Acetaminophen Overdose Research Articles

Underreporting Supplements: A Case of Drug-induced Liver Injury Due to a Testosterone Booster.

Acute liver injuries (ALIs) are caused by a wide range of etiologies, and determining the cause can often be challenging. Detailed history taking is essential in patients with liver injuries to promptly determine the underlying source of injury and for timely treatment and prognosis. A 27-year-old active duty man presented to the emergency department (ED) with jaundice. On medication reconciliation, he only reported taking acetaminophen for a recent upper respiratory infection. The patient had an ALI and was treated with N-acetyl cysteine for presumed acetaminophen toxicity. Initially, his liver-associated enzymes (LAEs) improved, but 2 weeks after discharge, he returned to the ED upon referral from ship medical for jaundice and worsening liver injury. Repeated query into the patient's history revealed that he was using a testosterone booster supplement for 6 months preceding initial hospitalization. After evaluation of other etiologies for liver injury returned negative, drug-induced liver injury from the testosterone booster was determined to be the underlying etiology. With discontinuation of the supplement, his liver injury improved. Hepatotoxicity is a major concern in supplement use; however, it is largely underreported. Supplements are often not recognized or reported as medications by patients, leading to failure to identify them as potential toxicants. This case highlights the importance of including supplement education and questioning in the evaluation of ALI and maintaining a high index of suspicion when other common etiologies of liver disease are negative.

Effect of exogenous IGF-1 administration on acetaminophen toxicity induced liver injury

Effect of exogenous IGF-1 administration on acetaminophen toxicity induced liver injury

Acute liver failure.

Acute liver failure, commonly caused by acetaminophen overdose, is associated with numerous systemic complications including cerebral edema, hypotension, acute kidney injury, and infection. Management is primarily supportive, with an emphasis on excellent neurocritical care. Although some antidotes and targeted treatments exist, the only definitive treatment remains orthotopic liver transplant.

Hepatic Sirt6 activation abrogates acute liver failure.

Acute liver failure (ALF) is a deadly illness due to insufficient detoxification in liver induced by drugs, toxins, and other etiologies, and the effective treatment for ALF is very limited. Among the drug-induced ALF, acetaminophen (APAP) overdose is the most common cause. However, the molecular mechanisms underlying APAP hepatoxicity remain incompletely understood. Sirtuin 6 (Sirt6) is a stress responsive protein deacetylase and plays an important role in regulation of DNA repair, genomic stability, oxidative stress, and inflammation. Here, we report that genetic and pharmacological activation of Sirt6 protects against ALF in mice. We first observed that Sirt6 expression was significantly reduced in the liver tissues of human patients with ALF and mice treated with an overdose of APAP. Then we developed an inducible Sirt6 transgenic mice for Cre-mediated overexpression of the human Sirt6 gene in systemic (Sirt6-Tg) and hepatic-specific (Sirt6-HepTg) manners. Both Sirt6-Tg mice and Sirt6-HepTg mice exhibited the significant protection against APAP hepatoxicity. In contrast, hepatic-specific Sirt6 knockout mice exaggerated APAP-induced liver damages. Mechanistically, Sirt6 attenuated APAP-induced hepatocyte necrosis and apoptosis through downregulation of oxidative stress, inflammation, the stress-activated kinase JNK activation, and apoptotic caspase activation. Moreover, Sirt6 negatively modulated the level and activity of poly (ADP-ribose) polymerase 1 (PARP1) in APAP-treated mouse liver tissues. Importantly, the specific Sirt6 activator MDL-800 exhibited better therapeutic potential for APAP hepatoxicity than the current drug acetylcysteine. Furthermore, in the model of bile duct ligation induced ALF, hepatic Sirt6-KO exacerbated, but Sirt6-HepTg mitigated liver damage. Collectively, our results demonstrate that Sirt6 protects against ALF and suggest that targeting Sirt6 activation could be a new therapeutic strategy to alleviate ALF.

Evaluation of capillary miR-122 as a prognostic biomarker of paracetamol-induced liver toxicity.

