Isoniazid-induced Liver Injury Research Articles

Folic acid protects against isoniazid-induced liver injury via the m6A RNA methylation of cytochrome P450 2E1 in mice.

Cytochrome P450 2E1 (CYP2E1) converts isoniazid (INH) to toxic metabolites and is critical in INH-induced liver injury. The aim is to investigate the effect of folic acid (FA) on CYP2E1 and INH-induced liver injury. Male Balb/c mice were used. The mice in the control group only received an AIN-93M diet. The AIN-93M diet was supplemented with 0.66 g INH/kg diet for the mice in the INH and FA groups. The mice in the FA group were treated with additional 0.01 g FA/kg diet. The one-carbon cycle metabolites, the expressions of CYP2E1 and the DNA and RNA methylation levels were detected to reveal the potential mechanism. FA treatment significantly reduced the alanine aminotransferase level and alleviated the liver necrosis. The mRNA and protein expressions of CYP2E1 were significantly lower in the FA group than those in the INH group. The N6-methyladenosine RNA methylation level of Cyp2e1 significantly increased in the FA group compared with the INH group, while the DNA methylation levels of Cyp2e1 were similar between groups. Additionally, the liver S-adenosyl methionine (SAM)/S-adenosyl homocysteine (SAH) was elevated in the FA group and tended to be positively correlated with the RNA methylation level of Cyp2e1. FA alleviated INH-induced liver injury which was potentially attributed to its inhibitory effect on CYP2E1 expressions through enhancing liver SAM/SAH and RNA methylation.

Lansoprazole Ameliorates Isoniazid-Induced Liver Injury.

Isoniazid is a first-line drug in antitubercular therapy. Isoniazid is one of the most commonly used drugs that can cause liver injury or acute liver failure, leading to death or emergency liver transplantation. Therapeutic approaches for the prevention of isoniazid-induced liver injury are yet to be established. In this study, we identified the gene expression signature for isoniazid-induced liver injury using a public transcriptome dataset, focusing on the differences in susceptibility to isoniazid in various mouse strains. We predicted that lansoprazole is a potentially protective drug against isoniazid-induced liver injury using connectivity mapping and an adverse event reporting system. We confirmed the protective effects of lansoprazole against isoniazid-induced liver injury using zebrafish and patients' electronic health records. These results suggest that lansoprazole can ameliorate isoniazid-induced liver injury. The integrative approach used in this study may be applied to identify novel functions of clinical drugs, leading to drug repositioning.

Isoniazid-induced liver injury risk level in different variants of N-acetyltransferase 2 (NAT2) polymorphisms: A literature review

Individual NAT2 genotype identity data should be enriched to prevent Isoniazid-induced liver injury (IDILI) and optimize the dose of Isoniazid (INH). Therefore, this study aims to present the level of IDILI risk for specific genotype alleles. The data collection involves literature indexed by Google Scholar, Scopus, and Pubmed databases. The search uses a combination of the following keyword variants “INH” OR “INH”, “liver injury” OR “hepatotoxicity”, “polymorphism” OR “pharmacogenomic”, and “N-acetyltransferase 2” OR “NAT2”. Furthermore, the screening results of library sources were narrowed to 11 original articles that met the inclusion criteria. The IDILI risk assessment analysis due to NAT2 enzyme polymorphism following the odds ratio has a 95% confidence interval. The results showed that the IDILI risk level of the slow acetylator group was 3.11 times higher than other populations. Meanwhile, the rapid and intermediate acetylator groups were not at risk. Three variants related to *6 allele were classified as high risk; *6A/*6A risk 5.76 times, *6A/*7B (5.54 times), and *6/*7 (4 times). The three allele configurations of the *5 and *7 were also classified as a risk; *5B/*7B (5 times), *7B/*7B (3.23 times), and *5/*7 (2,74 times).

Asiatic acid ameliorates rifampicin- and isoniazid-induced liver injury in vivo by regulating sphingolipid metabolism and mitogen-activated protein kinase signalling pathways.

