Chemical-induced Liver Injury Research Articles

Evaluation of a combinational use of serum microRNAs as biomarkers for liver diseases

Circulating microRNAs (miRNA) have been widely recognized as a novel noninvasive biomarker in a variety of physiological and pathological conditions. In order to assess the sensitivity and reliability of potential miRNAs as diagnostic markers for liver disease related to viral infection, alcohol abuse, or chemical exposure, we collected serum samples from 326 participants and evaluated the single and combination diagnostic values of three serum miRNAs (miR-122, miR-125b, miR-192) compared with a conventional marker ALT. We found that serum miR-122 is significantly elevated in patients with active HBV. MiR-125b increased in HCV positive patients, whereas miR-192 and miR-122 were associated with chemical-induced liver injury. None of the aforementioned miRNAs were shown to increase significantly in alcohol-related liver injuries. Furthermore, we analyzed different combinations and found that a set of miR-122 and miR-125b enhanced the sensitivity of detecting liver injury. Among the 58 ALI/ALF patients, miR-122 responded more rapidly than ALT in successful treatments. Patients with spontaneous recovery from ALI/ALF showed significantly higher serum levels of miR-122 and miR-125b compared to non-recovered patients. In conclusion, our results suggest that the combination of miR-122 and miR-125b may serve as efficient biomarkers for liver injury and may be of a prognostic value in predicting ALI/ALF outcome.

Plasma lipid profiling of chemical-induced liver injuries

Plasma lipid profiling of chemical-induced liver injuries

Network-based Assessment on Chemical-induced Cholestatic Liver Injury

The assessment of drug toxicity, especially hepatotoxicity, is a critical task in drug development process. To assist with early detection, various in silico approaches have been demonstrated to identify drugs with high hepatotoxicity potential. In this study, based on detailed review on previous reports on drug-induced cholestatic liver injury, we developed a network-based approach to predict cholestatic potential of chemicals using toxicogenomic data. First, the cholestasis network was constructed with 57 relevant genes and 78 connections between genes. Taking only genes in the disease network into account, the evaluation model was trained by genomic data of 17 typical chemicals associated with cholestasis and yielded the prediction accuracy at 88%. The performance of this model was further challenged by an X-permutation test and an external set of 98 chemicals. Among them, 14 chemicals were marked with high risk of inducing cholestasis by our approach. A survey of published literatures confirmed that 71.43% of our predicted chemicals have been shown to induce cholestatic liver injury experimentally and approximately 93% of them have been implicated to promote liver injury to various extents. Together, we concluded that network-based approaches greatly facilitate further understanding of molecular mechanisms for cholestatic liver injury and this concept could be easily generalized to other biological-relevant side-effect assessments.

Network-based Assessment on Chemical-induced Cholestatic Liver Injury

Network-based Assessment on Chemical-induced Cholestatic Liver Injury

Upregulation of hydroxysteroid sulfotransferase 2B1b promotes hepatic oval cell proliferation by modulating oxysterol-induced LXR activation in a mouse model of liver injury.

Hydroxysteroid sulfotransferase 2B1b (SULT2B1b) sulfates cholesterol and oxysterols. Hepatic oval cells (HOCs), thought to be progenitor cells, can be triggered in chemically injured livers. The present study focused on the role of SULT2B1b in HOC proliferation after liver injury. Our experiments revealed that the expression of SULT2B1b was increased dramatically in a chemical-induced liver injury model, mainly in HOCs. Upon challenge with a hepatotoxic diet containing 0.1% 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC), SULT2B1-/- mice presented alleviated liver injury and less HOC proliferation compared with wild-type (WT) mice, and these findings were verified by serum analysis, histopathology, immunofluorescence staining, RNA-seq, and Western blotting. HOCs derived from SULT2B1-/- mice showed lower proliferative capability than those from WT mice. SULT2B1b overexpression promoted growth of the WB-F344 hepatic oval cell line, whereas SULT2B1b knockdown inhibited growth of these cells. The IL-6/STAT3 signaling pathway also was promoted by SULT2B1b. Liquid chromatography and mass spectrometry indicated that the levels of 22-hydroxycholesterol, 25-hydroxycholesterol, and 24,25-epoxycholesterol were higher in the DDC-injured livers of SULT2B1-/- mice than in livers of WT mice. The above oxysterols are physiological ligands of liver X receptors (LXRs), and SULT2B1b suppressed oxysterol-induced LXR activation. Additional in vivo and in vitro experiments demonstrated that LXR activation could inhibit HOC proliferation and the IL-6/STAT3 signaling pathway, and these effects could be reversed by SULT2B1b. Our data indicate that upregulation of SULT2B1b might promote HOC proliferation and aggravate liver injury via the suppression of oxysterol-induced LXR activation in chemically induced mouse liver injury.