Paracetamol (acetaminophen) overdose is a leading cause of acute liver failure in many Western countries. Diagnostic tools for this poisoning may be suboptimal in some cases and new biomarkers have been investigated. We investigated the role of capillary microRNA-122 (miR-122) as a prognostic biomarker of liver injury in the clinical management of patients with paracetamol overdose. In a paracetamol overdose patient cohort, miR-122 was measured by quantitative polymerase chain reaction in a blood drop obtained by a finger prick at the end of an antidote cycle treatment with N-acetylcysteine treatment (12h). Liver injury was defined as serum alanine aminotransferase (ALT) activity > 100IU/L collected at 10 or 20h after the start of treatment. Pearson's correlation analyses were performed. In patients with paracetamol overdose, capillary miR-122 was positively correlated with ALT measured at 10h and at 20h (r = 0.83, P < 0.0001; r = 0.96, P < 0.0001, respectively). This work supports the potential use of capillary miR-122 as a prognostic biomarker of liver injury throughout clinical management of patients with paracetamol overdose. Capillary miR-122 can be measured in a blood drop collected by a finger prick, a minimally invasive diagnostic test for patient stratification.

Patterns and trends of medicinal poisoning substances: a population-based cohort study of injuries in 0–11 year old children from 1998–2018

BackgroundThere have been sharp increases in antidepressant and opioid prescriptions over the last 10 years, as well as increased over-the-counter medicine availability. However, the impact on childhood medicinal poisonings rates, particularly by socioeconomic deprivation is unclear. This study reports population level medicinal poisoning substance patterns in England among children aged 0–11 years, helping inform safety advice and poisoning prevention interventions.MethodsAn open cohort study of 1,489,620 0–11 year olds was conducted from 1998 to 2018, using the Clinical Practice Research Datalink, to examine inpatient hospital admissions for poisoning. Incidence rates and adjusted incidence rate ratios (aIRR) were calculated for poisoning substance groups by age, sex, socio-economic deprivation and year.Results3,685 medicinal poisoning hospital admissions were identified. The most common substances were paracetamol (33.2%), dependence/withdrawal risk drugs (DWRD - antidepressants, opioids, gabapentinoids, benzodiazepines) (13.5%) and other over-the-counter (OTC) analgesics/anti-common cold drugs (13.0%). Over the study period DWRD poisonings decreased 33% (aIRR 0.67, 95%CI 0.50–0.90 comparing 2013/14-2017/18 to 1998/99-2002/03), while paracetamol poisonings increased 43% (aIRR 1.43, 95%CI 1.20–1.70 for the same periods), with no change in incidence rates for other OTC drugs (aIRR 0.82, 95% CI 0.60–1.12) or all medications combined (aIRR 0.97, 95%CI 0.88–1.07). A gradient in poisonings by area-level socioeconomic deprivation was shown for all medications (aIRR 1.32, 95%CI 1.18–1.47 for most deprived compared to least deprived quintile), and DWRDs (aIRR 2.03, 95%CI 1.42–2.88 for 4th most deprived quintile and aIRR 1.88, 95%CI 1.32–2.66 for 5th most deprived quintile, compared to least deprived quintile), but not for paracetamol or other OTC drug poisonings.ConclusionsPoisonings from DWRDs decreased by 33%, while paracetamol poisonings increased by 43% during the study period. There was a gradient by area-level socioeconomic deprivation in prescribed medication poisonings, including drugs with withdrawal/dependence risk, but not OTC medication poisonings. Households in more socioeconomically deprived areas have the potential to benefit most from measures to improve safe storage of medicines and are likely to require targeted interventions providing education and safety equipment. In addition, universal promotion of the safe storage of OTC and prescribed medicines must be provided by prescribers, community pharmacies and other outlets of such medication.

