Hepatoprotective effect of Holothuria leucospilota methanolic extract on dimethyl nitrosamine-induced hepatotoxicity in rats

Background:Complementary medicine is an interesting field for extracting bio-active compounds from various plant and animal sources.The hepatoprotective effect of the methanolic extract of a species of sea cucumber called Holothuria leu-cospilota in an animal model of liver cancer caused by dimethyl nitrosamine(DMN)was studied.Methods:Wistar female rats were randomly divided into five groups(n=12):control(intact),positive control(received 1%DMN[10 mg/kg/week,intraperitoneally]for 12 weeks),and three treatment groups(received 50,100,and 200 mg/kg/day H.leu-cospilota extract orally for 12 weeks along with intraperitoneal administration of 1%DMN[10 mg/kg/week]).In all groups,ultrasound was performed on the liver every week to check its density.Blood sampling and liver isolation were performed on three occasions,at 4,8,and 12 weeks,to check liver enzymes and the histopathological condition of the liver tissue(every week,four animals from each group were randomly selected).Results:Liver density changes were evident from the eighth week onward in the positive control group.Histopathological results indicated pathologic changes in the positive control group after 4 weeks.The increase in liver enzymes in the posi-tive control group was significantly different from that in the treatment and control groups.Conclusions:We demonstrated the hepatoprotective effect of H.leucospilota on DMN-induced liver damage in rats using biochemical and histological parameters and ultrasonography.More additional research(in silico or in vitro)is needed to find the exact mechanism and the main biological compound in H.leucospilota.

The Protective Effect of Moringa oleifera Leaves Extract on Paracetamol Hepatotoxicity in Male Rats

In recent years, there has been an increase in concern regarding the effects of paracetamol poisoning on liver tissues, particularly when consumed in large amounts. Some studies have estimated that paracetamol is involved in 56% of acute liver diseases, whereas 0.4% of paracetamol overdose cases result in fatal-ity. In this study, the effects of Moringa oleifera on paracetamol toxicity in the liver were explored. It has been demonstrated that Moringa oleifera is highly nu-tritious, contains bioactive molecules, and is therapeutically beneficial. Many studies have shown that Moringa oleifera leaves possess a wide range of biologi-cal properties, including antioxidant, tissue protection, analgesic, antihyperten-sive, and immunomodulatory activities. This study highlights the protective role of Moringa oleifera on handling possible paracetamol hepatotoxicity in male rats. .

Functionalized selenium nanoparticles ameliorated acetaminophen-induced hepatotoxicity through synergistically triggering PKCδ/Nrf2 signaling pathway and inhibiting CYP 2E1

Selenium nanoparticles(SeNPs)have been demonstrated potential for use in diseases associated with oxidative stress.Functionalized SeNPs with lower toxicity and higher biocompatibility could bring better therapeutic activity and clinical application value.Herein,this work was conducted to investigate the protective effect of Pleurotus tuber-regium polysaccharide-protein complex funtionnalized SeNPs(PTR-SeNPs)against acetaminophen(APAP)-induced oxidative injure in HepG2 cells and C57BL/6J mouse liver.Further elucidation of the underlying molecular mechanism,in particular their modulation of Nrf2 signaling pathway was also performed.The results showed that PTR-SeNPs could significantly ameliorate APAP-induced oxidative injury as evidenced by a range of biochemical analysis,histopathological examination and immunoblotting study.PTR-SeNPs could hosphorylate and activate PKCδ,depress Keap1,and increase nuclear accumulation of Nrf2,resulting in upregulation of GCLC,GCLM,HO-1 and NQO-1 expression.Besides,PTR-SeNPs suppressed the biotransformation of APAP to generate intracellular ROS through CYP 2E1 inhibition,restoring the mitochondrial morphology.Furthermore,the protective effect of PTR-SeNPs against APAP induced hepatotoxicity was weakened as Nrf2 was depleted in vivo,indicating the pivotal role of Nrf2 signaling pathway in PTR-SeNPs mediated hepatoprotective efficacy.Being a potential hepatic protectant,PTR-SeNPs could serve as a new source of selenium supplement for health-promoting and biomedical applications.

