Predictors of severe hepatotoxicity among retroviral infected adults on HAART regimen in Ilubabor Zone, Southwest Ethiopia.

Nearly half of the deaths among hospitalized human immuno deficiency virus-infected patients in the highly active antiretroviral therapy era have been attributed to liver disease. This may range from an asymptomatic mild increase of liver enzymes to cirrhosis and liver failure. Different works of literature elucidated both retroviral infection and the adverse effects of highly active antiretroviral therapy as a cause of hepatotoxicity. Individual adaptations to medications and environmental exposures, shaped by cultural norms and genetic predispositions, could potentially modulate the risk and progression of liver disease in this population. Therefore, this study aims to assess the predictors of severe hepatotoxicity in retroviral-infected adults receiving highly active antiretroviral therapy regimens within the Ilubabor Zone, Southwest Ethiopia. A facility-based cross-sectional study was conducted among adult retroviral-infected patients in five selected anti-retro virus therapy clinics from May1 to July 30/2022. A systematic sampling technique was used to select 457 study participants and Binary logistic regression statistical data analysis was used, P value < 0.05 was considered statistically significant. The prevalence of severe hepatotoxicity was 21.44% in the study population. CD+4 count < 200 cells/mm3 (AOR = 2.19, 95% CI 1.04-5.22, P = 0.01), human immunodeficiency virus co-infection with tuberculosis (AOR = 2.82, 95% CI 1.01-8.29, P = 0.03) and human immuno deficiency virus co-infection with hepatitis-B/hepatitis C virus (AOR = 5.02, 95% CI 1.82-16.41) were predictors of severe hepatotoxicity. The magnitude of severe hepatotoxicity was high among adult retroviral-infected patients on highly active anti-retroviral drug regimens. Co-infection of human immuno deficiency virus with hepatitis B virus or hepatitis C virus, tuberculosis and CD4+T-cell count below 200 cells/mm3 were predictors of severe hepatotoxicity. Therefore, HIV patients on highly active antiretroviral therapy require close attention and regular monitoring of their liver function.

Prediction of Acute Hepatotoxicity With Human Pluripotent Stem Cell-Derived Hepatic Organoids.

Recent development of hepatic organoids (HOs) derived from human pluripotent stem cells (hPSCs) provides an alternative in vitro model that can mimic the human liver detoxification pathway for drug safety assessment. By recapitulating the high level of maturity and drug-metabolizing capacity of the liver in a three-dimensional organoid culture, HOs may allow researchers to assess drug toxicity and metabolism more accurately than animal models or hepatocellular carcinoma cells. Although this promising potential has contributed to the development of various protocols, only a few protocols are available to generate functional HOs with guaranteed CYP450 enzymatic activity, the key feature driving toxic responses during drug metabolism. Based on previously published protocols, we describe an optimized culture method that can substantially increase the expression and activity of CYP450s, in particular CYP3A4, CYP2C9, and CYP2C19, in HOs. To generate mass-produced and highly reproducible HOs required as models for toxicity evaluation, we first generated hepatic endodermal organoids (HEOs) from hPSCs capable of in vitro proliferation and cryopreservation. The stepwise protocol includes generating HEOs as well as efficient methods to enhance CYP450 expression and activity in terminally differentiated HOs. Furthermore, we present a simple protocol for the assessment of HO cytotoxicity, one of the hallmarks of drug-induced acute hepatotoxicity. The protocols are relatively straightforward and can be successfully used by laboratories with basic experience in culturing hPSCs. © 2024 The Authors. Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: Generation of hepatic endodermal organoids from human pluripotent stem cells Basic Protocol 2: Expansion and cryopreservation of hepatic endodermal organoids Basic Protocol 3: Differentiation of hepatic organoids from hepatic endodermal organoids Basic Protocol 4: Evaluation of hepatotoxicity using hepatic organoids Support Protocol: Human pluripotent stem cell culture.

