Adagrasib Treatment After Sotorasib-Related Hepatotoxicity in Patients With KRASG12C-Mutated Non-Small Cell Lung Cancer: A Case Series and Literature Review.

PURPOSE: KRAS is the most commonly mutated driver oncogene in non-small cell lung cancer (NSCLC). Sotorasib and adagrasib, KRASG12C inhibitors, have been granted accelerated US approval; however, hepatotoxicity is a common side effect with higher rates in patients treated with sotorasib proximal to checkpoint inhibitor (CPI) therapy. The aim of this study was to assess the feasibility and safety of adagrasib after discontinuation of sotorasib because of treatment-related grade 3 hepatotoxicity through real-world and clinical cases. METHODS: Medical records from five patients treated in real-world settings were retrospectively reviewed. Patients had locally advanced or metastatic KRASG12C-mutated NSCLC and received adagrasib after sotorasib in the absence of extracranial disease progression. Additional data were collected for 12 patients with KRASG12C-mutated NSCLC enrolled in a phase Ib cohort of the KRYSTAL-1 study and previously treated with sotorasib. The end points associated with both drugs included timing and severity of hepatotoxicity, best overall response, and duration of therapy. RESULTS: All patients were treated with CPIs followed by sotorasib (initiated 0-64 days after CPI). All five real-world patients experienced hepatotoxicity with sotorasib that led to treatment discontinuation, whereas none experienced treatment-related hepatotoxicity with subsequent adagrasib treatment. Three patients from KRYSTAL-1 transitioned from sotorasib to adagrasib because of hepatotoxicity; one experienced grade 3 ALT elevation on adagrasib that resolved with therapy interruption and dose reduction. CONCLUSION: Adagrasib may have a distinct hepatotoxicity profile from sotorasib and is more easily combined with CPIs either sequentially or concurrently. These differences may be used to inform clinical decisions regarding an initial KRASG12C inhibitor for patients who recently discontinued a CPI or experience hepatotoxicity on sotorasib.

Sex differences in the susceptibility to valproic acid-associated liver injury in epileptic patients.

BACKGROUND: Valproic acid has been widely used as an antiepileptic drug for several decades. Long-term valproic acid treatment is usually accompanied by liver injury. Although both men and women are susceptible to valproic acid-associated liver injury, hepatotoxicity differs between the sexes. However, the mechanisms underlying sex differences in valproic acid-associated liver injury remain unclear. METHODS: To explore potential risk factors for the susceptibility to valproic acid-associated liver injury, 231 pediatric patients with epilepsy (119 males, 112 females) were enrolled for laboratory and genetic analysis. RESULTS: Heterozygous genotype of catalase C-262T (P = 0.045) and the concentrations of glutathione (P = 0.002) and thiobarbituric acid-reactive substances (P = 0.011) were associated with the sex-specific susceptibility to valproic acid-associated liver injury. Meanwhile, logistic regression analysis revealed that carriers of heterozygous genotype of catalase C-262T (P = 0.010, odds ratio: 4.163; 95 percent confidence interval 1.400 - 7.378), glutathione concentration (P = 0.001, odds ratio: 2.421; 95 percent confidence interval 2.262 - 2.591) and male patients (P = 0.005, odds ratio: 1.344; 95% confidence interval 0.782 - 2.309) had a higher risk for valproic acid-associated liver injury. DISCUSSION: The mechanism underlying valproic acid-induced hepatotoxicity remains unclear. Additionally, factors that may contribute to the observed differences in the incidence of hepatotoxicity between males and females have yet to be defined. This study identifies several genetic factors that may predispose patients to valproic acid-associated hepatotoxicity. LIMITATIONS: This relatively small sample size of children with one ethnicity some of whom were taking other antiepileptics that are potentially hepatotoxic. CONCLUSION: Catalase C-262T genotype, glutathione concentration and gender (male) are potential risk factors for the susceptibility to valproic acid-associated liver injury.