The p21+ perinecrotic hepatocytes produce the chemokine CXCL14 after a severe acetaminophen overdose promoting hepatocyte injury and delaying regeneration

Fifty percent of all acute liver failure (ALF) cases in the United States are due to acetaminophen (APAP) overdose. Assessment of canonical features of liver injury, such as plasma alanine aminotransferase activities are poor predictors of acute liver failure (ALF), suggesting the involvement of additional mechanisms independent of hepatocyte death. Previous work demonstrated a severe overdose of APAP results in impaired regeneration, the induction of senescence by p21, and increased mortality. We hypothesized that a discrete population of p21+ hepatocytes acquired a secretory phenotype that directly impedes liver recovery after a severe APAP overdose. Leveraging in-house human APAP explant liver and publicly available single-nuclei RNAseq data, we identified a subpopulation of p21+ hepatocytes enriched in a unique secretome of factors, such as CXCL14. Spatial transcriptomics in the mouse model of APAP overdose confirmed the presence of a p21+ hepatocyte population that directly surrounded the necrotic areas. In both male and female mice, we found a dose-dependent induction of p21 and persistent circulating levels of the p21-specific constituent, CXCL14, in the plasma after a severe APAP overdose. In parallel experiments, we targeted either the putative senescent hepatocytes with the senolytic drugs, dasatinib and quercetin, or CXCL14 with a neutralizing antibody. We found that targeting CXCL14 greatly enhanced liver recovery after APAP-induced liver injury, while targeting senescent hepatocytes had no effect. These data support the conclusion that the sustained induction of p21 in hepatocytes with persistent CXCL14 secretion are critical mechanistic events leading to ALF in mice and human patients.

Sex differences in glutathione metabolism and acetaminophen toxicity

Aims: Clinical and experimental evidence has shown that females in humans and other mammals have higher glutathione (GSH) levels than males, which are caused by higher levels of estradiol. Understanding how hepatic GSH level and synthesis velocity depend on the sex hormones is an extremely important question since oxidative stress contributes to the risk for heart disease and cancer, and oxidative stress is reduced by GSH. Our aim is to develop a systems approach to understanding GSH metabolism and use this to explain the causes of GSH differences in males and females, how GSH changes during the menstrual cycle, and why women may be less susceptible to acetaminophen toxicity. Methods: We use mathematical models for hepatic glutathione metabolism, including one-carbon metabolism and acetaminophen detoxification, to investigate how the activation of certain enzymes by estradiol leads to dramatic changes in reaction velocities and metabolite concentrations. Results: The models explain why women of childbearing age have higher glutathione than men, and that this is caused by the balance of activation of glutamyl cysteine synthetase (GCL) and glutathione peroxidase (GPX) by estradiol. The steady-state concentration of glutathione in women depends on the strength of the activation of GCL and GPX and is quite homeostatic over a wide range of activations. Conclusions: During the menstrual cycle, the GSH concentration changes daily but over a relatively narrow range. We explain how this dynamic homeostasis depends on the biochemical network that produces GSH. The model is also consistent with published results that show that female mice are less susceptible than males to hepatotoxicity due to acetaminophen overdose and suggests that this might also be true for humans, though the human epidemiological data are contradictory.

Indole-3-carboxaldehyde alleviates acetaminophen-induced liver injury via inhibition of oxidative stress and apoptosis

Drug-induced liver injury (DILI) occurs frequently and can be life-threatening. Increasing researches suggest that acetaminophen (APAP) overdose is a leading cause of drug-induced liver injury. Indole-3-carboxaldehyde (I3A) alleviates hepatic inflammation, fibrosis and atherosclerosis, suggesting a potential role in different disease development. However, the question of whether and how I3A protects against acetaminophen-induced liver injury remains unanswered. In this study, we demonstrated that I3A treatment effectively mitigates acetaminophen-induced liver injury. Serum alanine/aspartate aminotransferases (ALT/AST), liver malondialdehyde (MDA) activity, liver glutathione (GSH), and superoxide dismutase (SOD) levels confirmed the protective effect of I3A against APAP-induced liver injury. Liver histological examination provided further evidence of I3A-induced protection. Mechanistically, I3A reduced the expression of apoptosis-related factors and oxidative stress, alleviating disease symptoms. Finally, I3A treatment improved survival in mice receiving a lethal dose of APAP. In conclusion, our study demonstrates that I3A modulates hepatotoxicity and can be used as a potential therapeutic agent for DILI.