Protective effect of glycyrrhetinic acid against cantharidin-induced hepatotoxicity through reducing oxidative stress in mice

Background:Cantharidin(CTD)is a commonly used natural product with anticancer properties;however,it has significant adverse effects,particularly hepatotoxicity.Glycyrrhetinic acid(GA),the active component of licorice,shows potential hepatoprotective effects.The protective effects and mechanism of GA against CTD-induced hepatotoxicity are still unclear.Objective:This study aims to elucidate the effect and mechanism of GA on CTD-induced hepatotoxicity in mice experiments.Methods:Construction of CTD-induced hepatotoxicity models and oral gavage GA intervention for 14 d.The liver index,ALT,AST and LDH levels in the serum of the mice were examined;HE staining was performed to observe pathological changes in the liver.The MDA level and SOD activities in liver tissue were tested.Western blot was conducted to determine Keap1/Nrf2 signaling pathway-related protein expression.Results:The results showed that GA significantly reduced the levels of ALT,AST,and LDH in the serum,which were increased by CTD.Additionally,it also exerted a substantial inhibitory effect on the reduction of SOD activity and the elevation of malondialdehyde content in liver tissue.Notably,the phenomena of nuclear swelling,necrosis,and inflammatory infiltration of liver tissue were significantly attenuated following oral administration of GA in mice.Subsequent research has demonstrated that GA effectively suppressed the CTD-triggered upregulation of Keap1 while increasing the CTD-induced downregulation of Nrf2,HO-1,and NQO1.Conclusion:These findings suggested that GA may protect against CTD-induced hepatotoxicity in mice by exerting antioxidative stress through the Keap1/Nrf2 signaling pathway.

Herbal hepatotoxicity:Challenges and pitfalls of causality assessment methods

The diagnosis of herbal hepatotoxicity or herb induced liver injury(HILI) represents a particular clinical and regulatory challenge with major pitfalls for the causality evaluation.At the day HILI is suspected in a patient,physicians should start assessing the quality of the used herbal product,optimizing the clinical data for completeness,and applying the Council for International Organizations of Medical Sciences(CIOMS) scale for initial causality assessment.This scale is structured,quantitative,liver specific,and validated for hepatotoxicity cases.Its items provide individual scores,which together yield causality levels of highly probable,probable,possible,unlikely,and excluded.After completion by additional information including raw data,this scale with all items should be reported to regulatory agencies and manufacturers for further evaluation.The CIOMS scale is preferred as tool for assessing causality in hepatotoxicity cases,compared to numerous other causality assessment methods,which are inferior on various grounds.Among these disputed methods are the Maria and Victorino scale,an insufficiently qualified,shortened version of the CIOMS scale,as well as various liver unspecific methods such as thead hoc causality approach,the Naranjo scale,the World Health Organization(WHO) method,and the Karch and Lasagna method.An expert panel is required for the Drug Induced Liver Injury Network method,the WHO method,and other approaches based on expert opinion,which provide retrospective analyses with a long delay and thereby prevent a timely assessment of the illness in question by the physician.In conclusion,HILI causality assessment is challenging and is best achieved by the liver specific CIOMS scale,avoiding pitfalls commonly observed with other approaches.