Are changes in olanzapine-induced liver enzyme levels associated with GSTT1, GSTM1, GSTP1, and OGG1 gene polymorphisms?

Olanzapine treatment sometimes produces transient liver biochemistry abnormalities, and such drug-induced liver injuries are mainly monitored by measuring blood levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), whereas alpha-glutathione-S-transferase (α-GST) is not routinely measured in clinics, even though it can serve as an earlier and more specific biomarker of liver damage. Susceptibility to drug-induced liver injury can much depend on the gene polymorphisms regulating the activity of DNA detoxification and repair enzymes. The aim of this study was to evaluate which of the three liver enzymes - α-GST, ALT, and AST - is the most sensitive biomarker of olanzapine-induced liver injury and how their blood levels are affected by the GSTT1, GSTM1, GSTP1, and OGG1 gene polymorphisms in 30 olanzapine-treated patients. Contrary to our hypothesis, the increase in serum α-GST levels was not significantly greater than that of the transaminases. ALT turned out to be an earlier biomarker of liver injury than the other two enzymes. No significant association was found between gene polymorphisms and liver enzyme levels, save for GSTP1 Ile/Val + Val/Val and ALT, which points to this genotype as a risk factor for drug-induced liver injury. Future studies might help to identify the underlying mechanisms of transient liver enzyme increase associated with this genotype.

Probing Liver Injuries Induced by Thioacetamide in Human In Vitro Pooled Hepatocyte Experiments.

Animal studies are typically utilized to understand the complex mechanisms associated with toxicant-induced hepatotoxicity. Among the alternative approaches to animal studies, in vitro pooled human hepatocytes have the potential to capture population variability. Here, we examined the effect of the hepatotoxicant thioacetamide on pooled human hepatocytes, divided into five lots, obtained from forty diverse donors. For 24 h, pooled human hepatocytes were exposed to vehicle, 1.33 mM (low dose), and 12 mM (high dose) thioacetamide, followed by RNA-seq analysis. We assessed gene expression variability using heat maps, correlation plots, and statistical variance. We used KEGG pathways and co-expression modules to identify underlying physiological processes/pathways. The co-expression module analysis showed that the majority of the lots exhibited activation for the bile duct proliferation module. Despite lot-to-lot variability, we identified a set of common differentially expressed genes across the lots with similarities in their response to amino acid, lipid, and carbohydrate metabolism. We also examined efflux transporters and found larger lot-to-lot variability in their expression patterns, indicating a potential for alteration in toxicant bioavailability within the cells, which could in turn affect the gene expression patterns between the lots. Overall, our analysis highlights the challenges in using pooled hepatocytes to understand mechanisms of toxicity.

Assessing the toxicity of pesticides exposure on hepatic miRNA-target gene alterations in rat liver tissues via molecular and integrated network bioinformatics analysis.

The prevalent use of pesticides, including pirimiphos-methyl (PPM) and bifenthrin (BF), poses a serious health risk, particularly to workers who encounter these chemicals daily. Despite the recognized hepatotoxic effects, the specific molecular mechanisms, especially those involving miRNAs in liver damage caused by PPM and BF, are not fully elucidated. Prior studies have not exhaustively analyzed the hepatic miRNA-target gene dynamics following exposure to these pesticides; thus, this research aims to fill that gap through an extensive miRNA analysis to discern their regulation in PPM or BF-induced hepatic toxicity. In this study, male Sprague-Dawley rats were exposed to BF or PPM for 28 days through oral gavage, simulating the chronic exposure faced by humans. We conducted a thorough assessment of the hepatotoxicity induced by PPM and BF, employing multiple evaluation levels, including histological analysis, liver enzyme measurements, and real-time PCR to detect changes in hepatic miRNA-target gene expressions. Additionally, we utilized DIANA-miRPath prediction tools to delineate the functional implications of these hepatic miRNA target genes. Our findings reveal a significant modulation in the expression of rno-miR-155-5p and rno-miR-122-5p, along with their target genes, following PPM and BF treatment. In contrast, rno-miR-21-5p levels remained unaltered. These observations suggest potential utility of these specific hepatic miRNAs as biomarkers for liver injury resulting from pesticide exposure. Subsequent GO enrichment analysis linked target genes to functions like molecular activity, protein binding, and cellular processes. Additionally, KEGG pathway analysis showed these genes, influenced by varied miRNA expressions, play significant roles in metabolic and signaling pathways In conclusion, this study enhances our comprehension of the biological roles of miRNAs in hepatic toxicity induced by PPM and BF. The insights gained here not only shed light on molecular mechanisms but also open avenues for considering these miRNAs as potential diagnostic biomarkers in conditions of pesticide-induced hepatotoxicity, thereby guiding future therapeutic strategies.

