Involvement of Th2 cytokines in the mouse model of flutamide-induced acute liver injury

Drug‐induced liver injury is a growing concern for pharmaceutical companies and patients because numerous drugs have been linked to hepatotoxicity and it is the most common reason for a drug to be withdrawn. Flutamide rarely causes liver dysfunction in humans, and immune allergic reactions have been suggested in some cases. In this study, we investigated the mechanisms of flutamide‐induced liver injury in BALB/c mice. Plasma alanine aminotransferase and aspartate aminotransferase levels were significantly increased 3, 6 and 9 h after flutamide (1500 mg kg^?1, p.o.) administration. The biomarker for oxidative stress was not changed, but Th2‐dominant immune‐related factors, such as interleukin (IL)‐4, IL‐5, STAT6 and GATA‐binding protein (GATA)‐3, were induced in flutamide‐administered mice. The pre‐administration of monoclonal‐IL‐4 antibody suppressed the hepatotoxicity of flutamide. In addition, we investigated the effect of 13,14‐dihydro‐15‐keto‐PGD₂ (DK‐PGD₂; 10 µg per mouse, i.p.) administration on flutamide‐induced acute liver injury. Coadministration of DK‐PGD₂ and flutamide resulted in a significant increase in alanine aminotransferase and a remarkable increase of macrophage inflammatory protein‐2. In conclusion, we demonstrated that flutamide‐induced acute liver injury is mediated by Th2‐dominant immune responses in mice. Copyright © 2011 John Wiley & Sons, Ltd.     

Kupffer cell‐mediated exacerbation of methimazole‐induced acute liver injury in rats

Methimazole (MTZ), an anti‐thyroid drug, is known to cause liver injury in humans. It has been demonstrated that MTZ‐induced liver injury in Balb/c mice is accompanied by T helper (Th) 2 cytokine‐mediated immune responses; however, there is little evidence for immune responses associated with MTZ‐induced liver injury in rats. To investigate species differences in MTZ‐induced liver injury, we administered MTZ with a glutathione biosynthesis inhibitor, L‐buthionine‐S,R‐sulfoximine (BSO), to F344 rats and subsequently observed an increase in plasma alanine aminotransferase (ALT) and high‐mobility group box 1 (HMGB1), which are associated with hepatic lesions. The hepatic mRNA expression of innate immune‐related genes significantly increased in BSO‐ and MTZ‐treated rats, but the change in Th2‐related genes was not much greater than the change observed in the previous mouse study. Moreover, an increase in Kupffer cells and an induction of the phosphorylation of extracellular signal‐regulated kinase (ERK)/c‐Jun N‐terminal kinase (JNK) proteins were accompanied by an increase in Toll‐like receptor 4 (TLR4) expression, indicating that Kupffer cell activation occurs through HMGB1‐TLR4 signaling. To elucidate the mechanism of liver injury in rats, gadolinium chloride, which inactivates the function of Kupffer cells, was administered before BSO and MTZ administration. The gadolinium chloride treatment significantly suppressed the increased ALT, which was accompanied by decreased hepatic mRNA expression related to innate immune responses and ERK/JNK phosphorylation. In conclusion, Kupffer cell‐mediated immune responses are crucial factors for the exacerbation of MTZ‐induced liver injury in rats, indicating apparent species differences in the immune‐mediated exacerbation of liver injury between mice and rats. Copyright © 2015 John Wiley & Sons, Ltd.     

Prediction of drug‐induced liver injury using keratinocytes

Drug‐induced liver injury (DILI) is one of the most common adverse drug reactions. DILI is often accompanied by skin reactions, including rash and pruritus. However, it is still unknown whether DILI‐associated genes such as S100 calcium‐binding protein A and interleukin (IL)‐1β are involved in drug‐induced skin toxicity. In the present study, most of the tested hepatotoxic drugs such as pioglitazone and diclofenac induced DILI‐associated genes in human and mouse keratinocytes. Keratinocytes of mice at higher risk for DILI exhibited an increased IL‐1β basal expression. They also showed a higher inducibility of IL‐1β when treated by pioglitazone. Mice at higher risk for DILI showed even higher sums of DILI‐associated gene basal expression levels and induction rates in keratinocytes. Our data suggest that DILI‐associated genes might be involved in the onset and progression of drug‐induced skin toxicity. Furthermore, we might be able to identify individuals at higher risk of developing DILI less invasively by examining gene expression patterns in keratinocytes. Copyright © 2017 John Wiley & Sons, Ltd.     