MicroRNAs as Signaling Mediators and Biomarkers of Drug- and Chemical-Induced Liver Injury.

Drug-induced liver injury (DILI) is major problem for both the drug industry and for clinicians. There are two basic categories of DILI: intrinsic and idiosyncratic. The former is the chief cause of acute liver failure in several developed countries, while the latter is the most common reason for post-marketing drug withdrawal and a major reason for failure to approve new drugs in the U.S. Although considerably more progress has been made in the study of intrinsic DILI, our understanding of both forms of drug hepatotoxicity remains incomplete. Recent work involving microRNAs (miRNAs) has advanced our knowledge of DILI in two ways: (1) possible roles of miRNAs in the pathophysiological mechanisms of DILI have been identified, and (2) circulating miRNA profiles have shown promise for the detection and diagnosis of DILI in clinical settings. The purpose of this review is to summarize major findings in these two areas of research. Taken together, exciting progress has been made in the study of miRNAs in DILI. Possible mechanisms through which miRNA species contribute to the basic mechanisms of DILI are beginning to emerge, and new miRNA-based biomarkers have the potential to greatly improve diagnosis of liver injury and prediction of patient outcomes.

Endoplasmic reticulum stress and oxidative stress are involved in ZnO nanoparticle-induced hepatotoxicity

Zinc oxide nanoparticles (Nano-ZnO) are widely used in sunscreens, clothes, medicine and electronic devices. However, the potential risks of human exposure and the potential for adverse health impacts are not well understood. Previous studies have demonstrated that exposure to Nano-ZnO caused liver damage and hepatocyte apoptosis through oxidative stress, but the molecular mechanisms that are involved in Nano-ZnO-induced hepatotoxicity are still unclear. Endoplasmic reticulum (ER) is sensitive to oxidative stress, and also plays a crucial role in oxidative stress-induced damage. Previous studies showed that ER stress was involved in many chemical-induced liver injuries. We hypothesized that exposure to Nano-ZnO caused oxidative stress and ER stress that were involved in Nano-ZnO-induced liver injury. To test our hypothesis, mice were gavaged with 200mg/kg or 400mg/kg of Nano-ZnO once a day for a period of 90 days, and blood and liver tissues were obtained for study. Our results showed that exposure to Nano-ZnO caused liver injury that was reflected by focal hepatocellular necrosis, congestive dilation of central veins, and significantly increased alanine transaminase (ALT) and aspartate transaminase (AST) levels. Exposure to Nano-ZnO also caused depletion of glutathione (GSH) in the liver tissues. In addition, our electron microscope results showed that ER swelling and ribosomal degranulation were observed in the liver tissues from mice treated with Nano-ZnO. The mRNA expression levels of ER stress-associated genes (grp78, grp94, pdi-3, xbp-1) were also up-regulated in Nano-ZnO-treated mice. Nano-ZnO caused increased phosphorylation of RNA-dependent protein kinase-like ER kinase (PERK) and eukaryotic initiation factor 2α (eIF2α). Finally, we found that exposure to Nano-ZnO caused increased ER stress-associated apoptotic protein levels, such as caspase-3, caspase-9, caspase-12, phosphorylation of JNK, and CHOP/GADD153, and up-regulation of pro-apoptotic genes (chop and bax). These results suggest that oxidative stress and ER stress-induced apoptosis are involved in Nano-ZnO-induced hepatotoxicity in mice.

