Hepatoprotective properties of extensively studied medicinal plant active constituents: Possible common mechanisms

Abstract

Context: We focused on certain plant active constituents considered to be the most promising/studied for liver disease and that were critically investigated from the basic science point of view and, to some extent, the clinical one. Due to insufficient pharmacological data, most of the herbal formulations containing these molecules cannot be recommended for the treatment of liver disease.

Objective: To present the most promising compounds tested experimentally and/or clinically and describe in brief popular models in experimental testing of potential hepatoprotective compounds.

Methods: A literature search using Web of Science (WOS), PubMed, and Google search was performed.

Results: Focusing on a few herbal hepatoprotective active constituents is useful to health professionals working in the field of therapeutics to develop evidence-based hepatoprotective agents by conducting research on pure chemical structures or on molecular modifications using computational chemistry. This review demonstrates that multi-pathways in the liver pathobiology can be interrupted at one or more levels by natural hepatoprotective studied, such as interference with the oxidative stress at multiple levels to reduce reactive oxygen/nitrogen species, resulting in ameliorating hepatotoxicity.

Conclusion: Hepatoprotective constituents of herbal medications are poorly absorbed after oral administration; methods that can improve their bioavailability are being developed. It is recommended that controlled prospective double-blind multicenter studies on isolated active plant constituents, or on related newly designed molecules after structural modifications, should be performed. This effort will lead to expanding the existing, limited drugs for the vast majority of liver diseases.     

Anti-hepatocellular carcinoma activity and mechanism of chemopreventive compounds: ursolic acid derivatives

Context: Hepatocellular carcinoma (HCC) is a common cancer around the world, with high mortality rate. Currently, there is no effective drug for the therapy of HCC. Ursolic acid (UA) is a natural product which exists in various medicinal herbs and fruits, exhibiting multiple biological effects such as its outstanding anticancer and hepatoprotective activity, which has drawn many pharmacists’ attention.

Objective: This paper summarizes the current status of the hepatoprotective activity of UA analogues and explains the related mechanism, providing a clear direction for the development of novel anti-HCC drugs.

Methods: All of the data resources were derived from PubMed. By comparing the IC₅₀ values and analyzing the structure–activity relationships, we listed compounds with good pharmacological activity from the relevant literature, and summarized their anti-HCC mechanism.

Results: From the database, 58 new UA derivatives possessing wonderful anticancer and hepatoprotective effects were listed, and the relevant anti-HCC mechanism were discussed.

Conclusion: UA’s anti-HCC effect is the result of combined action of many mechanisms. These 58 new UA derivatives, particularly compounds 45 and 53, can be used as potential drugs for the treatment of liver cancer.     

Clinical and causality assessment in herbal hepatotoxicity

Introduction: Herbal hepatotoxicity represents a poorly understood, neglected and multifaceted disease with numerous confounding variables and missing established causality in the majority of cases. This review discusses overt shortcomings in its clinical and causality assessment and suggests improvements.

Areas covered: A selective literature search of PubMed using the terms herbal hepatotoxicity, herb-induced liver injury, drug hepatotoxicity and drug-induced liver injury was performed to identify published case reports, spontaneous case reports, case series and review articles regarding hepatotoxicity due to herbs, herbal drugs and herbal dietary supplements. Covered areas focused on confounding variables related to the documentation of the herbal product and the clinical course, hepatotoxicity and reexposure criteria, temporal association, comedication and alternative causes with special attention to preexisting diseases of the liver, bile ducts and the pancreas. Of particular interest were recent discussions of approaches designed and validated for hepatotoxicity causality, such as the scale of CIOMS (Council for International Organizations of Medical Sciences).

Expert opinion: The authors call for substantial improvements in data quality of herbal products and case characteristics and strongly recommend using the CIOMS scale to assess causality in suspected herbal hepatotoxicity.     

Combinatorial Effects of Thymoquinone on the Anticancer Activity and Hepatotoxicity of the Prodrug CB 1954

Background:

One of the major causes of clinical trial termination is the liver toxicity induced by chemotherapeutic agents. Treatment with anticancer drugs like CB 1954 (5-(Aziridin-1-yl)-2,4-dinitrobenzamide) is associated with significant hepatotoxicity. Thymoquinone (TQ), extracted from Nigella sativa, is reported to possess anticancer and hepatoprotective effects. The aims of the present study were to use TQ to reduce hepatotoxicity associated with CB 1954 and to augment its anticancer activity against the resistant mouse mammary gland cell line (66 cl-4-GFP).