ABCG2 polymorphisms and susceptibility to ARV-associated hepatotoxicity.

BACKGROUND: The ABCG2 421C/A polymorphism contributes significantly to the distribution and absorption of antiretroviral (ARV) regimens and is associated with the undesirable side effects of efavirenz. METHODS: To investigate this, we examined ABCG2 34G/A (rs2231137) and 421C/A (rs2231142) genetic variations in 149 HIV-infected patients (116 without hepatotoxicity, 33 with ARV-induced hepatotoxicity) and 151 healthy controls through the PCR-restriction fragment length polymorphism (PCR-RFLP) technique. RESULTS AND DISCUSSION: The ABCG2 34GA genotype and 34A allele indicated a risk for antiretroviral therapy-associated hepatotoxicity development (p = 0.09, OR = 1.58, 95% CI: 0.93-2.69; p = 0.06, OR = 1.50, 95% CI: 0.98-2.30). The haplotype GA was associated with hepatotoxicity (p = 0.042, OR = 2.37, 95% CI: 1.04-5.43; p = 0.042, OR = 2.49, 95% CI: 1.04-5.96). Moreover, when comparing HIV patients with hepatotoxicity to healthy controls, the haplotype GA had an association with an elevated risk for the development of hepatotoxicity (p = 0.041, OR = 1.73, 95% CI: 1.02-2.93). Additionally, the association of the ABCG2 34GA genotype with the progression of HIV (p = 0.02, OR = 1.97, 95% CI: 1.07-3.63) indicated a risk for advanced HIV infection. Furthermore, the ABCG2 421AA genotype was linked to tobacco users and featured as a risk factor for the progression of HIV disease (p = 0.03, OR = 11.07, 95% CI: 1.09-270.89). CONCLUSION: The haplotype GA may enhance the risk of hepatotoxicity development and its severity. Individuals with the ABCG2 34A allele may also be at risk for the development of hepatotoxicity. Additionally, individuals with an advanced stage of HIV and the ABCG2 34GA genotype may be at risk for disease progression.

Synergistic toxicity with copper contributes to NAT2-associated isoniazid toxicity.