Circulating Liver-Specific miR-122 as a Novel Potential Biomarker for Diagnosis of Cholestatic Liver Injury

BackgroundCirculating microRNA-122 (miR-122) has been increasingly reported to be a potential biomarker for drug-, viral-, alcohol- and chemical-induced liver injury. The present study was initiated to determine the potential of circulating miR-122 as a biomarker for cholestatic liver injury.MethodsBoth bile-duct ligation (BDL) mice and patients with biliary calculi were employed as cholestatic liver injury models, and serum miR-122 level was determined by stem-loop real-time reverse-transcription PCR (SLqRT-PCR). All quantitative PCR values were normalized to those for U6 RNA and calculated with the 2−△Ct method.ResultsSerum miR-122 increased significantly after BDL-induced cholestatic injury and showed a similar time course to ALT concentrations. Compared with the sham controls, BDL mice had increased serum levels of miR-122 by 24.36±12.86, 423.63±322.89, 4.43±2.02 and 12.23±8.92 folds after 1, 3, 7 and 14 days, respectively. Moreover, serum miR-122 level was substantially higher in patients with biliary calculi than that in the healthy control group. In addition, patients with severe liver injury showed significantly higher levels of serum miR-122 when compared with healthy controls or patients with mild or moderate liver injury. Furthermore, serum miR-122 was found to show significant diagnostic value for biliary calculi by yielding an AUC (the areas under the receiver operating characteristic curve) of 0.931 with 77.4% sensitivity and 96.4% specificity in discriminating biliary calculi from healthy controls.ConclusionCollectively, these data suggest that serum miR-122 has strong potential as a novel, specific and noninvasive biomarker for diagnosis of cholestasis-induced liver injury.

Activation of Liver FGF21 in hepatocarcinogenesis and during hepatic stress

BackgroundFGF21 is a promising intervention therapy for metabolic diseases as fatty liver, obesity and diabetes. Recent results suggest that FGF21 is highly expressed in hepatocytes under metabolic stress caused by starvation, hepatosteatosis, obesity and diabetes. Hepatic FGF21 elicits metabolic benefits by targeting adipocytes of the peripheral adipose tissue through the transmembrane FGFR1-KLB complex. Ablation of adipose FGFR1 resulted in increased hepatosteatosis under starvation conditions and abrogation of the anti-obesogenic action of FGF21. These results indicate that FGF21 may be a stress responsive hepatokine that targets adipocytes and adipose tissue for alleviating the damaging effects of stress on the liver. However, it is unclear whether hepatic induction of FGF21 is limited to only metabolic stress, or to a more general hepatic stress resulting from liver pathogenesis and injury.MethodsIn this survey-based study, we examine the nature of hepatic FGF21 activation in liver tissues and tissue sections from several mouse liver disease models and human patients, by quantitative PCR, immunohistochemistry, protein chemistry, and reporter and CHIP assays. The liver diseases include genetic and chemical-induced HCC, liver injury and regeneration, cirrhosis, and other types of liver diseases.ResultsWe found that mouse FGF21 is induced in response to chemical (DEN treatment) and genetic-induced hepatocarcinogenesis (disruptions in LKB1, p53, MST1/2, SAV1 and PTEN). It is also induced in response to loss of liver mass due to partial hepatectomy followed by regeneration. The induction of FGF21 expression is potentially under the control of stress responsive transcription factors p53 and STAT3. Serum FGF21 levels correlate with FGF21 expression in hepatocytes. In patients with hepatitis, fatty degeneration, cirrhosis and liver tumors, FGF21 levels in hepatocytes or phenotypically normal hepatocytes are invariably elevated compared to normal health subjects.ConclusionFGF21 is an inducible hepatokine and could be a biomarker for normal hepatocyte function. Activation of its expression is a response of functional hepatocytes to a broad spectrum of pathological changes that impose both cellular and metabolic stress on the liver. Taken together with our recent data, we suggest that hepatic FGF21 is a general stress responsive factor that targets adipose tissue for normalizing local and systemic metabolic parameters while alleviating the overload and damaging effects imposed by the pathogenic stress on the liver. This study therefore provides a rationale for clinical biomarker studies in humans.