In this study, we aimed to determine whether asiatic acid (AA) exerts any therapeutic effects on rifampicin (RFP)- and isoniazid (INH)-induced liver injury and elucidate the underlying mechanisms. Briefly, liver injury in mice was induced via RFP and INH administration. We investigated the effects and potential action mechanisms of AA on liver injury using transcriptomics, metabolomics and various examinations. We found that AA significantly ameliorated the pathological changes in liver tissues and decreased the transaminase activity, inflammation and oxidative stress damage. Transcriptomics revealed 147 differentially expressed genes (DEGs) between the AA and model groups that were enriched in metabolic and mitogen-activated protein kinase (MAPK) signalling pathways. Metabolomics revealed 778 differentially expressed metabolites between the AA and model groups. Furthermore, integrated transcriptomics and metabolomics analyses revealed strong correlations between DEGs and differentially expressed metabolites and indicated that AA regulates the sphingolipid metabolism by inhibiting the expression of delta 4-desaturase, sphingolipid 1. Experimental results confirmed that AA inhibited the MAPK signalling pathway. In summary, AA inhibits inflammation and oxidative stress damage by regulating the sphingolipid metabolism pathway and blocking the MAPK signalling pathway, thereby relieving the RFP/INH-induced liver injury.

Gut microbiota affects sensitivity to immune-mediated isoniazid-induced liver injury

Isoniazid (INH) is a highly effective single and/or combined first-line anti-tuberculosis (anti-TB) therapy drug, and the hepatotoxicity greatly limits its clinical application. INH-induced liver injury (INH-DILI) is a typical immune-mediated idiosyncratic drug-induced liver injury. Existing mechanisms including genetic variations in drug metabolism and immune responses cannot fully explain the differences in susceptibility and sensitivity to INH-DILI, suggesting that other factors may be involved. Accumulating evidence indicates that the development and severity of immune-mediated liver injury is related to gut microbiota. In this study, INH exposure caused liver damage, immune disregulation and microbiota profile alteration. Depletion of gut microbiota ameliorated INH-DILI, and improved INH-DILI-associated immune disorder and inflammatory response. Moreover, hepatotoxicity of INH was ameliorated by fecal microbiota transplantation (FMT) from INH-treated mice. Notably, Bifidobacterium abundance was significantly associated with transaminase levels. In conclusion, our results suggested that the effect of gut microbiota on INH-DILI was related to immunity, and the difference in INH-DILI sensitivity was related to the structure of gut microbiota. Changes in the structure of gut microbiota by continuous exposure of INH resulted in the tolerance to liver injury, and probiotics such as Bifidobacterium might play an important role in INH-DILI and its "adaptation" phenomenon. This work provides novel evidence for elucidating the underlying mechanism of difference in individual’s response to INH-DILI and potential approach for intervening anti-TB drug liver injury by modulating gut microbiota.

Hepatotoxicity induced by isoniazid in patients with latent tuberculosis infection: a meta-analysis.

The aim of the present study was to conduct a meta-analysis of the frequency of isoniazid-induced liver injury (INH-ILI) in patients receiving isoniazid (INH) preventative therapy (IPT). The frequency of hepatotoxicity (drug-induced liver injury: DILI) of antituberculosis drugs has been studied, especially when INH, rifampin, and pyrazinamide are co-administered. However, little is known about the frequency of DILI in patients with latent tuberculosis infection (LTBI), where IPT is indicated. We searched PubMed, Google Scholar, and the Cochrane Database of Systematic Reviews for studies reporting the frequency of INH-ILI in patients with IPT using one or more diagnostic indicators included in the criteria of the DILI Expert Working Group. Thirty-five studies comprising a total of 22,193 participants were included. The overall average frequency of INH-ILI was 2.6% (95% CI, 1.7-3.7%). The mortality associated with INH-DILI was 0.02% (4/22193). Subgroup analysis revealed no significant differences in the frequency of INH-ILI in patients older or younger than 50 years, children, patients with HIV, candidates for liver, kidney, or lung transplant, or according to the type of study design. The frequency of INH-ILI in patients receiving IPT is low. Studies on INH-ILI are needed where the current DILI criteria are used.