Dexmedetomidine preconditioning for myocardial protection in ischaemia‐reperfusion injury in rats by downregulation of the high mobility group box 1‐toll‐like receptor 4‐nuclear factor κB signalling pathway

Pharmacological preconditioning reduces myocardial infarct size in ischaemia‐reperfusion (I‐R) injury. Dexmedetomidine, a selective α₂‐adrenoceptor agonist, has a proven cardioprotective effect when administered prior to I‐R, although the underlying mechanisms for this effect are not fully understood. We evaluated whether dexmedetomidine preconditioning could induce a myocardio‐protective effect against I‐R injury by inhibiting associated inflammatory processes through downregulation of the high mobility group box 1 (HMGB1)‐toll‐like receptor 4 (TLR4)‐nuclear factor κB (NF‐κB) signalling pathway. Seventy rats were randomly assigned to seven groups: a control and six test groups, involving I‐R for 30 and 120 minutes, respectively, in isolated rat hearts and different pretreatment protocols with dexmedetomidine (10 nmol/L) as well as yohimbine (1 μmol/L) and recombinant HMGB1 peptide (rHMGB1; 20 μg/L), alone or in combination with dexmedetomidine. Cardiac function was recorded; myocardial HMGB1, TLR4, and NF‐κB activities and levels of tumour necrosis factor‐α (TNF‐α) and interleukin‐6 (IL‐6) were measured as were lactate dehydrogenase (LDH) and creatine kinase (CK) in coronary outflow. Dexmedetomidine preconditioning significantly improved cardiac function (P<.05), downregulated the expression of HMGB1‐TLR4‐NF‐κB, reduced levels of TNF‐α and IL‐6 in isolated ventricles during I‐R injury, and significantly reduced CK and LDH levels in coronary outflow (P<.05). All of these effects were partially reversed by yohimbine (P<.05) or rHMGB1 (P<.05). Dexmedetomidine preconditioning alleviated myocardial I‐R injury in rats through inhibition of inflammatory processes associated with downregulation of the HMGB1‐TLR4‐NF‐κB signalling pathway via activation at α₂‐adrenergic receptors.     

T‐helper cell‐mediated factors in drug‐induced liver injury

Drug‐induced liver injury (DILI) leads to a large burden on the healthcare system due to its potential morbidity and mortality. The key for predicting and preventing DILI is to understand the underlying mechanisms. Hepatic inflammation is one of the most common features of DILI. The inflammation can be attributed to the innate immune response. The adaptive immune system is also affected by the innate immune response resulting in liver damage. T‐helper cells are important regulators of acquired immunity. T‐helper cell‐mediated immune responses play pivotal roles in the pathogenesis of a variety of liver disorders. This review summarizes recent advances in the T‐helper cell‐mediated factors in DILI and potential mechanisms, which may lead to a better understanding of DILI. Copyright © 2015 John Wiley & Sons, Ltd.     

Establishment of a mouse model for amiodarone‐induced liver injury and analyses of its hepatotoxic mechanism