Protective effects of jervine purified from Veratrum album on paracetamol-induced liver toxicity in rats

Purpose: Since paracetamol toxicity is a very common type of poisoning, we planned to investigate whether Jervine has an effect on paracetamol toxicity by utilizing its anti-inflammatory effect.&#x0D; Materials and Methods: In our study, 42 Sprague Dawley rats of 8 weeks of age were used. Seven groups were formed with 6 animals in each group. At the 24th hour of the study, all groups underwent laparotomy under anesthesia, and liver dissection was performed. Hematoxylin and Eosin (H&amp;E) staining was performed to evaluate liver histopathology. SOD, CAT, GSH, and MDA levels were analyzed biochemically.&#x0D; Results: Histopathological, while liver tissues were normal in the control group, we observed degeneration areas, inflammation, and hemorrhage in the paracetamol group. Jervine reduced the severity of paracetamol toxicity and prevented liver damage. Jervine significantly increased SOD levels. Paracetamol administration significantly decreased CAT levels. Paracetamol significantly decreased GSH levels compared to the control group. &#x0D; Conclusion: Jervine reduced the adverse effects of paracetamol toxicity on liver tissue, such as degeneration, inflammation, and hemorrhage. Jervine increased antioxidant activity and reduced the harmful effects of NAPQI, the toxic metabolite of paracetamol, on liver tissue.

Biofarmasetics and Pharmacokinetics Study Analysis of Paracetamol Excretion Through Urine and Saliva

The purpose of this study was to determine that Paracetamol, also known as acetaminophen, is a commonly used analgesic and antipyretic drug to relieve pain and reduce fever. The process of metabolism and elimination of paracetamol from the body is important to understand, especially in the context of the safe use of this drug. This study aims to analyze the biopharmaceutics and pharmacokinetics studies of paracetamol excretion through urine and saliva as important indicators in understanding the metabolic and elimination processes of this drug. Paracetamol is rapidly and efficiently absorbed through the gastrointestinal tract, reaches the highest concentration in plasma in a short time, and is dispersed throughout the body fluids. The metabolic process of paracetamol mainly occurs in the liver, through two main phases: oxidation and conjugation with glucuronic and sulfuric acids. Excretion of drugs and their metabolites can occur through urine and saliva, with the kidney as the main organ in the excretion process. Qualitative analytical methods were used in this study to identify paracetamol metabolite compounds in urine and saliva samples and to evaluate the metabolic pathways involved. Glucoronide, sulfate, and phenol conjugate assays were used to detect the presence of paracetamol metabolites in the samples. The assay results showed that urine was more effective in excreting paracetamol compared to saliva. In conclusion, this study provides a better understanding of the metabolic process and elimination of paracetamol from the human body through the analysis of biopharmaceutics and pharmacokinetics studies. These results are important for understanding the therapeutic effects and toxicity of paracetamol as well as for developing more effective and safe drug use management strategies.

Iguratimod, an allosteric inhibitor of macrophage migration inhibitory factor (MIF), prevents mortality and oxidative stress in a murine model of acetaminophen overdose

BackgroundMacrophage migration inhibitory factor (MIF) is a pleiotropic cytokine that has been implicated in multiple inflammatory and non-inflammatory diseases, including liver injury induced by acetaminophen (APAP) overdose. Multiple small molecule inhibitors of MIF have been described, including the clinically available anti-rheumatic drug T-614 (iguratimod); however, this drug’s mode of inhibition has not been fully investigated.MethodsWe conducted in vitro testing including kinetic analysis and protein crystallography to elucidate the interactions between MIF and T-614. We also performed in vivo experiments testing the efficacy of T-614 in a murine model of acetaminophen toxicity. We analyzed survival in lethal APAP overdose with and without T-614 and using two different dosing schedules of T-614. We also examined MIF and MIF inhibition effects on hepatic hydrogen peroxide (H2O2) as a surrogate of oxidative stress in non-lethal APAP overdose.ResultsKinetic analysis was consistent with a non-competitive type of inhibition and an inhibition constant (Ki) value of 16 µM. Crystallographic analysis revealed that T-614 binds outside of the tautomerase active site of the MIF trimer, with only the mesyl group of the molecule entering the active site pocket. T-614 improved survival in lethal APAP overdose when given prophylactically, but this protection was not observed when the drug was administered late (6 h after APAP). T-614 also decreased hepatic hydrogen peroxide concentrations during non-lethal APAP overdose in a MIF-dependent fashion.ConclusionsT-614 is an allosteric inhibitor of MIF that prevented death and decreased hepatic hydrogen peroxide concentrations when given prophylactically in a murine model of acetaminophen overdose. Further studies are needed to elucidate the mechanistic role of MIF in APAP toxicity.