ISONIAZID-INDUCED LIVER INJURY: PHARMACOGENETIC ASPECTS

Inter-individual differences in anti-tuberculosis chemotherapy outcomes have been demonstrated in clinical practice, such as, achievement of intended therapeutic effect in some patients, and insufficiency or absence of response to treatment in others, with development of adverse drug reactions, especially, isoniazid-induced liver injury. Isoniazid-induced liver injuries are the main reason for isoniazid discontinuation, which further leads to considerably reduced effectiveness of anti-tuberculosis chemotherapy, increased relapse risk, and secondary drug-resistance of M. tuberculosis. Hepatotoxic reactions to chemotherapy are predicated by mutations in genes encoding enzymes participating in isoniazid biotransformation: N-acetyltransferase 2 (NAT2), cytochrome P450 2Е1, and glutathione-S-transferase. NAT2 gene polymorphism has been identified as risk factor for isoniazid hepatotoxicity. Nucleotide substitutions in NAT2 gene cause modification of enzyme protein structure, reduction of enzyme synthesis and alteration of its activity. Based on genetically-determined isoniazid acetylation rate, patients are referred to three acetylator types: rapid, intermediate, and slow. Correlations have been established in meta-reviews and systematic reviews between slow acetylator type and frequency of hepatotoxic reactions to isoniazid. Based on study findings, interrelation was shown between cytochrome P450 CYP2E1 gene polymorphism and increased risk of liver injury during chemotherapy with isoniazid. Contribution of GSTM1 and GSTT1 genotypes to isoniazid toxicity requires further exploration, as the obtained results were ambiguous and controversial.

Perspectives of Healthcare Professionals on Factors Limiting Implementation of Isoniazid Preventive Therapy in People Living with HIV in Eritrea: A Qualitative Study.

PurposeIn Eritrea, a 6-month isoniazid preventive therapy (IPT) was introduced in Eritrea in 2014 to prevent/reduce risk of incident tuberculosis in people living with HIV (PLHIV). The global and local uptake of IPT in newly enrolled PLHIV was reported to be low. Anecdotal reports showed that there was resistance from clinicians against its implementation. This study was therefore conducted to explore the factors that affect implementation of IPT in Eritrea from the perspectives of healthcare professionals.Materials and MethodsAn exploratory qualitative study that used a framework content analysis using inductive approach was employed. Data were collected from a sample of HIV care clinic prescribers from regional and national referral hospitals through in-depth interviews. Senior program officers were also interviewed as key informants. A conceptual framework model was developed using a root cause analysis.ResultsOverall, five themes and 13 sub-themes emerged from the in-depth interviews with healthcare professionals and key informants. Several multi-level causes/factors related to the healthcare system, HIV control program, healthcare professionals, patients and the product were identified as barriers to the implementation of IPT. Information gap on IPT and fear of isoniazid-induced liver injury were identified as the main reasons for the reluctance in administering IPT. It was observed that healthcare professionals had significant information gap that resulted in rumors and doubts on the benefits and risks of IPT, which ultimately caused reluctance on its implementation. Inadequate planning and operationalization during the introduction of IPT and inadequate laboratory setups were found to be the possible root causes for the aforementioned central problems.ConclusionThe root causes/factors for the limited implementation of IPT in Eritrea were mainly related to the HIV control program and the healthcare system. Adequate planning, operationalization and capacitation of the existing laboratory setups are recommended for a successful implementation of IPT.