Investigation of hepatoprotective activity of Cyathea gigantea(Wall.ex.Hook.)leaves against paracetamol-induced hepatotoxicity in rats

Objective:To investigate the hepatoprotective activity of methanolic leaf extract of Cyathea gigantea(C.gigantea)against paracetamol induced liver damage in rats.Methods:The hepatoprotective activity for plant extract was investigated for paracetamol induced hepatoxicity in rats.Wislar albino rats of either sex were divided into five groups of 6 animals each and are given orally the following treatment for seven days.The normal control group was given 1%Na.CMC 1mL/kg bw,p.o.Paracetamol at dose of 1g/kg bw,p.o.was given as toxic dose for inducing hepatoloxicity.Silymarin(50mg/kg.p.o.) was given as reference standard.Two doses of C. gigantea extract i.e.,100 mg/kg.p.o.and 200 mg/kg,p.o.were tested for hepatoprotective activity. The treatment was given for seven days and after 24 h of last treatment blood was collected from retro-orbital plexus and analysed for various serum parameters like serum glutamic-oxaloacetic transaminase(SGOT),serum glutamic pyruvic transaminase(SGPT),alkaline phosphatase(ALP),total bilirubin(TB)and total protein(TP)in different groups.Results:The paracetamol intoxication lead to histological and biochemical deteriorations.The treatment with methanolic leaf extract of C.gigantea reduced the elevated levels of SCOT,SGPT,ALP,TB and also reversed the hepatic damage towards normal which further supports the hepatoprotective activity of leaf extract of C.gigantea.Conclusions:The methanolic extract of leaves of C.gigantea at doses of 100 mg/kg bw and 200 mg/kg bw have significant effect on liver of paracetamol induced hepatotoxicity model in rats.

Herbalife hepatotoxicity: Evaluation of cases with positive reexposure tests

AIM: To analyze the validity of applied test criteria and causality assessment methods in assumed Herbalife hepatotoxicity with positive reexposure tests. METHODS: We searched the Medline database for suspected cases of Herbalife hepatotoxicity and retrieved 53 cases including eight cases with a positive unintentional reexposure and a high causality level for Herbalife. First, analysis of these eight cases focused on the data quality of the positive reexposure cases, requiring a baseline value of alanine aminotransferase(ALT) < 5 upper limit of normal (N) before reexposure, with Nas the upper limit of normal, and a doubling of the ALT value at reexposure as compared to the ALT value at baseline prior to reexposure. Second, reported methods to assess causality in the eight cases were evaluated, and then the liver specific Council for International Organizations of Medical Sciences (CIOMS) scale validated for hepatotoxicity cases was used for quantitative causality reevaluation. This scale consists of various specific elements with scores provided through the respective case data, and the sum of the scores yields a causality grading for each individual case of initially suspected hepatotoxicity. RESULTS: Details of positive reexposure test conditions and their individual results were scattered in virtually all cases, since reexposures were unintentional and allowed only retrospective rather than prospective assessments. In 1/8 cases, criteria for a positive reexposure were fulfilled, whereas in the remaining cases the reexposure test was classified as negative (n = 1), or the data were considered as uninterpretable due to missing information to comply adequately with the criteria (n = 6). In virtually all assessed cases, liver unspecific causality assessment methods were applied rather than a liver specific method such as the CIOMS scale. Using this scale, causality gradings for Herbalife in these eight cases were probable (n = 1), unlikely (n = 4), and excluded (n = 3). Confounding variables in- cluded low data quality, alternative diagnoses, poor exclusion of important other causes, and comedication by drugs and herbs in 6/8 cases. More specifically, problems were evident in some cases regarding temporal association, daily doses, exact start and end dates of product use, actual data of laboratory parameters such as ALT, and exact dechallenge characteristics. Short-comings included scattered exclusion of hepatitis A-C, cytomegalovirus and Epstein Barr virus infection with only globally presented or lacking parameters. Hepatitis Evirus infection was considered in one single patient and found positive, infections by herpes simplexvirus and varicella zoster virus were excluded in none. CONCLUSION: Only one case fulfilled positive reexposure test criteria in initially assumed Herbalife hepatotoxicity, with lower CIOMS based causality gradings for the other cases than hitherto proposed.