Anti-tuberculosis (AT) medications, including isoniazid (INH), can cause drug-induced liver injury (DILI), but the underlying mechanism remains unclear. In this study, we aimed to identify genetic factors that may increase the susceptibility of individuals to AT-DILI and to examine genetic interactions that may lead to isoniazid (INH)-induced hepatotoxicity. We performed a targeted sequencing analysis of 380 pharmacogenes in a discovery cohort of 112 patients (35 AT-DILI patients and 77 controls) receiving AT treatment for active tuberculosis. Pharmacogenome-wide association analysis was also conducted using 1048 population controls (Korea1K). NAT2 and ATP7B genotypes were analyzed in a replication cohort of 165 patients (37 AT-DILI patients and 128 controls) to validate the effects of both risk genotypes. NAT2 ultraslow acetylators (UAs) were found to have a greater risk of AT-DILI than other genotypes (odds ratio [OR] 5.6 [95% confidence interval; 2.5-13.2], P = 7.2 × 10-6). The presence of ATP7B gene 832R/R homozygosity (rs1061472) was found to co-occur with NAT2 UA in AT-DILI patients (P = 0.017) and to amplify the risk in NAT2 UA (OR 32.5 [4.5-1423], P = 7.5 × 10-6). In vitro experiments using human liver-derived cell lines (HepG2 and SNU387 cells) revealed toxic synergism between INH and Cu, which were strongly augmented in cells with defective NAT2 and ATP7B activity, leading to increased mitochondrial reactive oxygen species generation, mitochondrial dysfunction, DNA damage, and apoptosis. These findings link the co-occurrence of ATP7B and NAT2 genotypes to the risk of INH-induced hepatotoxicity, providing novel mechanistic insight into individual AT-DILI susceptibility. Yoon et al. showed that individuals who carry NAT2 UAs and ATP7B 832R/R genotypes are at increased risk of developing isoniazid hepatotoxicity, primarily due to the increased synergistic toxicity between isoniazid and copper, which exacerbates mitochondrial dysfunction-related apoptosis.

Inhibition of ALK3-mediated signalling pathway protects against acetaminophen-induced liver injury.

Acetaminophen (APAP)-induced liver injury is one of the most prevalent causes of acute liver failure (ALF). We assessed the role of the bone morphogenetic protein (BMP) type I receptors ALK2 and ALK3 in APAP-induced hepatotoxicity. The molecular mechanisms that regulate the balance between cell death and survival and the response to oxidative stress induced by APAP was assessed in cultured human hepatocyte-derived (Huh7) cells treated with pharmacological inhibitors of ALK receptors and with modulated expression of ALK2 or ALK3 by lentiviral infection, and in a mouse model of APAP-induced hepatotoxicity. Inhibition of ALK3 signalling with the pharmacological inhibitor DMH2, or by silencing of ALK3, showed a decreased cell death both by necrosis and apoptosis after APAP treatment. Also, upon APAP challenge, ROS generation was ameliorated and, thus, ROS-mediated JNK and P38 MAPK phosphorylation was reduced in ALK3-inhibited cells compared to control cells. These results were also observed in an experimental model of APAP-induced ALF in which post-treatment with DMH2 after APAP administration significantly reduced liver tissue damage, apoptosis and oxidative stress. This study shows the protective effect of ALK3 receptor inhibition against APAP-induced hepatotoxicity. Furthermore, findings obtained from the animal model suggest that BMP signalling might be a new pharmacological target for the treatment of ALF.

Lead induced genotoxicity and hepatotoxicity in zebrafish (Danio rerio) at environmentally relevant concentration: Nrf2-Keap1 regulated stress response and expression of biomarker genes.

Genotoxic and hepatotoxic potentials of Pb at an environmentally relevant concentration (5 ppm) in zebrafish were investigated in the present study. Erythrocytic nuclear abnormality tests revealed the increased frequencies of abnormal erythrocytes after Pb exposure, indicating a strong genotoxic potential of Pb. Multiple stress-related parameters were further evaluated in liver, the major detoxifying organ. Pb caused increased production of ROS, which in turn caused severe oxidative stress. As a result, lipid peroxidation was increased, whereas reduced glutathione level and catalase activity was decreased. Alterations in liver histoarchitecture also served as evidence of Pb-induced hepatotoxicity. Pb-induced ROS stress triggered upregulation of Nrf2, Nqo1, Ho1; downregulation of Keap1, and altered mRNA expressions of Mn-sod, Cu/Zn-sod, gpx1, cyp1a, ucp2 suggesting involvement of Nrf2-Keap1-ARE signaling in cellular defence. Nrf2-keap1 is a sensitive biomarker of Pb-induced ROS stress. Overexpression of Hsp70 and other genes in hepatocytes might help cell survival under oxidative stress generation.