Interpretable machine learning in predicting drug-induced liver injury among tuberculosis patients: model development and validation study.

BACKGROUND: The objective of this research was to create and validate an interpretable prediction model for drug-induced liver injury (DILI) during tuberculosis (TB) treatment. METHODS: A dataset of TB patients from Ningbo City was used to develop models employing the eXtreme Gradient Boosting (XGBoost), random forest (RF), and the least absolute shrinkage and selection operator (LASSO) logistic algorithms. The model's performance was evaluated through various metrics, including the area under the receiver operating characteristic curve (AUROC) and the area under the precision recall curve (AUPR) alongside the decision curve. The Shapley Additive exPlanations (SHAP) method was used to interpret the variable contributions of the superior model. RESULTS: A total of 7,071 TB patients were identified from the regional healthcare dataset. The study cohort consisted of individuals with a median age of 47 years, 68.0% of whom were male, and 16.3% developed DILI. We utilized part of the high dimensional propensity score (HDPS) method to identify relevant variables and obtained a total of 424 variables. From these, 37 variables were selected for inclusion in a logistic model using LASSO. The dataset was then split into training and validation sets according to a 7:3 ratio. In the validation dataset, the XGBoost model displayed improved overall performance, with an AUROC of 0.89, an AUPR of 0.75, an F1 score of 0.57, and a Brier score of 0.07. Both SHAP analysis and XGBoost model highlighted the contribution of baseline liver-related ailments such as DILI, drug-induced hepatitis (DIH), and fatty liver disease (FLD). Age, alanine transaminase (ALT), and total bilirubin (Tbil) were also linked to DILI status. CONCLUSION: XGBoost demonstrates improved predictive performance compared to RF and LASSO logistic in this study. Moreover, the introduction of the SHAP method enhances the clinical understanding and potential application of the model. For further research, external validation and more detailed feature integration are necessary.

Toosendanin induces hepatotoxicity via disrupting LXRα/Lipin1/SREBP1 mediated lipid metabolism.

Toosendanin (TSN) is the main active compound derived from Melia toosendan Sieb et Zucc with various bioactivities. However, liver injury was observed in TSN limiting its clinical application. Lipid metabolism plays a crucial role in maintaining cellular homeostasis, and its disruption is also essential in TSN-induced hepatotoxicity. This study explored the hepatotoxicity caused by TSN in vitro and in vivo. The lipid droplets were significantly decreased, accompanied by a decrease in fatty acid transporter CD36 and crucial enzymes in the lipogenesis including ACC and FAS after the treatment of TSN. It was suggested that TSN caused lipid metabolism disorder in hepatocytes. TOFA, an allosteric inhibitor of ACC, could partially restore cell survival via blocking malonyl-CoA accumulation. Notably, TSN downregulated the LXRα/Lipin1/SREBP1 signaling pathway. LXRα activation improved cell survival and intracellular neutral lipid levels, while SREBP1 inhibition aggravated the cell damage and caused a further decline in lipid levels. Male Balb/c mice were treated with TSN (5, 10, 20 mg/kg/d) for 7 days. TSN exposure led to serum lipid levels aberrantly decreased. Moreover, the western blotting results showed that LXRα/Lipin1/SREBP1 inhibition contributed to TSN-induced liver injury. In conclusion, TSN caused lipid metabolism disorder in liver via inhibiting LXRα/Lipin1/SREBP1 signaling pathway.

A comprehensive review on the hepatotoxicity of herbs used in the Indian (Ayush) systems of alternative medicine.