Has the rescheduling of modified-release paracetamol in Australia affected the frequency of overdoses?

In June 2020, modified-release paracetamol (paracetamol-MR) preparations were up-scheduled from schedule-2 (available in pharmacy) to schedule-3 (available by request to a pharmacist only). The present study aims to ascertain whether up-scheduling affected the frequency of paracetamol-MR overdoses. This is a retrospective cohort study of two data sets from 1 June 2017 to 31 May 2022. Monash Health data were extracted using the diagnosis of paracetamol overdose coding and electronic medical records data. Calls regarding paracetamol-MR overdoses to Victorian Poisons Information Centre (VPIC) were extracted from the Poisons centre call database. We used a quasi-experimental research design with interrupted time series analysis to evaluate the immediate impact and change in trend of poisoning-related calls and ED presentations before and after June 2020. The change in proportion of paracetamol-MR cases in both databases was analysed using the Χ2 test. The proportion of paracetamol-MR cases in both data sets did not change. From Monash Health, there was no level change in monthly paracetamol-MR overdose-related presentations following re-scheduling (rate ratio [RR] = 1.08, 95% confidence interval [CI] = 0.57-2.01). There was no change in monthly paracetamol-MR overdose-related calls to VPIC following re-scheduling (RR = 1.05, 95% CI = 0.96-1.14). The proportion of paracetamol-MR overdoses did not decrease after the up-scheduling to S3. Similarly, the frequency of overdoses by month remained similar. Further limitations on access to paracetamol products may need to be considered.

Extra-corporeal non-liver transplant therapies for acute liver failure: Focus on plasma exchange and continuous renal replacement therapy.

The acute inflammatory milieu in patients with acute liver failure (ALF) results in 'toxic' blood in these patients. In vitro experiments have shown that the plasma obtained from ALF patients is toxic to rabbit hepatocytes and inhibits regeneration of rat hepatocytes. Treatments such as plasma exchange and continuous renal replacement therapy to cleanse the blood have improved survival in ALF patients. In the liver microcirculation, the exchange of fluid across fenestrae in liver sinusoidal endothelial cells (LSECs) is vital for proper functioning of hepatocytes. Clogging of the liver filter bed by inflammatory debris and cells ('traffic jam hypothesis') impeding blood flow in sinusoids may in turn reduce the exchange of fluid across LSEC fenestrae and cause dysfunction and necrosis of hepatocytes in ALF patients. In mouse model of paracetamol overdose, disturbances in microcirculation in the liver preceded the development of injury and necrosis of hepatocytes. This may represent a reversible pathophysiological mechanism in ALF which may be improved by the anti-inflammatory effect of plasma exchange. Wider access to urgent plasma exchange is a major advantage compared to urgent liver transplantation to treat ALF patients worldwide, especially so in resource constrained settings. Continuous hemo-filtration or dialysis is used toreduce ammonia levels and treat cerebral edema in ALF patients. In this review, we discuss the different modalities to cleanse the blood in ALF patients, with an emphasis on plasma exchange, from a hepatology perspective.

Cytokeratin-18 is a sensitive biomarker of alanine transaminase increase in a placebo-controlled, randomized, crossover trial of therapeutic paracetamol dosing (PATH-BP biomarker substudy).