Protective Effect of Hedyotis diffusa Willd. Ethanol Extract on Isoniazid-Induced Liver Injury in the Zebrafish Model

ObjectiveThis study aims to investigate the hepatoprotective effect and molecular mechanism of Hedyotis diffusa Willd. ethanol extract (HDWE) against isoniazid (INH)-induced liver injury in the zebrafish model.MethodsINH-induced liver injury model was established by adding an immersion bath of INH in 3 days post-fertilisation (dpf) healthy transgenic zebrafish with liver-specific fluorescence (L-FABP: EGFP). HDWE and INH were given to the zebrafish to observe liver morphology and pathology, fluorescence intensity, and the activities of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and superoxide dismutase (SOD), as well as the content of glutathione (GSH). The chemical composition of HDWE was analysed using high-performance liquid chromatography coupled with a quadrupole-time-of flight hybrid mass spectrometer (HPLC-Q-TOF-MS). The bioactive compounds, molecular targets and signalling pathways of HDWE were predicted using network pharmacology. Subsequently, molecular docking was adopted to analyze the affinities between the bioactive components and targets by Autodock. Finally, in vitro experiments were conducted to further verify the findings.ResultsOur findings showed that HDWE had a remarkable protective effect on INH-induced liver injury in zebrafish. Twenty compounds in HDWE were identified. Nineteen hub targets were identified as possible targets of HDWE, and a compound-target-pathway network was constructed. Nine bioactive compounds, ten molecular targets, and seven key signalling pathways were found to play a pivotal role in the hepatoprotective effect of HDWE against INH-induced liver injury. In vitro studies revealed that the important bioactive compound quercetin-3-O-sambubioside (QSA) could significantly reverse INH-induced cell viability decreases and had a significant effect on the associated targets predicted by network pharmacology and molecular docking.ConclusionIn this study, through the research of hepatoprotective effect of HDWE and bioinformatics analysis, the bioactive compounds, important pathways and key molecular targets were discovered. These findings could provide scientific evidence for the use of HDW in liver injury and prove to help explore its efficacy and the mechanism of action.

Engineering a Ratiometric Photoacoustic Probe with a Hepatocyte-Specific Targeting Ability for Liver Injury Imaging.

In situ imaging of biological indicators is imperative for pathological research by utilizing an activatable photoacoustic (PA) probe. However, precise imaging in actual applications is hampered by the inevitable poor accumulation and low sensitivity. Herein, an amphiphilic molecular probe (AP) was rationally constructed as proof of concept for in situ imaging of drug-induced liver injury, which consists of a hydrophilic target unit and a superoxide anion radical (O2•-)-sensitive small-molecule PA moiety. The probe AP successfully realizes the selectivity and sensitivity toward O2•- in vitro and in living cells. Notably, the amphiphilic probe AP can be selectively retained in the liver and activated toward endogenous O2•- through receptor-mediated endocytosis inside hepatocytes. By virtue of the highly efficient accumulation at the liver, AP was further applied to assess isoniazid-induced liver injury through desired ratiometric PA signals. In addition, based on the fluctuation of O2•-, the therapeutic efficacy of hepatoprotective medicines for hepatotoxicity was analyzed in vivo. Therefore, the O2•--specific probe could serve as a promising molecular tool for early diagnosis study of other liver diseases and analysis of new potential therapeutic agents.

Serum biomarkers of isoniazid-induced liver injury: Aminotransferases are insufficient, and OPN, L-FABP and HMGB1 can be promising novel biomarkers.