Complementary and alternative medicine-related liver injuries are increasing globally. Alternative medicine, as an inclusive healthcare practice, is widely accepted in developing and underdeveloped countries. In this context, the traditional systems of medicine in India have been at the forefront, catering to the preventive and therapeutic spectrum in the absence of conclusive evidence for benefits and lack of data on safety. Contrary to popular belief, it is evident that apart from adverse events caused by contamination and adulteration of alternative medicines, certain commonly used herbal components have inherent hepatotoxicity. This narrative review updates our current understanding and increasing publications on the liver toxicity potential of commonly used herbs in traditional Indian systems of medicine (Ayush), such as Tinospora cordifolia (Willd.) Hook.f. & Thomson (Giloy/Guduchi), Withania somnifera (L.) Dunal (Ashwagandha), Curcuma longa L. (Turmeric), and Psoralea corylifolia L. (Bakuchi/Babchi). This review also highlights the importance of the upcoming liver toxicity profiles associated with other traditional herbs used as dietary supplements, such as Centella asiatica (L.) Urb., Garcinia cambogia Desr., Cassia angustifolia Vahl (Indian senna), and Morinda citrofolia L. (Noni fruit). Fortunately, most reported liver injuries due to these herbs are self-limiting, but can lead to progressive liver dysfunction, leading to acute liver failure or acute chronic liver failure with a high mortality rate. This review also aims to provide adequate knowledge regarding herbalism in traditional practices, pertinent for medical doctors to diagnose, treat, and prevent avoidable liver disease burdens within communities, and improve public health and education.

Efficacy, safety, and pharmacokinetics of isoniazid affected by NAT2 polymorphisms in patients with tuberculosis: A systematic review.

N-acetyltransferase 2 (NAT2) genetic polymorphisms might alter isoniazid metabolism leading to toxicity. We reviewed the impact of NAT2 genotype status on the pharmacokinetics, efficacy, and safety of isoniazid, a treatment for tuberculosis (TB). A systematic search for research articles published in Scopus, PubMed, and Embase until August 31, 2023, was conducted without filters or limits on the following search terms and Boolean operators: "isoniazid" AND "NAT2." Studies were selected if NAT2 phenotypes with pharmacokinetics or efficacy or safety of isoniazid in patients with TB were reported. Patient characteristics, NAT2 status, isoniazid pharmacokinetic parameters, early treatment failure, and the prevalence of drug-induced liver injury were extracted. If the data were given as a median, these values were standardized to the mean. Forty-one pharmacokinetics and 53 safety studies were included, but only one efficacy study was identified. The average maximum concentrations of isoniazid were expressed as supratherapeutic concentrations in adults (7.16 ± 4.85 µg/mL) and children (6.43 ± 3.87 µg/mL) in slow acetylators. The mean prevalence of drug-induced liver injury was 36.23 ± 19.84 in slow acetylators, which was significantly different from the intermediate (19.49 ± 18.20) and rapid (20.47 ± 20.68) acetylators. Subgroup analysis by continent showed that the highest mean drug-induced liver injury prevalence was in Asian slow acetylators (42.83 ± 27.61). The incidence of early treatment failure was decreased by genotype-guided isoniazid dosing in one study. Traditional weight-based dosing of isoniazid in most children and adults yielded therapeutic isoniazid levels (except for slow acetylators). Drug-induced liver injury was more commonly observed in slow acetylators. Genotype-guided dosing may prevent early treatment failure.

Complementary and alternative medicines and liver disease.

Complementary and alternative medicines (CAM) include conventional medical treatments. Patients worldwide use CAM at alarming rates; thus, reports of CAM-related DILI have been on the rise. The clinical presentations include asymptomatic liver test abnormalities, acute hepatitis with or without jaundice, acute cholestatic liver disease (bland or with hepatitis), acute liver failure, severe hepatitis with features of portal hypertension, and acute decompensation of known or unknown cirrhosis that can lead to acute-on-chronic liver failure. Acute hepatitis with or without necrosis, hepatocellular and canalicular cholestasis, herb-induced or CAM-triggered autoimmune hepatitis, granulomatous hepatitis, severe steatohepatitis, and vanishing bile duct syndrome are common liver biopsy findings in CAM-DILI. The presence of preexisting liver disease predicts severe liver injury, risk of progression to liver failure, and decreased transplant-free survival in patients with CAM-DILI. This review discusses global epidemiology and trends in CAM-DILI, clinical presentation, assessment and outcomes, commonly emerging threats in the context of hepatotoxic herbs, pragmatic assessment of "liver beneficial" herbs and health care myths, patient communication, regulatory framework, and future directions on research in CAM.