Hepatoprotective potential of ethanolic extract of Ziziphus oenoplia(L.)Mill roots against antitubercular drugs induced hepatotoxicity in experimental models

Objective:To evaluate the hepatoprotective potential of ethanolic(50%) extract of Ziziphus oenoplia(L.) Mill(Z.oenoplia) root against isoniazid(INH) and rifampicin(RIF) induced liver damage in animal models.Methods:Five groups of six rats each were selected for the study.Ethanolic extract at a dose of 150 and 300 mg/kg as well as silymarin(100 mg/kg) were administered orally once daily for 21 d in INH + RIF treated groups.The serum levels of glutamic oxaloacetic transaminase(SGOT),glutamate pyruvate transaminase(SGPT),alkaline phosphatase (SALP),and bilirubin were estimated along with activities of superoxide dismutase,catalase, glutathione S-transferase,glutathione peroxidase,and hepatic melondialdehyde formation. Histopathological analysis was carried out to assess injury to the liver.Result:The considerably elevated serum enzymatic activities of glutamic oxaloacetic transaminase,glutamate pyruvate transaminase,alkaline phosphatase and bilirubin due to INH + RIF treatment were restored towards norma) in a dose dependent manner after the treatment with ethanolic extract of Z.oenoplia roots.Meanwhile,the decreased activities of superoxide dismutase,catalase, glutathione S-transferase and glutathione peroxidase were also restored towards normal dose dependency.In addition,ethanolic extract also significantly prevented the elevation of hepatic melondialdehyde formation in the liver of INH + RIF intoxicated rats in a dose dependent manner. The biochemical observations were supplemented with histopathological examination of rat liver sections.Conclusions:The results of this study slrongly indicate that ethanolic extract of Z.oenoplia has a potent hepatoprotective action against INH + RIF induced hepatic damage in rats.

Ketoconazole Associated Hepatotoxicity: A Systematic Review and Metaanalysis

Objective To evaluate the incidence of Ketoconazole associated hepatotoxicity and related factors Methods Literature retrieval was conducted by using multi-databases for meta-analysis on Ketoconazole associated hepatotoxicity. The data were collected with a standardized form. Overall estimation of incidence of hepatotoxicity for specific study type was calculated by using a DerSimonian-Laird random-effects model owing to the substantial differences among the studies. Results Totally 204 eligible studies were included in the analysis. The incidence of Ketoconazole associated hepatotoxicity was 3.6%-4.2%. The dosage and duration specific subgroup analyses did not show any significant difference among groups, while the age specific subgroup analysis showed the incidence in children and people aged 〉60 years was 1.4% （95% CI 0.5%-4.2%） and 3.2% （95% Cl： 1.1%-8.7%） respectively. Additionally, the incidence of the hepatotoxicity was higher in people who had oral administration of ketoconazole beyond the provisions of the usage instructions, and the incidence was 5.7% （95% CI： 4.5%-7.2%）. Conclusion Ketoconazole associated hepatotoxicity was common. Off-label use might increase the risk of liver damage. Well-designed large sample studies are needed to identify the risk factors in future.

The protection of Thymus vulgaris leaves alcoholic extract against hepatotoxicity of alcohol in rats