Induction of hepatic glutathione synthesis via alterations in sulfur amino acid metabolism in mice treated with silymarin acutely

It has been known that silymarin exhibits protective effects against chemical‐induced liver injury, but the underlying mechanism of its beneficial action remains unclear. We examined the silymarin‐induced changes in the metabolism of sulfur‐containing amino acids in association with its effects on antioxidant capacity of liver. Male mice were treated with silymarin (100 or 200 mg/kg, po) every 12 hr for a total of 3 doses. Hepatic methionine level was increased, but the activity and protein expression of methionine adenosyltransferase were decreased dose‐dependently in liver of the mice treated with silymarin. S‐Adenosylmethionine or homocysteine was not altered whereas cystathionine, cysteine and glutathione (GSH) were increased significantly. Betaine‐homocysteine methyltransferase and cysteine dioxygenase were down‐regulated, but cystathionine β‐synthase was induced. γ‐Glutamylcysteine synthetase was unchanged by silymarin treatment. Oxygen radical scavenging capacity of liver cytosol against peroxyl radical and peroxynitrite was increased, and hepatic lipid peroxidation was diminished in the silymarin‐treated mice. It is concluded that silymarin enhances hepatic GSH biosynthesis by elevating cysteine availability via increment in cysteine synthesis and inhibition of its catabolism to taurine, which may subsequently contribute to the antioxidant defense of liver.

Mechanisms of the hepatoprotective effects of tamoxifen against drug-induced and chemical-induced acute liver injuries

Although estrogen receptor (ER)α agonists, such as estradiol and ethinylestradiol (EE2), cause cholestasis in mice, they also reduce the degree of liver injury caused by hepatotoxicants as well as ischemia–reperfusion. The functional mechanisms of ERα have yet to be elucidated in drug-induced or chemical-induced liver injury. The present study investigated the effects of an ERα agonist, selective ER modulators (SERMs) and an ER antagonist on drug-induced and chemical-induced liver injuries caused by acetaminophen, bromobenzene, diclofenac, and thioacetamide (TA). We observed hepatoprotective effects of EE2, tamoxifen (TAM) and raloxifene pretreatment in female mice that were exposed to a variety of hepatotoxic compounds. In contrast, the ER antagonist did not show any hepatoprotective effects. DNA microarray analyses suggested that monocyte to macrophage differentiation-associated 2 (Mmd2) protein, which has an unknown function, is commonly increased by TAM and RAL pretreatment, but not by pretreatment with the ER antagonist. In ERα-knockout mice, the hepatoprotective effects of TAM and the increased expression of Mmd2 mRNA were not observed in TA-induced liver injury. To investigate the function of Mmd2, the expression level of Mmd2 mRNA was significantly knocked down to approximately 30% in mice by injection of siRNA for Mmd2 (siMmd2). Mmd2 knockdown resulted in a reduction of the protective effects of TAM on TA-induced liver injury in mice. This is the first report of the involvement of ERα in drug-induced or chemical-induced liver injury. Upregulation of Mmd2 protein in the liver was suggested as the mechanism of the hepatoprotective effects of EE2 and SERMs.