Drug‐induced liver injury (DILI) is the most frequent cause of post‐marketing warnings and withdrawals. Amiodarone (AMD), an antiarrhythmic, presents a risk of liver injury in humans, and its metabolites, formed by cytochrome P450 3A4, are likely more toxic to hepatocytes than AMD is. However, it remains to be clarified whether the metabolic activation of AMD is involved in liver injury in vivo. In this study, to elucidate the underlying mechanisms of AMD‐induced liver injury, mice were administered AMD [1000 mg kg^–1, per os (p.o.)] after pretreatment with dexamethasone [DEX, 60 mg kg^–1, intraperitoneal (i.p.)], which induces P450 expression, once daily for 3 days. The plasma alanine aminotransferase (ALT) levels were significantly increased by AMD administration in the DEX‐pretreated mice, and the liver concentrations of desethylamiodarone (DEA), a major metabolite of AMD, were correlated with the changes in the plasma ALT levels. Cytochrome c release into the hepatic cytosol and triglyceride levels in the plasma were increased in DEX plus AMD‐administered mice. Furthermore, the ratio of reduced glutathione to oxidized glutathione disulfide in the liver significantly decreased in the DEX plus AMD‐administered mice. The increase of ALT levels was suppressed by treatment with gadolinium chloride (GdCl₃), which is an inhibitor of Kupffer cell function. From these results, it is suggested that AMD and/or DEA contribute to the pathogenesis of AMD‐induced liver injury by producing mitochondrial and oxidative stress and Kupffer cell activation. This study proposes the mechanisms of AMD‐induced liver injury using an in vivo mouse model. Copyright © 2015 John Wiley & Sons, Ltd.     

Tissue influx of neutrophils and monocytes is delayed during development of trovafloxacin‐induced tumor necrosis factor‐dependent liver injury in mice

Idiosyncratic drug‐induced liver injury (iDILI) has a poorly understood pathogenesis. However, iDILI is often associated with inflammatory stress signals in human patients as well as animal models. Tumor necrosis factor (TNF) and neutrophils play a key role in onset of trovafloxacin (TVX)‐induced iDILI, but the exact role of neutrophils and other leukocytes remains to be defined. We therefore set out to study the kinetics of immunological changes during the development of TVX‐induced iDILI in the established murine model of acute liver injury induced by administration of TVX and TNF. Initially, TNF stimulated the appearance of leukocytes, in particular neutrophils, into the liver of TVX‐treated mice, but even more so in control mice treated with the non‐DILI inducing analogue levofloxacin (LVX) or saline as vehicle (Veh). This difference was apparent at 2 hours after TNF administration, but at 4 hours, the relative neutrophil amounts were reduced again in Veh‐ and LVX‐treated mice whereas the amounts in TVX‐treated mice remained at the same increased level as at 2 hours. The influx of monocytes/macrophages, which was unaffected in Veh‐ and LVX‐treated mice was markedly reduced or even absent in TVX‐treated mice. Unlike controls, mice receiving TVX + TNF display severe hepatotoxicity with clear pathology and apoptosis, coagulated hepatic vessels and increased alanine aminotransferase levels and interleukin 6/10 ratios. Findings indicate that TVX delays the acute influx of neutrophils and monocytes/macrophages. Considering their known anti‐inflammatory functions, the disruption of influx of these innate immune cells may hamper the resolution of initial cytotoxic effects of TVX and thus contribute to liver injury development.     

Protective effects of coffee‐derived compounds on lipopolysaccharide/d‐galactosamine induced acute liver injury in rats