GenX analogs exposure induced greater hepatotoxicity than GenX mainly via activation of PPARα pathway while caused hepatomegaly in the absence of PPARα in female mice.

Despite their use as substitutes for perfluorooctanoic acid, the potential toxicities of hexafluoropropylene oxide dimer acid (HFPO-DA, commercial name: GenX) and its analogs (PFDMOHxA, PFDMO2HpA, and PFDMO2OA) remain poorly understood. To assess the hepatotoxicity of these chemicals on females, each chemical was orally administered to female C57BL/6 mice at the dosage of 0.5 mg/kg/d for 28 d. The contribution of peroxisome proliferator-activated receptors (PPARα and γ) and other nuclear receptors involving in these toxic effects of GenX and its analogs were identified by employing two PPAR knockout mice (PPARα-/- and PPARγΔHep) in this study. Results showed that the hepatotoxicity of these chemicals increased in the order of GenX < PFDMOHxA < PFDMO2HpA < PFDMO2OA. The increases of relative liver weight and liver injury markers were significantly much lower in PPARα-/- mice than in PPARα+/+ mice after GenX analog exposure, while no significant differences were observed between PPARγΔHep and its corresponding wildtype groups (PPARγF/F mice), indicating that GenX analog induce hepatotoxicity mainly via PPARα instead of PPARγ. The PPARα-dependent complement pathways were inhibited in PFDMO2HpA and PFDMO2OA exposed PPARα+/+ mice, which might be responsible for the observed liver inflammation. In PPARα-/- mice, hepatomegaly and increased liver lipid content were observed in PFDMO2HpA and PFDMO2OA treated groups. The activated pregnane X receptor (PXR) and constitutive activated receptor (CAR) pathways in the liver of PPARα-/- mice, which were highlighted by bioinformatics analysis, provided a reasonable explanation for hepatomegaly in the absence of PPARα. Our results indicate that GenX analogs could induce more serious hepatotoxicity than GenX whether there is a PPARα receptor or not. These chemicals, especially PFDMO2HpA and PFDMO2OA, may not be appropriate PFOA alternatives.

The integrated stress response-related expression of CHOP due to mitochondrial toxicity is a warning sign for DILI liability.

BACKGROUND AND AIMS: Drug-induced liver injury (DILI) is one of the most frequent reasons for failure of drugs in clinical trials or market withdrawal. Early assessment of DILI risk remains a major challenge during drug development. Here, we present a mechanism-based weight-of-evidence approach able to identify certain candidate compounds with DILI liabilities due to mitochondrial toxicity. METHODS: A total of 1587 FDA-approved drugs and 378 kinase inhibitors were screened for cellular stress response activation associated with DILI using an imaging-based HepG2 BAC-GFP reporter platform including the integrated stress response (CHOP), DNA damage response (P21) and oxidative stress response (SRXN1). RESULTS: In total 389, 219 and 104 drugs were able to induce CHOP-GFP, P21-GFP and SRXN1-GFP expression at 50 µM respectively. Concentration response analysis identified 154 FDA-approved drugs as critical CHOP-GFP inducers. Based on predicted and observed (pre-)clinical DILI liabilities of these drugs, nine antimycotic drugs (e.g. butoconazole, miconazole, tioconazole) and 13 central nervous system (CNS) agents (e.g. duloxetine, fluoxetine) were selected for transcriptomic evaluation using whole-genome RNA-sequencing of primary human hepatocytes. Gene network analysis uncovered mitochondrial processes, NRF2 signalling and xenobiotic metabolism as most affected by the antimycotic drugs and CNS agents. Both the selected antimycotics and CNS agents caused impairment of mitochondrial oxygen consumption in both HepG2 and primary human hepatocytes. CONCLUSIONS: Together, the results suggest that early pre-clinical screening for CHOP expression could indicate liability of mitochondrial toxicity in the context of DILI, and, therefore, could serve as an important warning signal to consider during decision-making in drug development.