Isoniazid (INH)-induced liver injury is a great challenge for tuberculosis treatment. Existing biomarkers cannot accurately determine the occurrence of this injury in the early stage. Therefore, developing early specific sensitive biomarkers of INH-induced liver injury is urgent. A rat model of liver injury was established with gastric infusion of INH or INH plus rifampicin (RFP). We examined seven potential novel serum biomarkers, namely, glutamate dehydrogenase (GLDH), liver-fatty acid-binding protein (L-FABP), high-mobility group box-1 (HMGB1), macrophage colony-stimulating factor receptor (MCSF1R), osteopontin (OPN), total cytokeratin 18 (K18), and caspase-cleaved cytokeratin-18 (ccK18), to evaluate their sensitivity and specificity on INH-induced liver injury. With the increase of drug dosage, combining with RFP and prolonging duration of administration, the liver injury was aggravated, showing as decreased weight of the rats, upgraded liver index and oxidative stress level, and histopathological changes of liver becoming marked. But the activity of serum aminotransferases decreased significantly. The area under the curve (AUC) of receiver-operating characteristic (ROC) curve of OPN, L-FABP, HMGB1, MCSF1R, and GLDH was 0.88, 0.87, 0.85, 0.71, and 0.70 (≥0.7), respectively, and 95% confidence interval of them did not include 0.5, with statistical significance, indicating their potential abilities to become biomarkers of INH-induced liver injury. In conclusion, we found traditional biomarkers ALT and AST were insufficient to discover the INH-induced liver injury accurately and OPN, L-FABP, and HMGB1 can be promising novel biomarkers.

Fasting Enhances Biochemical and Histopathological Changes of Isoniazid Induced Liver Injury in Mouse

Fasting can up regulate the expression of cytochrome P450 2E1 and induce glutathione levels to decrease, protecting the liver from hepatotoxic agents. The aim of this study was to research the mechanism of fasting aggravates isoniazid induced liver injury in mouse. 7 w old male C57 black 6 mice were randomly assigned to two groups: mice fed ad libitum on commercial chow (A group) and mice fasted for 12 h during the day and fed ad libitum on commercial chow (F group). All animals were administered with 100 mg/kg of isoniazid daily by gavage for 6 w (isoniazid levels were selected on basis of screening multiple concentrations). Sera were collected to measure biochemical parameters. Liver sections were stained with hematoxylin and eosin to evaluate hepatic histology. Cytokines was detected by cytometric bead array, flow cytometry. Isoniazid administration (100 mg/kg) daily for 6 w did not significantly induce histological damage in mice of A group. Compared with normal mice, there was no significant difference in serum alanine aminotransferase and aspartate aminotransferase. However, the level of alanine aminotransferase and aspartate aminotransferase levels in F group remained elevated for 6 w, reached its peak on the 3rd d and gradually returned to normal. The liver sections revealed hepatic edema around the central vein on the 3rd d. At 1st or 2nd w, hepatic edema around the central vein with inflammatory cell infiltration and focal necrosis was present. After 4 w, liver histology gradually recovered. Fasting condition influences the cytokine concentration in peripheral blood and liver tissue.

Pyridoxal isonicotinoyl hydrazone inhibition of FXR is involved in the pathogenesis of isoniazid-induced liver injury

Isoniazid (INH)-induced liver injury may be associated with inhibition of the liver farnesoid X receptor (FXR). However, the relationship between FXR and INH-induced liver injury remained unclear. The present study was performed to clarify the role of inhibition of FXR in the pathogenesis of INH-induced liver injury and to further identify potential inhibitors of FXR from INH and its metabolites. HepaRG cells were treated with INH (10 mM) plus mixed bile acids (BA) and rats were treated with INH (60–600 mg/kg p.o.) or INH plus obeticholic acid (OCA, 10 mg/kg), a potent FXR agonist, for seven days. INH can cause BA-dependent toxicity and apoptosis with elevated intracellular bile acids in vitro; indeed, in these studies, liver bile acids and mRNA levels for Cyp7a1, an FXR target gene were increased, while mRNA levels for FXR and Shp were significantly decreased, and these changes could be prevented by co-treatment with the FXR agonist OCA. In silico molecular docking studies showed that INH, acetyl isoniazid, isonicotinic acid and PIH may be potential FXR inhibitors, and a TR-FRET FXR-coactivator assay confirmed that PIH is a strong antagonist of FXR (IC50 = 52 nM). To further determine if PIH also inhibits FXR activity in vivo, rats were treated with PIH directly (5 mg/kg). Liver total bile acids were significantly increased while FXR expression was not changed, but Shp mRNA levels were significantly decreased and Cyp7a1 mRNA was significantly increased, consistent with PIH acting as an FXR antagonist. In summary, PIH inhibition of liver FXR function leading to bile acid accumulation in hepatocytes may be an early pathogenesis event in INH-induced liver injury.