Objectives The protective effects of coffee‐derived compounds on lipopolysaccharide/d‐galactosamine (LPS/d‐GalN) induced acute liver injury in rats were investigated. Methods Wistar rats were orally administered saline (control) or one of the test compounds (caffeine, chlorogenic acid, trigonelline, nicotinic acid or eight ***pyrazinoic acids) at a dose of 100 mg/kg, respectively. This was followed by intraperitoneal injection with LPS (100 μg/kg)/d‐GalN (250 mg/kg) 1 h after administration of the test compounds. Blood samples were collected up to 12 h after LPS/d‐GalN injection, followed by determination of plasma aspartate aminotransferase, alanine aminotransferase, tumour necrosis factor α (TNF‐α) and interleukin 10 (IL‐10) levels. Key findings Plasma aspartate aminotransferase and alanine aminotransferase levels were significantly increased after LPS/d‐GalN‐treatment, but were suppressed by pretreatment with caffeine (n = 5), nicotinic acid, non‐substituted pyrazinoic acid or 5‐methylpyrazinoic acid (n = 6, respectively) 12 h after LPS/d‐GalN‐treatment (P < 0.01, respectively). Moreover, the animals pretreated with these test compounds showed significantly higher survival rates (83–100%) compared with the control (23%). Only pretreatment with caffeine significantly suppressed the LPS/d‐GalN induced elevation of plasma TNF‐α levels 1 and 2 h after LPS/d‐GalN‐treatment (P < 0.01, respectively). Pretreatment with caffeine, nicotinic acid or non‐substituted pyrazinoic acid activated the LPS/d‐GalN induced elevation of plasma IL‐10 levels at 1 and 2 h, although there were no statistically significant differences in IL‐10 levels between control and nicotinic acid or non‐substituted pyrazinoic acid treated rats. Conclusions The results suggest that caffeine, nicotinic acid, non‐substituted pyrazinoic acid and 5‐methylpyrazinoic acid can protect against LPS/d‐GalN induced acute liver injury, which may be mediated by the reduction of TNF‐α production and/or increasing IL‐10 production.     

Pharmacological inhibition of TLR4/NF‐κB with TLR4‐IN‐C34 attenuated microcystin‐leucine arginine toxicity in bovine Sertoli cells

This study investigated the pharmacological inhibition of the toll‐like receptor 4 (TLR4) genes as a measure to attenuate microcystin‐LR (MC‐LR) reproductive toxicity. Bovine Sertoli cells were pretreated with TLR4‐IN‐C34 (C34) for 1 hour. Thereafter the pretreated and non‐pretreated Sertoli cells were cultured in medium containing 10% heat‐activated fetal bovine serum + 80 μg/L MC‐LR for 24 hours to assess the ability of TLR4‐IN‐C34 to attenuate the toxic effects of MC‐LR. The results showed that TLR4‐IN‐C34 inhibited MC‐LR‐induced mitochondria membrane damage, mitophagy and downregulation of blood‐testis barrier constituent proteins via TLR4/nuclear factor‐kappaB and mitochondria‐mediated apoptosis signaling pathway blockage. The downregulation of the mitochondria electron transport chain, energy production and DNA replication related genes (mt‐ND2, COX‐1, COX‐2, ACAT, mtTFA) and upregulation of inflammatory cytokines (interleukin [IL]‐6, tumor necrosis factor‐α, IL‐1β, interferon‐γ, IL‐4, IL‐10, IL‐13 and transforming growth factor β1) were modulated by TLR4‐IN‐C34. Taken together, we conclude that TLR4‐IN‐C34 inhibits MC‐LR‐related disruption of mitochondria membrane, mitophagy and downregulation of blood‐testis barrier proteins of the bovine Sertoli cell via cytochrome c release and TLR4 signaling blockage.     

Hepatoprotective effect of ginsenoside Rg1 from Panax ginseng on carbon tetrachloride‐induced acute liver injury by activating Nrf2 signaling pathway in mice

Oxidative stress and inflammatory response are well known to be involved in the pathogenesis of acute liver injury. This study was performed to examine the hepatoprotective effect of ginsenoside Rg1 (Rg1) against CCl₄‐induced acute liver injury, and further to elucidate the involvement of Nrf2 signaling pathway in vivo and in vitro. Mice were orally administered Rg1 (15, 30, and 60 mg/kg) or sulforaphane (SFN) once daily for 1 week prior to 750 μL/kg CCl₄ injection. The results showed that Rg1 markedly altered relative liver weights, promoted liver repair, increased the serum level of TP and decreased the serum levels of ALT, AST and ALP. Hepatic oxidative stress was inhibited by Rg1, as evidenced by the decrease in MDA, and increases in GSH, SOD, and CAT in the liver. Further research demonstrated that Rg1 suppressed liver inflammation response through repressing the expression levels of inflammation‐related genes including TNF‐α, IL‐1β, IL‐6, COX‐2, and iNOS. In addition, Rg1 enhanced antioxidative stress and liver detoxification abilities by up‐regulating Nrf2 and its target‐genes such as GCLC, GCLM, HO‐1, NQO1, Besp, Mrp2, Mrp3, Mrp4, and down‐regulating Cyp2e1. However, the changes in Nrf2 target‐genes, as well as ameliorative liver histology induced by Rg1 were abrogated by Nrf2 antagonist all‐transretinoic acid in vivo and Nrf2 siRNA in vitro. Overall, the findings indicated that Rg1 might be an effective approach for the prevention against acute liver injury by activating Nrf2 signaling pathway.     