Drug-induced liver injury (DILI) is a challenge in clinical medicine and drug development. Highly sensitive novel biomarkers have been identified for detecting DILI following a paracetamol overdose. The study objective was to evaluate biomarker performance in a 14-day trial of therapeutic dose paracetamol. The PATH-BP trial was a double-blind, placebo-controlled, crossover study. Individuals (n = 110) were randomized to receive 1 g paracetamol 4× daily or matched placebo for 2 weeks followed by a 2-week washout before crossing over to the alternate treatment. Blood was collected on days 0 (baseline), 4, 7, and 14 in both arms. Alanine transaminase (ALT) activity was measured in all patients. MicroRNA-122 (miR-122), cytokeratin-18 (K18), and glutamate dehydrogenase (GLDH) were measured in patients who had an elevated ALT on paracetamol treatment (≥50% from baseline). ALT increased in 49 individuals (45%). All 3 biomarkers were increased at the time of peak ALT (K18 paracetamol arm: 18.9 ± 9.7 ng/ml, placebo arm: 11.1 ± 5.4 ng/ml, ROC-AUC = 0.80, 95% CI 0.71-0.89; miR-122: 15.1 ± 12.9fM V 4.9 ± 4.7fM, ROC-AUC = 0.83, 0.75-0.91; and GLDH: 24.6 ± 31.1U/l V 12.0 ± 11.8U/l, ROC-AUC = 0.66, 0.49-0.83). All biomarkers were correlated with ALT (K18 r = 0.68, miR-122 r = 0.67, GLDH r = 0.60). To assess sensitivity, biomarker performance was analyzed on the visit preceding peak ALT (mean 3 days earlier). K18 identified the subsequent ALT increase (K18 ROC-AUC = 0.70, 0.59-0.80; miR-122 ROC-AUC = 0.60, 0.49-0.72, ALT ROC-AUC = 0.59, 0.48-0.70; GLDH ROC-AUC = 0.70, 0.50-0.90). Variability was lowest for ALT and K18. In conclusion, K18 was more sensitive than ALT, miR-122, or GLDH and has potential significant utility in the early identification of DILI in trials and clinical practice.

Two versus Three Infusion Regimens of N-Acetylcysteine for Acetaminophen Overdose.

Acetaminophen overdose is a common clinical condition, often leading to liver toxicity. Current treatments involve the three-infusion N-Acetylcysteine (NAC) regimen (FDA-labeled), which may be complex, time-consuming, and need to be changed. An alternative uses two infusions instead, which offers possible advantages regarding simplicity and administration errors. This study sought to compare the respective efficacies and safety outcomes when treating acute acetaminophen overdose among children and adolescents. At Montreal Children's Hospital, a retrospective study was conducted comparing pre-2003 FDA-labelled three-infusion NAC therapy with a two-infusion regimen. Information was collected regarding patient demographics, NAC administration details, errors, rates of hepatotoxicity, and adverse reactions, and the statistical test Chi-square test was employed to obtain the results. A total of 126 patients met the inclusion criteria. Of these patients, 65 received a two-infusion regimen, and 61 patients received the FDA-labeled regimen. The two-infusion group experienced significantly fewer administration errors (4 errors vs. 23 errors; p < 0.001), while the rates of hepatotoxicity between them were similar. There were no instances of liver transplantation or mortality due to either regimen. Adverse reactions occurred equally frequently between both regimens with no discernible difference-the meantime to administer NAC was 9 h for the two-infusion regimen and 8.5 h for FDA-labeled regimen groups, respectively. Three cases of hepatitis were successfully treated with timely NAC therapy, and no liver transplantation or mortality occurred. Adverse reactions, including anaphylactoid reactions, were observed in both groups but were resolved when temporarily stopped and restarted at a slower infusion rate. The two-infusion NAC regimen proved similar efficacy at protecting liver damage and improving patient outcomes compared to its FDA-labeled three-stage counterpart, with significantly fewer administration errors for this version of NAC treatment, suggesting potential advantages in terms of safety and simplicity. Future research should investigate larger cohorts and more variables to validate these results further and optimize the management of acetaminophen overdose cases; further investigation should focus on dosing strategies, personalized approaches, and long-term patient care in this context.

The Use and Potential Benefits of N-Acetylcysteine in Non-Acetaminophen Acute Liver Failure: An Etiology-Based Review.