Drug-induced liver injury as assessed by the updated Roussel Uclaf Causality Assessment Method following mild COVID-19 in a patient under anastrozole therapy-A case report.

BACKGROUND: Anastrozole is a selective aromatase inhibitor used for the treatment of postmenopausal hormone-sensitive breast cancer. The major side effects include osteoporosis, hypercholesterolemia, and musculoskeletal events, such as arthralgia and myalgia. Other adverse events are rare, including symptoms of acne, masculinization, and drug-induced liver injury, with the latter reported in a few cases only. CASE: Here, we report on a patient under anastrozole therapy who developed drug-induced liver injury as assessed by the updated Roussel Uclaf Causality Assessment Method 5 weeks after a mild SARS-CoV-2 infection, which is, to the best of our knowledge, the first report of its kind involving anastrozole. Discontinuation of anastrozole resulted in a marked improvement of the alanine aminotransaminase, and aspartate aminotransaminase as well as normalized lactate dehydrogenase serum levels already seen after 26 days. Surprisingly, however, the cholestatic serum markers gamma-glutamyl transpeptidase and alkaline phosphatase showed a further rise, and took another 4 weeks to drop significantly. CONCLUSION: The presentation of this case is meant to alert physicians to a potential drug-induced liver injury following mild SARS-CoV-2 infection in patients under anastrozole medication.

A novel approach combining network pharmacology and experimental validation to study the protective effect of ginsenoside Rb1 against cantharidin-induced hepatotoxicity in mice.

Cantharidin (CTD) is a widely used anticancer compound, but its clinical use is mainly limited due to hepatotoxicity. Ginsenoside Rb1 (GRb1) shows potential hepatoprotective effects. Nonetheless, the protective effect and underlying mechanism of GRb1 against CTD-induced hepatotoxicity in mice have not been investigated. This study aims to elucidate the effect and mechanism of GRb1 on CTD-induced hepatotoxicity using network pharmacology and in vivo experiments. Network pharmacology studies have shown that 263 targets were the main mechanisms by which GRb1 alleviates CTD-induced hepatotoxicity. KEGG enrichment analysis revealed that 75 hub genes were mainly enriched in TNF, IL-17 and apoptosis signalling pathways. Molecular docking analysis showed that GRb1 exhibited high affinity with Akt1, Tnf, Il6, Bcl2 and Caspase3. In addition, results from animal studies demonstrated that GRb1 could ameliorate CTD-induced hepatotoxicity by inhibiting protein expression of Caspase-3, Caspase-8, Bcl-2/Bax, GRP78, ATF6, ATF4, CHOP, IRE1α and PERK. This research revealed the mechanism of GRb1 against CTD-induced hepatotoxicity by inhibiting apoptosis and endoplasmic reticulum stress (ERS) and it may provide a scientific rationale for the potential use of GRb1 in the treatment of hepatotoxicity induced by CTD.

Hepatotoxicity in patients with non-small cell lung cancer treated with sotorasib after prior immunotherapy: a comprehensive clinical and pharmacokinetic analysis.