Toxicoproteomic Profiling of hPXR Transgenic Mice Treated with Rifampicin and Isoniazid.

Tuberculosis is a global health threat that affects millions of people every year, and treatment-limiting toxicity remains a considerable source of treatment failure. Recent reports have characterized the nature of hPXR-mediated hepatotoxicity and the systemic toxicity of antitubercular drugs. The antitubercular drug isoniazid plays a role in such pathologic states as acute intermittent porphyria, anemia, hepatotoxicity, hypercoagulable states (deep vein thrombosis, pulmonary embolism, or ischemic stroke), pellagra (vitamin B3 deficiency), peripheral neuropathy, and vitamin B6 deficiency. However, the mechanisms by which isoniazid administration leads to these states are unclear. To elucidate the mechanism of rifampicin- and isoniazid-induced liver and systemic injury, we performed tandem mass tag mass spectrometry-based proteomic screening of mPxr−/− and hPXR mice treated with combinations of rifampicin and isoniazid. Proteomic profiling analysis suggested that the hPXR liver proteome is affected by antitubercular therapy to disrupt [Fe–S] cluster assembly machinery, [2Fe–2S] cluster-containing proteins, cytochrome P450 enzymes, heme biosynthesis, homocysteine catabolism, oxidative stress responses, vitamin B3 metabolism, and vitamin B6 metabolism. These novel findings provide insight into the etiology of some of these processes and potential targets for subsequent investigations. Data are available via ProteomeXchange with identifier PXD019505.

Mitochondrial DNA Variants in Patients with Liver Injury Due to Anti-Tuberculosis Drugs.

Background: Hepatotoxicity is the most severe adverse effect of anti-tuberculosis therapy. Isoniazid’s metabolite hydrazine is a mitochondrial complex II inhibitor. We hypothesized that mitochondrial DNA variants are risk factors for drug-induced liver injury (DILI) due to isoniazid, rifampicin or pyrazinamide. Methods: We obtained peripheral blood from tuberculosis (TB) patients before anti-TB therapy. A total of 38 patients developed DILI due to anti-TB drugs. We selected 38 patients with TB but without DILI as controls. Next-generation sequencing detected point mutations in the mitochondrial DNA genome. DILI was defined as ALT ≥5 times the upper limit of normal (ULN), or ALT ≥3 times the ULN with total bilirubin ≥2 times the ULN. Results: In 38 patients with DILI, the causative drug was isoniazid in eight, rifampicin in 14 and pyrazinamide in 16. Patients with isoniazid-induced liver injury had more variants in complex I’s NADH subunit 5 and 1 genes, more nonsynonymous mutations in NADH subunit 5, and a higher ratio of nonsynonymous to total substitutions. Patients with rifampicin- or pyrazinamide-induced liver injury had no association with mitochondrial DNA variants. Conclusions: Variants in complex I’s subunit 1 and 5 genes might affect respiratory chain function and predispose isoniazid-induced liver injury when exposed to hydrazine, a metabolite of isoniazid and a complex II inhibitor.

Establishing the Genotyping Method for NAT2 Polymorphism in Vietnamese Tuberculoma Patients

The metabolism of Isoniazid, one of the first-line antituberculosis drugs for TB treatment and prophylaxis, depends on the acetyltransferase 2 acetylation (NAT2) phenotype. Different phenotypes of NAT2 will lead to differences in drug concentration and the risk of uncontrolled side effects, such as hepatitis, peripheral neuropathy, gastrointestinal disorders (nausea, vomiting, and stomach pain). These risks are related to the presence of mutant NAT2 alleles such as NAT2*5 (c.341T> C), *6 (c.590G> A) and *7 (c.857G> A), that reduce the N- acetyltransferase activity. Therefore, the genotyping method for NAT2 polymorphism using RFLP and Sanger sequencing was established. The method was successfully applied to determine the polymorphism of 84 TB patients. This study provides a better tool for analyzing NAT2 gene to assist clinicians in treating isoniazid.
 Keywords
 Enzyme NAT2, isoniazid, single nucleotide polymorphism, RFLP, Sanger sequencing.
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Rotenone Increases Isoniazid Toxicity but Does Not Cause Significant Liver Injury: Implications for the Hypothesis that Inhibition of the Mitochondrial Electron Transport Chain Is a Common Mechanism of Idiosyncratic Drug-Induced Liver Injury.