CYP2E1 and miRNA‐378a‐3p contribute to acetaminophen‐ or tripterygium glycosides‐induced hepatotoxicity

Increased expression of CYP2E1 may represent the main factor contributing to oxidative stress‐mediated liver damage in drug‐induced liver injury (DILI). However, the regulation mechanism of CYP2E1 expression is poorly described. The present study was aimed to investigate the role of CYP2E1 in acetaminophen (APAP)‐ or tripterygium glycosides (TG)‐induced hepatotoxicity as well as the regulation of CYP2E1 and miR‐378a‐3p expression by APAP or TG. Rats were randomly divided and treated with APAP, TG, chlormethiazole (CMZ), APAP + CMZ and TG + CMZ, respectively, for 4 weeks. Then, blood and liver samples were collected. Serum and hepatic biochemical parameters were measured using commercial kits. Liver histopathology was tested by H&E staining. Expression levels of CYP2E1 mRNA and miR‐378a‐3p were detected by qRT‐PCR. CYP2E1 protein expression was determined by Western blot. Our results showed that CMZ effectively restored the hepatic histopathological changes, oxidative stress biomarkers and TNF‐α levels induced by APAP or TG. CYP2E1 mRNA and/or protein expression levels were dramatically increased after chronic APAP or TG treatment, while this induction was significantly reversed by CMZ co‐treatment. Of note, miR‐378a‐3p expression levels were significantly suppressed after APAP, TG and/or CMZ treatment. These results suggested that CYP2E1 were highly induced after chronic APAP or TG treatment, which in turn play an important role in APAP‐ or TG‐induced hepatotoxicity. These inductions of CYP2E1 expression were probably carried out by inhibition of miR‐378a‐3p. Our findings might provide a new molecular basis for DILI.     

Anakinra‐Induced Acute Liver Failure in an Adolescent Patient with Still's Disease

The interleukin‐1 (IL‐1) family consists of 11 cytokines that play key regulatory roles in many immune and inflammatory processes. Anakinra (Kineret, Amgen, Inc.) is an IL‐1 receptor antagonist (IL‐1ra). Increased levels of IL‐1 are found in several disease states suggesting that anakinra may be beneficial in disorders associated with elevated IL‐1 levels. Anakinra has been effectively used in the treatment of systemic juvenile idiopathic arthritis and adult‐onset Still's disease (AOSD). Despite its therapeutic benefits, anakinra also has potential side effects, including hepatotoxicity. We present a case of AOSD in an adolescent male that was treated with anakinra. During treatment, the patient developed acute liver failure that resolved upon withdrawal of anakinra. Although anakinra‐induced liver injury has been reported in adults, including one case of subacute liver failure, we believe our case is the first to show severe acute liver failure in an adolescent treated with anakinra. This case provides significant insight into a potentially serious complication associated with anakinra. It is important to further delineate these complications as the treatment indications for this drug expand.     

Toxicological role of an acyl glucuronide metabolite in diclofenac‐induced acute liver injury in mice