BACKGROUND: Sotorasib given after immunotherapy could put patients at increased risk of hepatotoxicity. Therefore, there is a need to gain insight into the potential correlation between anti-PD-(L)1 treatment, anti-PD-(L)1 concentrations, sotorasib concentrations, and the incidence of hepatotoxicity during sotorasib. METHODS: Patients with KRASG12C-mutated NSCLC treated with sotorasib were prospectively enrolled in our biomarker cohort study (NCT05221372). Plasma samples were collected prior and during sotorasib treatment for anti-PD-1 and sotorasib concentrations. ALT/AST/ALP/GGT increases were collected prospectively and graded according to CTCAEv5.0. Severe hepatotoxicity was defined as grade ≥3 ALT/AST/ALP/GGT increase. FINDINGS: Of the 91 included patients, 80 (88%) received prior anti-PD-(L)1. Prior anti-PD-(L)1 and prior immune-related hepatotoxicity were associated with a higher incidence of severe hepatotoxicity (35% versus 0%, p = 0.016 and 75% versus 31%, p = 0.019, respectively). Patients with an interval of ≤6 weeks between anti-PD-(L)1 and sotorasib (n = 18) had a significantly higher incidence of severe hepatotoxicity than those with a 6-12 week (n = 24) and ≥12 week (n = 38) interval (83% versus 33% versus 13%, respectively, p < 0.0001). Sotorasib trough concentrations did not differ significantly between those with or without severe hepatotoxicity (106 versus 126 ng/mL, p = 0.16). Pembrolizumab concentrations were higher in those with severe hepatotoxicity versus those without (25.6 versus 6.1 µg/mL, p < 0.0001). INTERPRETATION: In this preliminary prospective study, sotorasib after PD-(L)1 blockade was associated with severe hepatotoxicity, especially in patients with a short interval between treatments, prior immune-related hepatitis and higher anti-PD-1 plasma concentrations. Our results suggest a minimum interval of 6 weeks between anti-PD-(L)1 and sotorasib to minimize the risk of hepatotoxicity. FUNDING: None.

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

RATIONALE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

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.

Acute grade IV toxic hepatitis due to the e-cigarette.

A 46-year-old woman presented at the emergency department because of acute hepatitis with jaundice. After hepatological work-up including liver biopsy, drug induced liver disease (DILI) was suspected. Patient recovered completely within a few months. One year later she presented again with jaundice due to acute hepatitis. Vaping was the only agent that could be identified as causative agent for DILI. After VAPING cessation, the hepatitis resolved completely. Calculated RUCAM score was 10, making the diagnosis of toxic hepatitis very likely. During follow-up liver tests remained normal. This is the first report of severe DILI secondary to the use of e-cigarettes. In future vaping can be included in the differential diagnosis of DILI.

Fasting potentiates diclofenac-induced liver injury via inductions of oxidative/endoplasmic reticulum stresses and apoptosis, and inhibition of autophagy by depleting hepatic glutathione in mice.

Diclofenac, a widely used non-steroidal anti-inflammatory drug, can cause liver damage via its metabolic activation by hepatic CYP450s and UGT2B7. Fasting can affect drug-induced liver injury by modulating the hepatic metabolism, but its influence on diclofenac hepatotoxicity is unknown. Thus, we investigated diclofenac-induced liver damage after fasting in mice, and the cellular events were examined. Male ICR mice fasted for 16 h showed the elevation of CYP3A11, but the decreases of UGT2B7, glutathione (GSH), and GSH S-transferase-µ/-π levels in the livers. Diclofenac (200 mg/kg) injection into the mice after 16-h fasting caused more significant liver damage compared to that in the diclofenac-treated fed mice, as shown by the higher serum ALT and AST activities. Diclofenac-promoted hepatic oxidative stress (oxidized proteins, 4-hydroxynonenal, and malondialdehyde), endoplasmic reticulum (ER) stress (BiP, ATF6, and CHOP), and apoptosis (cleaved caspase-3 and cleaved PARP) were enhanced by fasting. Autophagic degradation was inhibited in the diclofenac-treated fasting mice compared to that of the corresponding fed mice. The results suggest that fasting can make the liver more susceptible to diclofenac toxicity by lowering GSH-mediated detoxification; increased oxidative/ER stresses and apoptosis and suppressed autophagic degradation may be the cellular mechanisms of the aggravated diclofenac hepatotoxicity under fasting conditions.

Exposure to Synthetic Psychoactive Substances: A Potential Cause for Increased Human Hepatotoxicity Markers.