Hepatocyte miR-21-5p-deficiency alleviates APAP-induced liver injury by inducing PPARγ and autophagy.

Acetaminophen (APAP)-induced liver injury is one of the most frequent causes of acute liver failure worldwide. Significant increases in the levels of miRNA-21 in both liver tissues and plasma have been observed in APAP-overdosed animals and humans. However, the mechanistic effect of miRNA-21 on acute liver injury remains unknown. In this study, we generated a new hepatocyte-specific miRNA-21 knockout (miR-21-HKO) mouse line. miR-21-HKO and the background-matched sibling wild-type (WT) mice were treated with a toxic dose of APAP. Compared with WT mice, miR-21 HKO mice showed an increased survival, a reduction of necrotic hepatocytes, and an increased expression of light chain 3 beta, which suggested an autophagy activation. The expression of PPARγ was highly induced in the livers of miR-21-HKO mice after a 2-h APAP treatment, which preceded the activation of LC3B at the 12 h APAP treatment. miR-21 negatively regulated PPARγ protein expression by targeting its 3'-UTR. When PPARγ function was blocked by a potent antagonist GW9662 in miR-21-HKO mice, the autophage activation was significantly diminished, suggesting an indispensable role of PPARγ signaling pathway in miR-21-mediated hepatotoxicity. Taken together, hepatocyte-specific depletion of miRNA-21 alleviated APAP-induced hepatotoxicity by activating PPARγ and autophagy, demonstrating a crucial new regulatory role of miR-21 in APAP-mediated liver injury.

Biomarker discovery in acetaminophen hepatotoxicity: leveraging single-cell transcriptomics and mechanistic insight.

INTRODUCTION: Acetaminophen (APAP) overdose is the leading cause of drug-induced liver injury and can cause a rapid progression to acute liver failure (ALF). Therefore, the identification of prognostic biomarkers to determine which patients will require a liver transplant is critical for APAP-induced ALF. AREAS COVERED: We begin by relating the mechanistic investigations in mouse models of APAP hepatotoxicity to the human APAP overdose pathophysiology. We draw insights from the established sequence of molecular events in mice to understand the progression of events in the APAP overdose patient. Through this mechanistic understanding, several new biomarkers, such as CXCL14, have recently been evaluated. We also explore how single-cell RNA sequencing, spatial transcriptomics, and other omics approaches have been leveraged for identifying novel biomarkers and how these approaches will continue to push the field of biomarker discovery forward. EXPERT OPINION: Recent investigations have elucidated several new biomarkers or combination of markers such as CXCL14, a regenerative miRNA signature, a cell death miRNA signature, hepcidin, LDH, CPS1, and FABP1. While these biomarkers are promising, they all require further validation. Larger cohort studies analyzing these new biomarkers in the same patient samples, while adding these candidate biomarkers to prognostic models will further support their clinical utility.

Influence of N-acetyltransferase 2 polymorphisms and clinical variables on liver function profile of tuberculosis patients.

BACKGROUND: Single nucleotide polymorphisms (SNPs) in the N-acetyltransferase 2 (NAT2) gene as well as several other clinical factors can contribute to the elevation of liver function test values in tuberculosis (TB) patients receiving antitubercular therapy (ATT). RESEARCH DESIGN AND METHODS: A prospective study involving dynamic monitoring of the liver function tests among 130 TB patients from baseline to 98 days post ATT initiation was undertaken to assess the influence of pharmacogenomic and clinical variables on the elevation of liver function test values. Genomic DNA was extracted from serum samples for the assessment of NAT2 SNPs. Further, within this study population, we conducted a case control study to identify the odds of developing ATT-induced drug-induced liver injury (DILI) based on NAT2 SNPs, genotype and phenotype, and clinical variables. RESULTS: NAT2 slow acetylators had higher mean [90%CI] liver function test values for 8-28 days post ATT and higher odds of developing DILI (OR: 2.73, 90%CI: 1.05-7.09) than intermediate acetylators/rapid acetylators. CONCLUSION: The current study findings provide evidence for closer monitoring among TB patients with specific NAT2 SNPs, genotype and phenotype, and clinical variables, particularly between the period of more than a week to one-month post ATT initiation for better treatment outcomes.