Objective:This study was performed to investigate the protective effect of Thymus vulgaris(T.vulgaris) leaves 70%alcoholic extract against alcohol-mediate hepatotoxicity rats.Methods:The protective effect of extract was investigated at dose of 500 mg/kg/day orally against alcohol-mediate hepatotoxicity using adult male Wister albino rats during 21 days.Protective effect of T.vulgaris extract was evaluated comparing with silymarin standard drug al recommended dose(25 mg/kg/day) orally for 21 days.Results:Alcohol-mediate hepatotoxicity rats(alcohol-control) showed hepatocytes distortion represented as marked increment on liver biomarkers;alkaline phosphatase(ALP),aspartate transaminase(AST) and alanine transaminase(ALT) activities,as well as pronounced reduction on total protein and its fractions albumin and globulin corresponding to normal ranges.Addition to oxidative stress status as depletion on glutathione concentration,catalase(CAT),superoxide dismutase(SOD),glutathione reductase(GR),glutathione-S-transferase(GST) and glutathione peroxidase(GPx)activities,concurrence with augmentation oxidative stress parameters;malondyaldchydc(MDA) and hydrogen peroxide(H_2O_2) concentrations comparing to normal values.Alcohol administration elevated total cholesterol(TC),low density lipoprotein cholesterol(LDL-C) and high density lipoprotein cholesterol(HDL-C) comparing to normal ranges.Co-administration T.vulgaris extract with alcohol showed protective effect on hepatocytes manifested as minimizing on ALP.AST and ALT activities and increment on total protein,albumin and globulin production compared to alcohol-control.Antioxidant enzymes activities;CAT.SOD.GR,GST and GPx were significantly magnified,while MDA and H_2O_2 concentration were lessened corresponding to alcohol-control.Also,lipid profile was markedly improved and risk ratio was lowered compared to alcohol-control.These results were confirmed by normalization of degenerated and fibrotic liver tissue as of alcohol-control.Conclusion:T.vulgaris extract appeared hepatoprotective,hypolipidemic and antioxidant activities on alcohol-mediate hepatotoxicity rats compared to silymarin.

Protective effects of Balanites aegyptiaca extract, melatonin and ursodeoxycholic acid against hepatotoxicity induced by methotrexate in male rats

Objective: To compare the degree of ameliorative effects of Melatonin(MEL), Ursodeoxycholic acid(UDCA) and Balanites aegyptiaca(BA) against hepatotoxicity induced by MTX for one month. Methods: Eighty adult male rats(Sprague Dawely) weighing(190±10g), were randomly divided into eight equal groups: Control, MTX, MEL, BA, UDCA, MTX+MEL, MTX+BA, MTX+UDCA. Liver function biomarker enzymes, liver tissue oxidative stress parameters, together with total antioxidant capacity and tumor necrosis factor(TNF-α) were determined. Histopathological and immunohistochemistry examinations for TNF-α were also done. Results: MTX showed significant increase in alanine transaminase(ALT), aspartate transaminase(AST), alkaline phosphatase(ALP), gamma glutamyl transferase(GGT), total and direct bilirubin, as well as TNF-α levels, oxidized glutathione(GSSG), malodialdehyde(MDA) and nitric oxide(NO). whereas, total protein, albumin, total antioxidant capacity, reduced glutathione(GSH), glutathione peroxidase(GPx), glutathione reductase(GR), glutathione S-transferase(GST), superoxide dismutase(SOD) and catalase(CAT) levels were significantly decreased in MTX treated group. These alterations were improved by MEL and BA treatment, whereas no improvement was noticed in UDCA treatment. Conclusions: BA may be as promising as MEL in the hepatoprotection against MTX toxicity through their antioxidant and radical scavenging activities. In addition, it is not recommended to co-administer UDCA with MTX as it enhanced inflammation and damage to the liver.

Herbal extracts as hepatoprotectants against acetaminophen hepatotoxicity

Many plant-derived natural products have the potential to be hepatoprotective and therefore can be used to treat acute and chronic liver diseases. The challenge is to identify the most promising compounds and evaluate their protective mechanism. In a recently published article, Wang et al evaluated extracts of the plant Gentiana manshurica Kitagawa (GM) in a model of acetaminophen hepatotoxicity. The authors concluded that GM is hepatoprotective against acetaminopheninduced liver injury due to its antioxidant properties and anti-apoptotic capacity. We would like to discuss the limitations of this experimental approach and question the conclusion based on the data presented in this manuscript and the published literature.