Idiosyncratic drug reactions (IDRs) significantly increase the risk of failure in drug development. The major IDR leading to drug candidate failure is idiosyncratic drug-induced liver injury (IDILI). Although most evidence suggests that IDRs are mediated by the immune system, there are other hypotheses, such as mitochondrial dysfunction. Many pharmaceutical companies routinely screen for mitochondrial toxicity in an attempt to "derisk" drug candidates. However, the basic hypothesis has never been rigorously tested. A major assay used for this screening involves measurement of inhibition of the mitochondrial electron transport chain. One study found that the combination of rotenone and isoniazid, which inhibit mitochondrial complex I and II, respectively, were synergistic in causing hepatocyte toxicity in vitro and suggested the combination of another drug that inhibited complex I would increase the risk of isoniazid-induced liver injury in patients. We tested this hypothesis in vivo where wild-type and PD-1-/- mice administered anti-CTLA-4, our impaired immune tolerance mouse model, were given 0.02% (w/v) rotenone in water or 0.1%, 0.05%, and 0.01% (w/w) rotenone alone or in combination with isoniazid in food. The cotreatment led to lethality in 100% of the animals receiving 0.1% rotenone and 0.2% isoniazid and 83% of the animals cotreated with 0.05% rotenone and 0.2% isoniazid in food. Nevertheless, there was no significant increase in GLDH or histological evidence of liver injury. No signs of toxicity were observed in any of the mice given rotenone or isoniazid alone. Even though inhibition of the mitochondrial electron transport chain did not lead to significant liver toxicity, it could provide danger signals that promote immune-mediated liver injury. However, rotenone did not significantly increase the liver injury induced by isoniazid in our impaired immune tolerance model. Overall, we conclude that inhibition of the mitochondrial electron transport chain is not a significant mechanism of IDILI.

Mitochondrial Damage and Drp1 Overexpression in Rifampicin- and Isoniazid-induced Liver Injury Cell Model.

Background and Aims: Rifampicin (RFP) and isoniazid (INH) are widely used as anti-tuberculosis agents. However, the mechanisms underlying the involvement of reactive oxygen species and mitochondria in RFP- and INH-related hepatotoxicity have not been established yet. This study aimed to observe the intracellular mechanisms leading to mitochondrial dysfunction and morphological changes in RFP- and INH-induced hepatocyte injury.Methods: Cell injury, changes in mitochondrial function, and expression and activation of dynamin related protein 1 (Drp1), known as the main protein for mitochondrial fission, were analyzed in cultured QSG7701 cells exposed to RFP and INH.Results: INH and RFP treatment induced pronounced hepatocyte injury and increased cell death. In the similar context of aspartate aminotransferase elevation and adenosine triphosphate synthesis decrease, changes in mitochondrial membrane permeability and reactive oxygen species in hepatocytes induced by RFP were significantly different from those induced by INH (p < 0.05). Particularly, we observed the overactivation and mitochondrial translocation of Drp1 in RFP-induced cell injury, which was not occurred with exposure to INH.Conclusions: RFP-induced hepatotoxicity may be closely related to mitochondrial dysfunction and Drp1-mediated mitochondrial fission.