Osteopontin is involved in estrogen-mediated protection against diethylnitrosamine-induced liver injury in mice

Diethylnitrosamine (DEN) is a potent hepatotoxin and hepatocarcinogen in animals and possible in humans. Estrogen has been reported to play a protective role against DEN exposure. Osteopontin (OPN), a downstream molecular of estrogen, plays a role in many pathophysiological processes. In this study, we evaluate the role of OPN in estrogen-mediated hepatoprotection in DEN-treated mice. DEN was administrated intraperitoneally to C57BL/6 and OPN−/− mice. Compared to male mice, female mice exhibited significantly higher hepatic OPN expression with less liver damage 48h after DEN treatment. Interestingly, enhanced OPN expression was predominantly detected in hepatocytes after DEN treatment. OPN deficiency enhanced the susceptibility to DEN, which was more apparent in females than males. Estrogen-mediated protection against DEN in males was abrogated by OPN deficiency. The protective activities of estrogen could be mimicked by exogenous OPN. Consistent with liver injury, oxidative stress in liver was enhanced with OPN depletion. OPN reduced DEN-induced oxidative stress likely through inhibition of CYP2A5 expression. In conclusion, we demonstrate that OPN may be involved in estrogen-mediated hepatoprotection in DEN-induced liver injury through enhancement of hepatocyte survival and inhibition of DEN biotransformation. Our findings may provide new insight into gender differences in chemical-induced liver injury and related diseases.

Molecular mechanisms underlying chemical liver injury

The liver is necessary for survival. Its strategic localisation, blood flow and prominent role in the metabolism of xenobiotics render this organ particularly susceptible to injury by chemicals to which we are ubiquitously exposed. The pathogenesis of most chemical-induced liver injuries is initiated by the metabolic conversion of chemicals into reactive intermediate species, such as electrophilic compounds or free radicals, which can potentially alter the structure and function of cellular macromolecules. Many reactive intermediate species can produce oxidative stress, which can be equally detrimental to the cell. When protective defences are overwhelmed by excess toxicant insult, the effects of reactive intermediate species lead to deregulation of cell signalling pathways and dysfunction of biomolecules, leading to failure of target organelles and eventual cell death. A myriad of genetic factors determine the susceptibility of specific individuals to chemical-induced liver injury. Environmental factors, lifestyle choices and pre-existing pathological conditions also have roles in the pathogenesis of chemical liver injury. Research aimed at elucidating the molecular mechanism of the pathogenesis of chemical-induced liver diseases is fundamental for preventing or devising new modalities of treatment for liver injury by chemicals.

Hepatoprotective effect of tamoxifen on steatosis and non-alcoholic steatohepatitis in mouse models

Non-alcoholic fatty liver disease (NAFLD) is characterized by hepatic lipid accumulation that starts with steatosis and progresses to non-alcoholic steatohepatitis (NASH). Recently, the number of patients with such liver diseases has increased, but the understanding of the fundamental mechanisms and appropriate therapies are lacking. Tamoxifen (TAM) is a selective estrogen receptor modulator. We previously reported that TAM plays a protective role against drug-induced and chemical-induced acute liver injuries. However, the effects of TAM on chronic liver injury, including steatosis and NASH, remain to be addressed. We first found that the administration of TAM to mouse models of steatosis and NASH significantly decreased the plasma ALT and AST levels. The administration of TAM decreased the accumulated fat and inflammation in the livers in both mouse models. In addition, we observed decreased hepatic mRNA levels of triglyceride synthesis, acyl-CoA: diacylglycerol acyltransferase 2 (DGAT2), proinflammatory cytokines, tumor necrosis factor (TNF) α, and chemokines, monocyte chemoattractant protein (MCP) -1. TAM increased the extracellular signal-regulated kinase (ERK) phosphorylation, which is related to the proliferation and regeneration of liver and to decreased DGAT2 gene expression. Furthermore, a decrease in eukaryotic translational initiation factor (eIF2α), which is involved in apoptosis, was observed in both models. These findings suggest that TAM treatment exerts a hepatoprotective effect against steatosis and NASH, presumably via up-regulation of the ERK pathways and attenuation of eIF2α activation. These pathways represent a potential therapeutic target for steatosis and NASH in drug development.