A network-based transcriptomic landscape of HepG2 cells uncovering causal gene-cytotoxicity interactions underlying drug-induced liver injury.

Drug-induced liver injury (DILI) remains the main reason for drug development attritions largely due to poor mechanistic understanding. Toxicogenomic to interrogate the mechanism of DILI has been broadly performed. Gene coregulation network-based transcriptome analysis is a bioinformatics approach that potentially contributes to improve mechanistic interpretation of toxicogenomic data. Here we performed an extensive concentration time course response-toxicogenomic study in the HepG2 cell line exposed to 20 DILI compounds, 7 reference compounds for stress response pathways, and 10 agonists for cytokines and growth factor receptors. We performed whole transcriptome targeted RNA sequencing to more than 500 conditions and applied weighted gene coregulated network analysis to the transcriptomics data followed by the identification of gene coregulated networks (modules) that were strongly modulated upon the exposure of DILI compounds. Preservation analysis on the module responses of HepG2 and PHH demonstrated highly preserved adaptive stress response gene coregulated networks. We correlated gene coregulated networks with cell death onset and causal relationships of 67 critical target genes of these modules with the onset of cell death was evaluated using RNA interference screening. We identified GTPBP2, HSPA1B, IRF1, SIRT1, and TSC22D3 as essential modulators of DILI compound-induced cell death. These genes were also induced by DILI compounds in PHH. Altogether, we demonstrate the application of large transcriptome datasets combined with network-based analysis and biological validation to uncover the candidate determinants of DILI.

HLA-B*53:01 Is a Significant Risk Factor of Liver Injury due to Phenytoin and Other Antiepileptic Drugs in African Americans.

INTRODUCTION: To investigate human leukocyte antigen alleles associated with liver injury due to antiepileptic drugs (AEDs) in African Americans (AA). METHODS: In this study, 21 AA with AED drug-induced liver injury (DILI), 176 AA with DILI due to non-AEDs, and 5816 AA population controls were included. RESULTS: HLA-B*53:01 was significantly associated with aromatic AED-DILI (odds ratio: 4.52, 95% confidence interval: 2.42-8.44, P = 1.46 × 10 -5 ). Phenytoin DILI showed the strongest association with HLA-B*53:01 (odds ratio: 9.17; 95% confidence interval: 3.61-23.28, P = 1.1 × 10 -5 ). The HLA-B*53:01 allele was carried by 8 of 9 AA phenytoin DILI cases. DISCUSSION: HLA-B*53:01 is a significant risk factor of liver injury due to antiepileptics, particularly phenytoin, in AA.

Vancomycin-Induced Liver Injury, DRESS, and HLA-A∗32:01.

BACKGROUND: Intravenous vancomycin therapy can cause liver injury as well as "drug reaction with eosinophilia and systemic symptoms" (DRESS) syndrome. This study aimed to better define the clinical features and HLA associations of vancomycin-induced liver injury. OBJECTIVE: To describe clinical, biochemical, and temporal characteristics of vancomycin-induced liver injury. METHODS: Cases of liver injury with recent exposure to vancomycin who were enrolled in the US Drug-induced Liver Injury Network between 2004 and 2020 were assessed. Sequencing of HLA alleles was performed on stored blood samples. RESULTS: Among 1697 cases of drug-induced liver injury identified between 2004 and 2021, 9 (0.5%) were attributed to intravenous vancomycin. The 9 cases included 6 men, median age 60 years (range, 23-85 days), and treatment for 26 days (range, 1-34 days). The clinical presentation was DRESS syndrome in 8 patients, of whom 6 received corticosteroids. Liver injury varied from hepatocellular to cholestatic and from mild (n = 5) to fatal (n = 1). In survivors, liver injury and DRESS syndrome ultimately resolved. HLA typing demonstrated the HLA-A∗32:01 allele in 7 vancomycin cases (78%, all with DRESS syndrome), versus 1 of 81 cases (1.2%) exposed but not attributed to vancomycin, and 113 of 1708 cases (6.6%) without vancomycin exposure. The allele frequency in vancomycin cases was 0.44 compared with less than 0.04 in US populations. CONCLUSIONS: Vancomycin-induced liver injury is commonly associated with DRESS syndrome and linked to HLA-A∗32:01. HLA-A∗32:01 testing could be considered early to risk-stratify patients using long-term intravenous vancomycin therapy.

