in isoniazid-induced hepatotoxicity remain to be thoroughly investigated. In the current study, isoniazid was administered to wild-type and Cyp2e1-null mice to investigate the potential toxicity of isoniazid in vivo. The results revealed that isoniazid caused no hepatotoxicity in wild-type and Cyp2e1-null mice, but produced elevated serum cholesterol and triglycerides, and hepatic bile acids in wild-type mice, as well as decreased abundance of free fatty acids in wild-type mice and not in Cyp2e1-null mice. Metabolomic analysis demonstrated that production of isoniazid metabolites was elevated in wild-type mice along with a higher abundance of bile acids, bile acid metabolites, carnitine and carnitine derivatives; these were not observed in Cyp2e1-null mice. In addition, the enzymes responsible for bile acid synthesis were decreased and proteins involved in bile acid transport were significantly increased in wild-type mice. Lastly, treatment of targeted isoniazid metabolites to wild-type mice led to similar changes in cholesterol, triglycerides and free fatty acids. These findings suggest that while CYP2E1 is not involved in isoniazid-induced hepatotoxicity, while an isoniazid metabolite might play a role in isoniazid-induced cholestasis through enhancement of bile acid accumulation and mitochondria β-oxidation.

Protective effects of Asparagusracemosus on oxidative damage in isoniazid-induced hepatotoxic rats

To investigate the hepatoprotective activity of Asparagus racemosus against isoniazid-induced hepatotoxicity in male albino rats. Rats (n = 6 per group)were divided into four groups: saline-treated control, saline-treated control with A. racemosus extract (50 mg/kg), isoniazid treatment alone (100 mg/kg, intraperitoneal [i.p.]), and isoniazid-A. racemosus extract (50 mg/kg)administered orally as cotreatment. Animals were treated for 21 days and euthanized 1 h after the last drug administration. Evaluated body weight, serum levels of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, g-glutamyl transferase, total protein, albumin, hepatic malondialdehyde content, superoxide dismutase, catalase, cytochrome P450 2E1 (CYP2E1)activity and glutathione (GSH). A. racemosus extract prevented isoniazid-induced hepatotoxicity, indicated by both diagnostic indicators of liver damage, liver functional profile, significantly (p < 0.05)inhibited CYP2E1 activity, markedly attenuated oxidative stress by improved enzymatic, non-enzymatic antioxidants levels and mitigate malondialdehyde, lipid hydroperoxide significantly (p < 0.05). These results suggest that A. racemosus extract exerts its hepatoprotective activity by inhibiting the production of free radicals and acts as a scavenger, reducing the free radical generation via inhibition of hepatic CYP2E1 activity, increasing the removal of free radicals through the induction of antioxidant enzymes and improving non-enzymatic thiol antioxidant GSH.

A Fresh Look at the Mechanism of Isoniazid-Induced Hepatotoxicity

Isoniazid (INH)-induced hepatotoxicity remains a significant clinical problem, and the current mechanistic hypothesis is incomplete; it is simply referred to as metabolic idiosyncrasy,1 which is believed to involve cytotoxicity caused by bioactivation of acetylhydrazine,2 a metabolite of INH. However, this hypothesis is based on animal studies, involving characteristics that are very different from those that pertain to hepatotoxicity in humans, such as delayed onset. This issue therefore deserves a fresh look. Clinical Pharmacology & Therapeutics (2011) 89 6, 911–914. doi:10.1038/clpt.2010.355