BACKGROUND: Approximately 30 million people worldwide consume new psychoactive substances (NPS), creating a serious public health issue due to their toxicity and potency. Drug-induced liver injury is the leading cause of liver disease, responsible for 4% of global deaths each year. CONTENT: A systematic literature search revealed 64 case reports, in vitro and in vivo studies on NPS hepatotoxicity. Maximum elevated concentrations of aspartate aminotransferase (136 to 15 632 U/L), alanine transaminase (121.5 to 9162 U/L), total bilirubin (0.7 to 702 mg/dL; 0.04 to 39.03 mmol/L), direct (0.2-15.1 mg/dL; 0.01-0.84 mmol/L) and indirect (5.3 mg/dL; 0.29 mmol/L) bilirubin, alkaline phosphatase (79-260 U/L), and gamma-glutamyltransferase (260 U/L) were observed as biochemical markers of liver damage, with acute and fulminant liver failure the major toxic effects described in the NPS case reports. In vitro laboratory studies and subsequent in vivo NPS exposure studies on rats and mice provide data on potential mechanisms of toxicity. Oxidative stress, plasma membrane stability, and cellular energy changes led to apoptosis and cell death. Experimental studies of human liver microsome incubation with synthetic NPS, with and without specific cytochrome P450 inhibitors, highlighted specific enzyme inhibitions and potential drug-drug interactions leading to hepatotoxicity. SUMMARY: Mild to severe hepatotoxic effects following synthetic NPS exposure were described in case reports. In diagnosing the etiology of liver damage, synthetic NPS exposure should be considered as part of the differential diagnosis. Identification of NPS toxicity is important for educating patients on the dangers of NPS consumption and to suggest promising treatments for observed hepatotoxicity.

A comprehensive analysis of liver safety across zibotentan oncology trials: knowledge of the past offers new perspectives on the present.

BACKGROUND: Endothelin receptor antagonists (ERAs) are associated with liver injury. We used data from previous oncology clinical trials to determine the liver safety profile of zibotentan, which is currently in clinical development (in combination with dapagliflozin) for chronic kidney disease and cirrhosis. RESEARCH DESIGN AND METHODS: Six global, double-blinded, phase 2b and 3 clinical trials from the zibotentan oncology development program were pooled to analyze liver safety. Descriptive statistics, proportion of liver-related adverse events, liver biochemistry parameter elevation, and shifts from baseline were analyzed, with individual case assessment. RESULTS: A total of 1532 patients received zibotentan for 285 days (mean), and 1486 patients received placebo for 320 days (mean). The frequency of any hepatic disorder preferred term was similar across zibotentan monotherapy (22/947 patients, 2.3%) and placebo monotherapy arms (30/881 patients, 3.4%). A total of 4 (0.4%) patients receiving zibotentan monotherapy experienced ALT elevations >5× ULN versus 8 (0.9%) receiving placebo. Of the seven patients receiving zibotentan who met criteria for potential Hy's Law, there were no cases of drug-induced liver injury. CONCLUSIONS: We found no evidence of zibotentan-related liver biochemistry changes among cancer-treated patients, suggesting that hepatotoxicity of ERAs is molecule-dependent, and allowing exploration of zibotentan for new indications.

Liver toxicity in oncology trials and beyond: a simplified concept for management of hepatocellular drug-induced liver injury in patients with abnormal baseline liver tests.