Adaptive gene regulation of pyruvate dehydrogenase kinase isoenzyme 4 in hepatotoxic chemical-induced liver injury and its stimulatory potential for DNA repair and cell proliferation

The processes involved in the adaptation of animals to environmental factors remain unclear. We examined the mechanisms underlying the adaptive potential of the mouse against hepatotoxic chemical-induced injury. Microarray analysis revealed that ethylbenzene, a hepatotoxic chemical, upregulated PDK4 (encoding pyruvate dehydrogenase kinase isoenzyme 4) in mouse livers and that the upregulation was enhanced by previous exposure to the chemical. Although PDK4 is an energy resource regulator induced by starvation, expression of other fasting-inducible genes was unaffected. PDK4 induced by chemical stress developed hepatic accumulation of sirtuin 1 by regulating pyruvate concentration and activated the Nbn and ATM, which are critical for DNA repair and checkpoint activation. PDK4 overexpression on carbon tetrachloride (CCl4)-induced liver injury resulted in delayed necrotic tissue recovery with cell cycle arrest and decreased γH2AX foci and micronucleus formation. PDK4 silencing on CCl4-induced liver injury accelerated necrotic tissue recovery and increased γH2AX foci and micronucleus formation, indicating the essential role of PDK4 in DNA repair and checkpoint activation. PDK4 overexpression induced pancreas-specific transcription factor 1a (Ptf1a) upregulation and transcriptional activation of several pancreatic genes in the liver. Ptf1a overexpression by adenoviral gene delivery resulted in accelerated tissue recovery on CCl4-induced liver injury. Our data identified PDK4 as a novel pivotal factor in adaptation to chemical stress.

Plasma MicroRNA-122 as a Biomarker for Viral-, Alcohol-, and Chemical-Related Hepatic Diseases

The liver is frequently subject to insult because of viral infection, alcohol abuse, or toxic chemical exposure. Extensive research has been conducted to identify blood markers that can better discern liver damage, but little progress has been achieved in clinical practice. Recently, circulating microRNAs (miRNAs) have been reported as potential biomarkers for the noninvasive diagnosis of cancer. In this study, we investigated whether plasma miRNAs have diagnostic utility in identifying liver disease. The study was divided into 2 phases: marker selection by real-time quantitative PCR analysis of a small set of plasma samples, and marker validation with a large set of plasma samples from 83 patients with chronic hepatitis B viral infections, 15 patients with skeletal muscle disease, and 40 healthy controls. Two mouse model systems, d-galactosamine- and alcohol-induced liver injury, were also developed to evaluate whether differences in miRNA concentration were associated with various liver diseases. Among the miRNA candidates identified, miR-122 presented a disease severity-dependent change in plasma concentration in the patients and animal models. Compared with an increase in aminotransferase activity in the blood, the change in miR-122 concentration appeared earlier. Furthermore, this change was more specific for liver injury than for other organ damage and was more reliable, because the change was correlated with liver histologic stage. Our findings suggest that circulating miR-122 has potential as a novel, predictive, and reliable blood marker for viral-, alcohol-, and chemical-induced liver injury.

An in vitro system for studying potential biological mechanisms of human sex differences in susceptibility to acute liver injury

Women are more susceptible than men to acute liver injury from drugs and other xenobiotics. The biological mechanisms for this sex difference are unknown, but known sex differences in steroid hormone levels and immune response could play a role. A human hepatocyte cell line, HepG2, was cultured for 8 days in either a male hormone, female hormone, or sex hormone-free medium. The cells were then exposed to a mixture of pro-inflammatory cytokines (interleukin (IL)-1β, IL-6, TNFα) for 72 h to simulate acute inflammation. Cell viability (total DNA) and various metabolic functions (reactive oxygen species (ROS), neutral and polar lipid (PL) accumulation, mitochondrial membrane potential, cytochrome P450 (CYP) activities) were measured fluorometrically. Acute phase proteins (albumin, IL-1ra) were measured in the culture medium by ELISA. This model gave both significant hormone only effects (ROS, PL accumulation) and cytokine only effects (total DNA, CYP1A, neutral and PL accumulation, albumin, IL-1ra) consistent with known biological responses. Significant hormone–cytokine interactions were observed for several endpoints (total DNA, ROS, neutral and PL accumulation, albumin). These findings suggest that sex hormones and pro-inflammatory cytokines can interact to alter liver metabolism in ways that may contribute to the marked sex difference in susceptibility to chemical-induced acute liver injury.