Interventional effect of bicyclol on isoniazid-induced liver injury in rats and the expression of glucose-regulated protein 78, and growth arrest and DNA-damage-inducible gene 153

Objective: To investigate the interventional effect of bicyclol on isoniazid-induced liver injury in rats and the expression of endoplasmic reticulum stress (ERS) protein, glucose regulatory protein 78 (GRP78), and growth arrest and DNA-damage-inducible gene 153(CHOP). Methods: Eighty Wistar rats were randomly divided into control group (8 rats) and model group (72 rats). After 10 days of intragastric administration of isoniazid, the model group rats were randomly divided into treatment group (A), natural recovery group (B), etiological persistence group (C) and etiological persistence plus treatment group (D). Sixteen rats from each group were sacrificed after 1 and 2 weeks of intervention with different methods. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were detected. Liver pathological morphology was observed. Apoptotic cells were detected by TUNEL assay. ERS protein expression was detected by Western blot. A t-test or randomized block analysis of variance, K-S test and Levene's test were used to analyze the normality and homogeneity of variance. Kruskal-Wallis rank sum test was used for data that did not suit the conditions of t-test and variance analysis. Results: ALT and AST were elevated in the model group, and liver pathological examination showed liver tissue damage. Apoptotic index was higher than control group (7.13% ± 1.55% vs. 0.75% ± 0.71%, Z = -3.411, P < 0.01), and the expression value of ERS protein in model group was significantly higher than control group (GRP78: 1.16 ± 0.30 vs. 0.23 ± 0.05, t = -6.008, P < 0.01; CHOP: 0.98±0.23 vs. 0.20 ± 0.10, t = -6.378, P < 0.01). Serum enzymes, apoptotic index and ERS protein expressions of rats were decreased after treatment with bicyclol, and the pathological damage was eased. Rats in natural recovery group recovered less than the treatment group. Conclusion: Isoniazid-induced liver injury is associated to ERS-related excessive apoptosis and the therapeutic effect of bicyclol on drug-induced liver injury may minimize ERS-induced apoptosis.

802. Use of N-Acetylcysteine for Prevention and Treatment of Isoniazid Induced Liver Injury During Treatment of Mycobacterial Infections

BackgroundHepatotoxicity secondary to therapy for Mycobacterium tuberculosis (MTB) is a common complication that may lead to treatment interruption. N-Acetylcysteine (NAC) exerts a hepatoprotective effect by repleting glutathione stores and enhancing the cellular antioxidant defense mechanism. NAC has been found to be protective against liver toxicity in animals treated for MTB infection. Randomized controlled trials have shown that its use in humans also decreases the risk of hepatotoxicity associated with anti-MTB treatment but there is minimal data regarding its utility for treatment of liver toxicity.MethodsPatients who received NAC from January 2012 to March 2018 for prophylaxis and treatment of increasing liver function tests (LFTs) while on isoniazid (INH) were included. A retrospective review of the medical record system was performed.ResultsNineteen patients were included. Eight received NAC for treatment. The average age was 49 years. Seventy percent of patients were male. The mean BMI was 25. Five patients had underlying liver cirrhosis and two had hepatic steatosis. Eleven patients had Hepatitis C (HCV) and one had active Hepatitis B infection. Ten patients had MTB pulmonary infection, thee had latent TB infection, two meningitis, and three had disseminated disease. One patient was treated for atypical mycobacterial infection. The dose of NAC used was 600 mg oral twice daily and the duration was variable.The prophylaxis group had stable LFTs during treatment, except for two patients whose enzymes increased more than three times the upper limit of normal. These two patients had underlying HCV and liver cirrhosis. Only one required discontinuation of INH. This group received NAC for an average of 47 days. The treatment group had a favorable trend of liver enzymes after NAC initiation, with levels significantly improving by day 14 (Figures 1 and 2). Three patients did not require discontinuation of antibiotics. INH was stopped prior to NAC initiation in four patients. No side effects of NAC were documented in any patient.ConclusionNAC is a safe and effective measure to prevent and treat hepatotoxicity secondary to INH therapy. More studies are needed to determine its optimal dose and duration for this indication.Figure 1.Figure 2.Disclosures All authors: No reported disclosures.