Hepatotoxicity associated with glucosamine and chondroitin sulfate in patients with chronic liver disease

Glucosamine and chondroitin sulfate are molecules involved in the formation of articular cartilage and are frequently used for symptom relief in patients with arthrosis.These molecules are well tolerated with scarce secondary effects.Very few cases of possible hepatotoxicity due to these substances have been described.The aim of this paper is to report the frequency of presumed glucosamine hepatotoxicity in patients with liver disease.A questionnaire was given to 151 consecutive patients with chronic liver disease of different etiology(mean age 59 years,56.9%women)attended in an outpatient clinic with the aim of evaluating the frequency of consumption of these drugs and determine whether their use coincided with a worsening in liver function test results.Twenty-three patients(15.2%)recognized having taken products containing glucosamine or chondroitin sulfate previously or at the time of the questionnaire.Review of the clinical records and liver function tests identified 2 patients presenting an elevation in aminotransferase values temporarily associated with glucosamine treatment;one of the cases simultaneously presented a skin rash attributed to the drug.Review of these two patients and the cases described in the literature suggest toxicity of glucosamine and chondroitin sulfate.The clinical spectrum is variable,and the mechanism of toxicity is not clear but may involve reactions of hypersensitivity.The consumption of products containing glucosamine and/or chondroitin sulfate is frequent among patients with chronic liver diseases and should be taken into account on the appearance of alterations in liver function tests not explained by the underlying disease.

NAT2＊6A, a haplotype of the N-acetyltransferase 2 gene, is an important biomarker for risk of anti-tuberculosis drug-induced hepatotoxicity in Japanese patients with tuberculosis

AIM: To investigate an association between N -acetyltransferase 2 (NAT2 )-haplotypes/diplotypes and adverse effects in Japanese pulmonary tuberculosis patients. METHODS: We studied 100 patients with pulmonary TB treated with anti-TB drugs including INH. The frequencies and distributions of single nucleotide polymorphisms, haplotypes, and diplotypes of NAT2 were determined by the PCR-restriction fragment length polymorphism method, and the results were compared between TB patients with and without adverse effect, using multivariate logistic regression analysis.RESULTS: Statistical analysis revealed that the frequency of a variant haplotype, NAT2*6A , was signifi cantly increased in TB patients with hepatotoxicity, compared with those without hepatotoxicity [P = 0.001, odds ratio (OR) = 3.535]. By contrast, the frequency of a wild-type (major) haplotype, "NAT2*4", was signif icantly lower in TB patients with hepatotoxicity than those without hepatotoxicity (P < 0.001, OR = 0.265). There was no association between NAT2-haplotypes and skin rash or eosinophilia. CONCLUSION: The present study shows that NAT2 is one of the determinants of anti-TB drug-induced hepatotoxicity. Moreover, the haplotypes, NAT2*4 and NAT2*6A, are useful new biomarkers for predicting anti- TB drug-induced hepatotoxicity.

Assessment of drug-induced hepatotoxicity in clinical practice: A challenge for gastroenterologists

Currently, pharmaceutical preparations are serious contributors to liver disease; hepatotoxicity ranking as the most frequent cause for acute liver failure and post-commercialization regulatory decisions. The diagnosis of hepatotoxicity remains a difficult task because of the lack of reliable markers for use in general clinical practice. To incriminate any given drug in an episode of liver dysfunction is a step-by-step process that requires a high degree of suspicion, compatible chronology, awareness of the drug’s hepatotoxic potential, the exclusion of alternative causes of liver damage and the ability to detect the presence of subtle data that favors a toxic etiology. This process is time-consuming and the final result is frequently inaccurate. Diagnostic algorithms may add consistency to the diagnostic process by translating the suspicion into a quantitative score. Such scales are useful since they provide a framework that emphasizes the features that merit attention in cases of suspected hepatic adverse reaction as well. Current efforts in collecting bona fide cases of drug-induced hepatotoxicity will make refinements of existing scales feasible. It is now relatively easy to accommodate relevant data within the scoring system and to delete low-impact items. Efforts should also be directed toward the development of an abridged instrument for use in evaluating suspected drug-induced hepatotoxicity at the very beginning of the diagnosis and treatment process when clinical decisions need to be made. The instrument chosen would enable a confident diagnosis to be made on admission of the patient and treatment to be fine-tuned as further information is collected.