The acyl glucuronide (AG) metabolites of carboxylic acid‐containing drugs are potentially chemically reactive and are suggested to be implicated in toxicity, including hepatotoxicity, nephrotoxicity and drug hypersensitivity reactions. However, it remains unknown whether AG formation is related to toxicity in vivo . In this study, we sought to determine whether AG is involved in the pathogenesis of liver injury using a mouse model of diclofenac (DIC)‐induced liver injury. Mice that were administered DIC alone exhibited significantly increased plasma alanine aminotransferase levels, whereas mice that were pretreated with the UDP‐glucuronosyltransferase inhibitor (−)‐borneol (BOR) exhibited suppressed alanine aminotransferase levels at 3 and 6 h after DIC administration although not significant at 12 h. The plasma DIC‐AG concentrations were significantly lower in BOR‐ and DIC‐treated mice than in mice treated with DIC alone. The mRNA expression levels of chemokine (C‐X‐C motif) ligand 1 (CXCL1), CXCL2 and the neutrophil marker CD11b were reduced in the livers of mice that had been pretreated with BOR compared to those that had been administered DIC alone, whereas mRNA expression of the macrophage marker F4/80 was not altered. An immunohistochemical analysis at 12 h samples revealed that the numbers of myeloperoxidase‐ and lymphocyte antigen 6 complex‐positive cells that infiltrated the liver were significantly reduced in BOR‐ and DIC‐treated mice compared to mice that were treated with DIC alone. These results indicate that DIC‐AG is partly involved in the pathogenesis of DIC‐induced acute liver injury in mice by activating innate immunity and neutrophils. Copyright © 2016 John Wiley & Sons, Ltd.     

Association between genetic polymorphisms of SLCO1B1 and susceptibility to methimazole‐induced liver injury

Methimazole (MMI) has been used in the therapy of Grave's disease (GD) since 1954, and drug‐induced liver injury (DILI) is one of the most deleterious side effects. Genetic polymorphisms of drug‐metabolizing enzymes and drug transporters have been associated with drug‐induced hepatotoxicity in many cases. The aim of this study was to investigate genetic susceptibility of the drug‐metabolizing enzymes and drug transporters to the MMI‐DILI. A total of 44 GD patients with MMI‐DILI and 118 GD patients without MMI‐DILI development were included in the study. Thirty‐three single nucleotide polymorphisms (SNPs) in twenty candidate genes were genotyped. We found that rs12422149 of SLCO2B1, rs2032582_AT of ABCB1, rs2306283 of SLCO1B1 and rs4148323 of UGT1A1 exhibited a significant association with MMI‐DILI; however, no significant difference existed after Bonferroni correction. Haplotype analysis showed that the frequency of SLCO1B1*1a (388A521T) was significantly higher in MMI‐DILI cases than that in the control group (OR = 2.21, 95% CI = 1.11‐4.39, P = 0.023), while the frequency of SLCO1B1*1b (388G521T) was significantly higher in the control group (OR = 0.52, 95% CI = 0.29‐0.93, P = 0.028). These results suggested that genetic polymorphisms of SLCO1B1 were associated with susceptibility to MMI‐DILI. The genetic polymorphism of SLCO1B1 may be important predisposing factors for MMI‐induced hepatotoxicity.     

Proanthocyanidin protects against cisplatin‐induced oxidative liver damage through inhibition of inflammation and NF‐κβ/TLR‐4 pathway

Although cisplatin (CIS) is a highly effective anticancer drug, hepatotoxicity is one of the most common adverse effects associated with its use. Recently, reactive oxygen species (ROS) and inflammation are suggested to be key factors in the pathophysiology of CIS‐induced acute liver damage. The aim of this study is to investigate the possible protective effect of proanthocyanidin (PRO) against CIS‐induced acute hepatotoxicity. Rats were divided into four groups: 1, Control; 2, PRO; 3, CIS; and 4, PRO + CIS. Biochemical studies and histopathology were used to assess liver damage. ROS, inflammatory cytokines, nuclear factor kappa beta (NF‐κβ), inducible cyclooxygenase enzyme (COX‐2), inducible nitric oxide synthase (iNOS), toll‐like receptor‐4 (TLR‐4) gene expression, and apoptotic markers were also assessed. PRO pretreatment protected the liver against CIS‐induced toxicity as indicated by decreased plasma levels of liver function enzymes and the normal liver histopathology observed in the PRO + CIS group. PRO pretreatment also diminished indicators of oxidative stress in the liver, including nitric oxide (NO) and malondialdehyde (MDA). It also increased the antioxidants, reduced glutathione (GSH), glutathione peroxidase (GPx), superoxide dismutase (SOD), and catalase (CAT) in the liver. Plasma interleukin‐1 beta (IL‐1β), IL‐6, and tumor necrosis factor‐alpha (TNF‐α) were all reduced. Liver gene expression of NF‐κβ, COX‐2, iNOS, and TLR‐4 were all downregulated. Furthermore, PRO administration downregulated the liver expression of the apoptotic marker, Bax, while upregulated the antiapoptotic marker, Bcl2. In conclusion, our results revealed that PRO may protect against CIS‐induced acute liver damage mainly through inhibition of ROS, inflammation, and apoptosis.     