Alterations in hepatic metabolism of sulfur‐containing substances by silymarin in mice

Silymarin has been shown to exhibit hepatoprotective effects against chemical‐induced liver injury, but the underlying mechanism of its beneficial action remains unclear. In this study we examined the changes in hepatic metabolism of sulfur‐amino acids induced by silymarin. Male mice were treated with silymarin (100 or 200 mg/kg, po) every 12 hr for a total of 3 doses. Methionine level was increased, but methionine adenosyltransferase (MAT) activity was decreased by silymarin in a dose‐dependent manner. S‐Adenosylmethione or homocysteine was not altered whereas cystathionine, cysteine and glutathione levels were increased significantly by silymarin treatment. Western blotting analysis revealed that silymarin treatment decreased protein expression of betaine‐homocysteine methyl transferase, MATI/III and cysteine dioxygenase, but increased cystathione β‐synthase expression in liver. Expression of γ‐glutamylcysteine synthetase, the rate‐limiting enzyme of glutathione synthesis, was not influenced. The present results show that silymarin induces significant changes in the metabolomics of sulfur‐containing substances in liver, which appears to be associated with the hepatoprotective effects of this substance. Further studies to identify its significance in chemical‐induced liver injury are currently being conducted in this laboratory.Grant Funding Source: KOSEF

Curcumin improves sclerosing cholangitis in Mdr2−/− mice by inhibition of cholangiocyte inflammatory response and portal myofibroblast proliferation

Background and aimChronic cholangiopathies have limited therapeutic options and represent an important indication for liver transplantation. Curcumin, the yellow pigment of the spice turmeric, has pleiotropic actions and attenuates hepatic...

Protective effect of crude extract from Wedelia paludosa (Asteraceae) on the hepatotoxicity induced by paracetamol in mice

Several in-vitro and in-vivo ethnopharmacological studies carried out with plants of the genus Wedelia have already demonstrated hepatoprotective effects in chemically-induced liver injury, including those induced by paracetamol. Here, the effects of the crude extract from Wedelia paludosa on paracetamol-induced hepatotoxicity in mice was investigated. Intraperitoneal injection of paracetamol (1,000 mg kg(-1)) caused 80% death after 24 h in mice, which was significantly reduced by oral pretreatment with W. paludosa (500 mg kg(-1)). Hepatotoxicity was observed 24 h after an intraperitoneal injection of paracetamol (600 mg kg(-1)), as evidenced by an increase in plasma activity of aspartate and alanine aminotransferases. That hepatotoxicity was significantly attenuated by W. paludosa pretreatment (100-500 mg kg(-1)) in a dose-response manner. Paracetamol (1,000 mg kg(-1)) drastically depleted total glutathione levels and decreased glutathione peroxidase and delta-aminolevulinate dehydratase activity in the liver, such effects not being prevented by pretreatment with W. paludosa. Neither paracetamol treatment alone nor pretreatment with W. paludosa altered glutathione reductase and glutathione S-transferase activity or the levels of end-products of lipid peroxidation. In conclusion, we found that W. paludosa protected against paracetamol-induced hepatotoxicity, an effect not observed over oxidative stress-related parameters. Hepatoprotection is likely mediated by some terpenes present in W. paludosa extract. However, further studies will be required to explain the mechanisms involved in the hepatoprotection afforded by W. paludosa.