Protective effect of tea polyphenols against paracetamol-induced hepatotoxicity in mice is significanly correlated with cytochrome P450 suppression

AIM： To investigate the hepatoprotective activity of tea polyphenols （TP） and its relation with cytochrome P450 （CYP450） expression in mice. METHODS： Hepatic CYP450 and CYPbs levels were measured by UV-spectrophotometry in mice 2 d after intraperitoneal TP （25, 50 and 100 mg/kg per day）. Then the mice were intragastricly pre-treated with TP （100, 200 and 400 mg/kg per day） for six days before paracetamol （1000 mg/kg） was given. Their acute mortality was compared with that of control mice. The mice were pre-treated with TP （100, 200, and 400 mg/kg per day） for five days before paracetamol （500 mg/kg） was given. Hepatic CYP2E1 and CYPIA2 protein and mRNA expression levels were evaluated by Western blotting, immunohistochemical staining and transcriptase-polymerase chain reaction. RESULTS： The hepatic CYP450 and CYPb5 levels in mice of TP-treated groups （100, 200 and 400 mg/kg per day） were decreased in a dose-dependent manner compared with those in the negative control mice.TP significantly attenuated the paracetamol-induced hepatic injury and dramatically reduced the mortality of paracetamol-treated mice. Furthermore, TP reduced CYP2E1 and CYPIA2 expression at both protein and mRNA levels in a dose-dependent manner. CONCLUSION： TP possess potential hepatoprotective properties and can suppress CYP450 expression.

The interaction between polyphyllin I and SQLE protein induces hepatotoxicity through SREBP-2/HMGCR/SQLE/LSS pathway

Polyphyllin I(PPI)and polyphyllin II(PII)are the main active substances in the Paris polyphylla.However,liver toxicity of these compounds has impeded their clinical application and the potential hepatotoxicity mechanisms remain to be elucidated.In this work,we found that PPI and PII exposure could induce significant hepatotoxicity in human liver cell line L-02 and zebrafish in a dose-dependent manner.The results of the proteomic analysis in L-02 cells and transcriptome in zebrafish indicated that the hepatotoxicity of PPI and PII was associated with the cholesterol biosynthetic pathway disorders,which were alleviated by the cholesterol biosynthesis inhibitor lovastatin.Additionally,3-hydroxy-3-methy-lglutaryl CoA reductase(HMGCR)and squalene epoxidase(SQLE),the two rate-limiting enzymes in the cholesterol synthesis,selected as the potential targets,were confirmed by the molecular docking,the overexpression,and knockdown of HMGCR or SQLE with siRNA.Finally,the pull-down and surface plasmon resonance technology revealed that PPI could directly bind with SQLE but not with HMGCR.Collectively,these data demonstrated that PPI-induced hepatotoxicity resulted from the direct binding with SQLE protein and impaired the sterol-regulatory element binding protein 2/HMGCR/SQLE/lanosterol synthase pathways,thus disturbing the cholesterol biosynthesis pathway.The findings of this research can contribute to a better understanding of the key role of SQLE as a potential target in drug-induced hepatotoxicity and provide a therapeutic strategy for the prevention of drug toxic effects with similar structures in the future.