Rossicaside B Protects against Carbon Tetrachloride‐induced Hepatotoxicity in Mice

Abstract: The protective effect of rossicaside B, the major phenylpropanoid glycoside from Boschniakia rossica, on CCl₄‐induced hepatotoxicity and the mechanisms underlying its protective effect were investigated. The mice were administered orally with rossicaside B (100 or 200 mg/kg of body weight) 48, 24 and 1 hr before CCl₄ (0.5 ml/kg of body weight) administration. The CCl₄ challenge caused a marked increase in the levels of serum aspartate aminotransferase, alanine aminotransferase and of tumour necrosis factor‐α, and propagated lipid peroxidation with a concomitant reduction in reduced glutathione (GSH) and antioxidative enzyme activities in the liver. The administration of rossicaside B to CCl₄‐treated mice not only decreased the serum toxicity marker enzymes and TNF‐α but also reduced hepatic oxidative stress, as demonstrated by decreased lipid hydroperoxide and thiobarbituric acid‐reactive substance concentrations, combined with elevated GSH content and antioxidative enzyme activities in the liver tissues. Furthermore, the contents of hepatic nitrite, inducible nitric oxide synthase (iNOS), cyclooxygenase‐2 (COX‐2) and haem oxygenase‐1 (HO‐1) were elevated after CCl₄ treatment while the cytochrome P450 2E1 (CYP2E1)‐specific monooxygenase activity was suppressed. Rossicaside B treatment inhibited the formation of liver nitrite, reduced the over‐expression of iNOS and COX‐2 proteins, but increased the CYP2E1 function compared with the CCl₄‐treated mice. However, the protein expression of HO‐1 was further elevated by rossicaside B treatment. The results demonstrate that rossicaside B provides a protective action on CCl₄‐induced acute hepatic injury, which may be related to its antioxidative activity, suppressed inflammatory responses, induced HO‐1 expression and improved CYP2E1 function in the liver.     

Duloxetine hepatotoxicity: a case‐series from the drug‐induced liver injury network

Aliment Pharmacol Ther 2010; 32: 1174–1183

Summary

Background Case reports suggest that duloxetine hepatotoxicity may arise, but risk factors, presenting features and clinical course are not well‐described. Aim To describe the presenting features and outcomes of seven well‐characterized patients with suspected duloxetine hepatotoxicity. Methods Patients enrolled in the Drug‐Induced Liver Injury Network Prospective Study underwent an extensive laboratory and clinical evaluation to exclude competing aetiologies of liver injury as well as a standardized assessment for causality and disease severity. Results Between 1/2006 and 9/2009, six of the seven cases of DILI attributed to duloxetine were assessed as definite or very likely. Median patient age was 49 years, six (86%) were women and the median latency from drug initiation to DILI onset was 50 days. Six patients developed jaundice and the median peak alanine aminotransferase in the five patients with acute hepatocellular injury was 1633 IU/L. Ascites developed in one patient and acute renal dysfunction in two others (29%). All patients recovered without liver transplantation even though three had pre‐existing chronic liver disease. Liver histology in four cases demonstrated varying patterns of liver injury. Conclusions Duloxetine hepatotoxicity developed within 2 months of drug intake and led to clinically significant liver injury. A spectrum of laboratory, histological and extra‐hepatic features were noted at presentation.