The expanding role of HLA gene tests for predicting drug side effects.

Adverse drug reactions can be either dose-dependent (Type A) or idiosyncratic (Type B). Type B adverse drug reactions tend to be extremely rare and difficult to predict. They are usually immune-mediated. Examples include severe skin reactions and drug-induced liver injury. For many commonly prescribed drugs (such as antibiotics), the risk of developing an idiosyncratic adverse drug reaction is influenced by variability in the human leukocyte antigen (HLA) genes. Because these HLA-mediated adverse drug reactions can be lethal, there is growing interest in defining which specific drug-gene relationships might benefit from pre-emptive HLA genotyping and automated clinical decision support. This review summarizes the literature for HLA-mediated adverse reactions linked to common drugs.

Relevance of NAT2 genotype and clinical factors to risk for antituberculosis drug-induced liver injury.

The study analyzes the risk factors associated with antituberculosis drug-induced liver injury (ATB-DILI), and the relationship between ATB-DILI and NAT2 gene polymorphisms. Out of the 324 included patients, 57 (17.59%) developed ATB-DILI. Age, history of liver disease, alcohol consumption and timing of antituberculosis (ATB) treatment were independent risk factors for ATB-DILI in the patients with tuberculosis (TB; p < 0.05). There was a significant difference in the distribution of NAT2 metabolic phenotypes between the study group and the control group (p < 0.05). The ATB drug treatment for pulmonary TB can cause a high incidence of ATB-DILI. Age, history of liver disease, alcohol consumption and timing of ATB treatment are independent risk factors for ATB-DILI in patients with TB.

Sting mutation attenuates acetaminophen-induced acute liver injury by limiting NLRP3 activation.

Acetaminophen (N-acetyl-p-aminophenol; APAP), a widely used effective nonsteroidal anti-inflammatory drug, leads to acute liver injury at overdose worldwide. Evidence showed that the severity of liver injury associated with the subsequent involvement of inflammatory mediators and immune cells. The innate immune stimulator of interferon genes protein (STING) pathway was critical in modulating inflammation. Here, we show that STING was activated and inflammation was enhanced in the liver in APAP-overdosed C57BL/6J mice, and Sting mutation (Stinggt/gt) mice exhibited less liver damage. Multiplexing flow cytometry displayed that Sting mutation changed hepatic recruitment and replacement of macrophages/monocytes in APAP-overdosed mice, which was inclined to anti-inflammation. In addition, Sting mutation limited NLRP3 activation in the liver in APAP-overdosed mice, and inhibited the expression of inflammatory cytokines. Finally, MCC950, a potent and selective NLRP3 inhibitor, significantly ameliorated APAP-induced liver injury and inflammation. Besides, pretreatment of MCC950 in C57 mice resulted in changes of immune cells infiltration in the liver similar to Stinggt/gt mice. Our study revealed that STING played a crucial role in APAP-induced acute liver injury, possibly by maintaining liver immune cells homeostasis and inhibiting NLRP3 inflammasome activation, suggesting that inhibiting STING-NLRP3 pathway might be a potential therapeutic strategy for acute liver injury.