Protective effects of 2,4-dihydroxybenzophenone against acetaminophen-induced hepatotoxicity in mice

AIM:To examine the effects of 2,4-dihydroxybenzophenone(BP-1),a benzophenone derivative used as an ultraviolet light absorbent,on acetaminophen(APAP)induced hepatotoxicity in C57BL/6J mice.METHODS:Mice were administered orally with BP-1 at doses of 200,400 and 800 mg/kg body weight respectively every morning for 4 d before a hepatotoxic dose of APAP(350 mg/kg body weight) was given subcutaneously.Twenty four hours after APAP intoxication,the serum enzyme including serum alaine aminotransferase(ALT),aspartate aminotransferase(AST),lactate dehydrogenase(LDH) were measured and liver histopathologic changes were examined.RESULTS:BP-1 administration dramatically reduced serum ALT,AST and LDH levels.Liver histopathological examination showed that BP-1 administration antagonized APAP-induced liver pathological damage in a dose-dependent manner.Further tests showed that APAP-induced hepatic lipid peroxidation was reduced significantly by BP-1 pretreatment,and glutathione depletion was ameliorated obviously.CONCLUSION:BP-1 can effectively protect C57BL/6J mice from APAP-induced hepatotoxicity,and reduction of oxidative stress might be part of the protection mechanism.

Modulatory effects of dietary inclusion of garlic(Allium sativum) on gentamycin-induced hepatotoxicity and oxidative stress in rats

Objective:To investigate die ameliorative effect of dietary inclusion of garlic(Allium sativum)on gentamycin-induced hepatotoxicity in rats.Methods:Adult male rats were randomly divided into four groups with sis animals in each group.Groups 1 and 2 were fed basal diet while Groups 3 and 4 were fed diets containing 2%and 4%garlic respeetively for 27 d prior to gentamycin administration.Hepatotoxicity was induced by the intraperitoneal administration at gentamycin(100 mg/kg body weight)for 3 d.The liver and plasma were studied for hepatotoxicity and antioxidant indices.Results:Gentamycin induces hepatic damage as revealed by significant(P<0.05)elevation of liver damage marker enzymes(aspartate transaminase and alanine aminotransferase)and reduction in plasma albumin level.Gentamycin also eaused a significant(P<0.05)alteration in plasma and liver enzymatic(catalase,glutathione and super oxygen dehydrogenises)and non-enzymatic(glutathione and vitamin C)antioxidant indices with concomitant increase in the malondialdehyde content;however,there was a significant(P<0.05)restoration of the antioxidant status coupled with significant(P<0.05)decrease in the tissues malondialdehyde content,following consumption of diets containing garlic.Conclusions:These results suggest that dietary inclusion of garlic powder could protect against gentamycin-induced hepatotoxicity,improve antioxidant status and modulate oxidative stress;a function attributed to their phenolic constituents.

Protective Effect of Coleus aromaticus Benth(Lamiaceae)against Naphthalene-induced Hepatotoxicity

Objective To investigate protective effect of Coleus aromaticus leaf extract against naphthalene induced hepatotoxicity in rats. Methods Eighteen male rats were divided into three groups. Group I rats were treated as control. Group II rats were intraperitoneally administered with naphthalene （435 mg/kg b.wt） dissolved in corn oil once a day for a period of 30 days. Group III rats were treated with leaf extract （100 mg/kg b.wt） dissolved in 0.9% saline and naphthalene （435 mg/kg b.wt） dissolved in corn oil once a day for a period of 30 days. Results Significant protective effect was observed against naphthalene induced liver damage, which appeared evident from the response levels of marker enzymes （aspartate transaminase, alanine transaminase, acid phosphatase, alkaline phosphatase and lactate dehydrogenase）. The biochemical components viz. triglycerides, free fatty acids, cholesterol acyl transferase, high-density lipoprotein, low-density lipoprotein, cholesterol and bilirubin were found to be increased in liver and serum of naphthalene stressed rats when compared to control. Conclusion Treatment of naphthalene intoxicated rats with plant extract reversed these distorted parameters to near normal levels. Liver histology showed supportive evidence regarding the protective nature of plant extract against fatty changes induced by naphthalene. The present study provides a scientific rationale for using C. aromaticus in the management of liver disorders.