BACKGROUND: Management of side effects in clinical trials has to balance generation of meaningful data with risk for patients. A toxicity area requiring detailed management guidelines is drug-induced liver injury (DILI). In oncology trials, patients are often included despite baseline liver test abnormalities, for whom there is no consensus yet on levels of liver test changes that should trigger action, such as drug interruption or discontinuation. METHODS: We provide an innovative approach to manage hepatocellular DILI in oncology trials for patients with abnormal baseline alanine aminotransferase (ALT) levels. The algorithm proposed is based on mathematical derivation of action thresholds from those generally accepted for patients with normal baselines. RESULTS: The resulting algorithm is grouped by level of baseline abnormality and avoids calculation of baseline multiples. Suggested layered action levels are 4, 6, and 11 × Upper Limit of Normal (ULN) for patients with baseline ALT between 1.5 and 3 × ULN, and 6, 8, and 12 × ULN for patients with baseline ALT between 3 and 5 × ULN, respectively. CONCLUSIONS: Our concept and resulting algorithm are consistent, transparent, and easy to follow, and the method for derivation from consensus-based thresholds may also be applicable to other drug toxicity areas.

Metformin inhibits OCTN1- and OCTN2-mediated hepatic accumulation of doxorubicin and alleviates its hepatotoxicity in mice.

Doxorubicin (DOX) is a widely used antitumor agent; however, its clinical application is limited by dose-related organ damage. Because organic cation/carnitine transporters (OCTN1 and OCTN2), which are critical for DOX uptake, are highly expressed in hepatocytes, we aimed to elucidate the role of these transporters in hepatic DOX uptake. The results indicated that inhibitors and RNA interference both significantly reduced DOX accumulation in HepG2 and HepaRG cells, suggesting that OCTN1/2 contribute substantially to DOX uptake by hepatocytes. To determine whether metformin (MET, an inhibitor of OCTN1 and OCTN2) ameliorates DOX-induced hepatotoxicity, we conducted in vitro and in vivo studies. MET (1-100 µM) inhibited DOX (500 nM) accumulation and cytotoxicity in vitro in a concentration-dependent manner. Furthermore, intravenous MET administration at 250 or 500 mg/kg or by gavage at 50, 100, or 200 mg/kg reduced DOX (8 mg/kg) accumulation in a dose-dependent manner in the mouse liver and attenuated the release of alanine aminotransferase, aspartate aminotransferase, and carboxylesterase 1. Additionally, MET reduced the distribution of DOX in the heart, liver, and kidney and enhanced the urinary elimination of DOX; however, it did not increase the nephric toxicity of DOX. In conclusion, our study demonstrated that MET alleviates DOX hepatotoxicity by inhibiting OCTN1- and OCTN2-mediated DOX uptake in vitro (mouse hepatocytes and HepaRG or HepG2 cells) and in mice.

Hepatotoxicity induced in rats by chronic exposure to F-53B, an emerging replacement of perfluorooctane sulfonate (PFOS).

A plethora of studies have shown the prominent hepatotoxicity caused by perfluorooctane sulfonate (PFOS), yet the research on the causality of F-53 B (an alternative for PFOS) exposure and liver toxicity, especially in mammals, is largely limited. To investigate the effects that chronic exposure to F-53 B exert on livers, in the present study, male SD rats were administrated with F-53 B in a certain dose range (0, 1, 10, 100, 1000 µg/L, eight rats per group) for 6 months via drinking water and the hepatotoxicity resulted in was explored. We reported that chronic exposure to 100 and 1000 µg/L F-53 B induced remarkable histopathological changes in liver tissues such as distinct swollen cells and portal vein congestion. In addition, the increase of cytokines IL-6, IL-2, and IL-8 upon long-term administration of F-53 B demonstrated the high level of inflammation. Moreover, F-53 B exposure was revealed to disrupt the lipid metabolism in the rat livers, mainly manifesting as the upregulation of some proteins involved in lipid synthesis and degradation, including ACC, FASN, SREBP-1c as well as ACOX1. These findings provided new evidence for the adverse effects caused by chronic exposure to F-53 B in rodents. It is crucial for industries, regulatory agencies as well as the public to remain vigilant about the adverse health effects associated with the emerging PFOS substitutes such as F-53 B. Implementation of regular monitoring and risk assessments is of great importance to alleviate environmental concerns towards PFOS alternatives exposure, and furthermore, to minimize the latent health risks to the public health.