Acute liver failure represents a life-threatening organ dysfunction with high mortality rates and an urgent need for liver transplantation. The etiology of the disease varies widely depending on various socio-economic factors and is represented mainly by paracetamol overdose and other drug-induced forms of liver dysfunction in the developed world and by viral hepatitis and mushroom poisoning in less developed countries. Current medical care constitutes either specific antidotes or supportive measures to ensure spontaneous recovery. Although it has been proven to have beneficial effects in paracetamol-induced liver failure, N-acetylcysteine is widely used for all forms of acute liver failure. Despite this, few well-designed studies have been conducted on the assessment of the potential benefits, dose regimens, or route of administration of N-acetylcysteine in non-acetaminophen liver failure. This review aims to summarize the current evidence behind the use of this drug in different forms of liver failure.

Острое отравление парацетамолом у детей. Оказание неотложной помощи в реанимационном отделении многопрофильной больницы на примере клинических случаев

The article presents a three -year analysis of the structure of acute paracetamol poisoning in children. On the example of clinical cases, the tactics of treating patients with acute paracetamol poisoning are described.The effectiveness of the recommended doses and antidote therapy schemes is evaluated. The main factors contributing to the adverse outcome of the disease are indicated.

A novel HDAC6 inhibitor attenuate APAP-induced liver injury by regulating MDH1-mediated oxidative stress

Glutathione (GSH) depletion, mitochondrial damage, and oxidative stress have been implicated in the pathogenesis of acetaminophen (APAP) hepatotoxicity. Here, we demonstrated that the expression of histone deacetylase 6 (HDAC6) is highly elevated, whereas malate dehydrogenase 1 (MDH1) is downregulated in liver tissues and AML-12 cells induced by APAP. The therapeutic benefits of LT-630, a novel HDAC6 inhibitor on APAP-induced liver injury, were also substantiated. On this basis, we demonstrated that LT-630 improved the protein expression and acetylation level of MDH1. Furthermore, after overexpression of MDH1, an upregulated NADPH/NADP+ ratio and GSH level and decreased cell apoptosis were observed in APAP-stimulated AML-12 cells. Importantly, MDH1 siRNA clearly reversed the protection of LT-630 on APAP-stimulated AML-12 cells. In conclusion, LT-630 could ameliorate liver injury by modulating MDH1-mediated oxidative stress induced by APAP.

Perturbations in human bile acid profiles following drug-induced liver injury investigated using semitargeted high-resolution mass spectrometry.

Acetaminophen (APAP) overdose is the leading cause of acute liver failure (ALF) in North America. To investigate the effect of drug-induced liver injury (DILI) on circulating bile acid (BA) profiles, serum from ALF patients and healthy controls were analyzed using a semitargeted high-resolution mass spectrometry approach to measure BAs in their unconjugated and amidated forms and their glucuronide and sulfate conjugates. Human serum samples from 20 healthy volunteers and 34 ALF patients were combined with deuterated BAs and extracted, prior to liquid chromatography high-resolution tandem mass spectrometry analysis. A mix of 46 standards helped assign 26 BAs in human serum by accurate mass and retention time matching. Moreover, other isomers of unconjugated and amidated BAs, as well as glucuronide and sulfate conjugates, were assigned by accurate mass filtering. In vitro incubations of standard BAs provided increased information for certain peaks of interest. A total of 275 BA metabolites, with confirmed or putative assignments, were measured in human serum samples. APAP overdose significantly influenced the levels of most BAs, promoting glycine conjugation, and, to a lesser extent, taurine conjugation. When patient outcome was considered, 11 BAs were altered significantly, including multiple sulfated species. Although many of the BAs measured did not have exact structures assigned, several putatively identified BAs of interest were further characterized using in vitro incubations. An optimized chromatographic separation tailored to BAs of ranging polarities was combined with accurate mass measurements to investigate the effect that DILI has on their complex profiles and metabolism to a much wider extent than previously possible. The analysis of complex BA profiles enabled in-depth analysis of the BA metabolism perturbations in ALF, including certain metabolites related to patient outcomes.