Method:

Balb/C mice were transplanted with the 66cl-4-GFP cell line and in vivo antitumor activity was assessed for CB 1954 (141 mg/kg), TQ (10 mg/kg), and a combination of CB 1954 and TQ. Changes in tumor size and body weight were measured for each treatment. Histological examination of tumors and liver tissue samples was performed using the standard hematoxylin/eosin staining protocol, and serum levels of the liver enzymes AST and ALT were used as biomarkers of hepatotoxicity.

Results:

Severe liver damage and elevated plasma levels of AST and ALT were observed in the group treated with CB 1954. Treatment of tumor-bearing mice with a combination of CB 1954 and TQ caused a significant regression in tumor size and induced extensive necrosis in these tumors. The combination also protected the liver from drug-induced damage and reduced the plasma levels of AST and ALT to their normal ranges.

Conclusion:

These results suggest that the use of TQ with CB 1954 can reduce CB 1954-induced hepatotoxicity and enhance its anticancer activity, indicating the potential use of this combination in clinical studies.     

Hepatotoxicity of targeted therapy for cancer

Introduction: Understanding the mechanism of DILI with MTA, and how to avoid and manage these toxicities is essential for minimising inferior cancer treatment outcomes. An organised and comprehensive overview of MTA-associated hepatotoxicity is lacking; this review aims to fill the gap.

Areas covered: A literature review was performed based on published case reports and relevant studies or articles pertaining to the topics on PubMed. Food and Drug Administration drug information documents and search on the US National Library of Medicine LiverTox database was performed for all relevant MTA.

Expert opinion: MTA-associated hepatotoxicity is common but rarely fatal. The pattern of hepatotoxicity is predominantly idiosyncratic. Pharmacogenomics show potential in predicting patients at risk of poorly metabolising or developing immunoallergic responses to MTA, but prospective data is scant. Preventing reactivation of viral hepatitis using anti-viral drugs, and avoidance of drug combinations at high risk of negative interactions are the most readily preventable measures for DILI.     

Role of food-derived antioxidant agents against acetaminophen-induced hepatotoxicity

Context Acetaminophen (APAP), also known as paracetamol and N-acetyl p-aminophenol, is one of the most frequently used drugs for analgesic and antipyretic purposes on a worldwide basis. It is safe and effective at recommended doses but has the potential for causing hepatotoxicity and acute liver failure (ALF) with overdose. To solve this problem, different strategies have been developed, including the use of compounds isolated from food, which have been studied to characterize their efficacy as natural dietary antioxidants.

Objective The objective of this study is to show the beneficial effects of a variety of natural compounds and their use against acetaminophen-induced hepatotoxicity.

Methods PubMed database was reviewed to compile data about natural compounds with hepatoprotective effects against APAP toxicity.

Results and conclusion As a result, the health-promoting properties of 13 different food-derived compounds with protective effect against APAP-induced hepatotoxicity were described as well as the mechanisms involved in hepatoprotection.     

Human biology-based drug safety evaluation: scientific rationale,current status and future challenges

Introduction: Animal toxicity studies used to assess the safety of new candidate pharmaceuticals prior to their progression into human clinical trials are unable to assess the risk of non-pharmacologically mediated idiosyncratic adverse drug reactions (ADRs), the most frequent of which are drug-induced liver injury and cardiotoxicity. Idiosyncratic ADRs occur only infrequently and in certain susceptible humans, but are caused by many hundreds of different drugs and may lead to serious illness.

Areas covered: Idiosyncratic ADRs are initiated by drug-related chemical insults, which cause toxicity due to susceptibility factors that manifest only in certain patients. The chemical insults can be detected using in vitro assays. These enable useful discrimination between drugs that cause high versus low levels of idiosyncratic ADR concern. Especially promising assays, which have been described recently in peer-reviewed scientific literature, are highlighted.

Expert opinion: Effective interpretation of in vitro toxicity data requires integration of endpoints from multiple assays, which each address different mechanisms, and must also take account of human systemic and tissue drug exposure in vivo. Widespread acceptance and use of such assays has been hampered by the lack of correlation between idiosyncratic human ADR risk and toxicities observed in vivo in animals.     

Idiosyncratic Liver Toxicity of Nonsteroidal Antiinflammatory Drugs: Molecular Mechanisms and Pathology

Abstract

This review explores the clinical hepatic pathology associated with the use of nonsteroidal antiinflammatory drugs (NSAIDs), possible cellular and molecular mechanisms of injury, and future challenges. NSAIDs comprise a group of widely used compounds that have been associated with rare adverse reactions in the liver, including fulminant hepatitis and cholestasis. These reactions are idiosyncratic, mostly independent of the dose administered, and host-dependent. The mechanisms responsible for the initiation and perpetuation of NSAID-induced hepatotoxicity remain poorly understood and have been largely inferred from clinical manifestation. A mounting body of evidence, however, indicates that many acidic NSAIDs are metabolized to reactive acyl glucuronides that can form covalent adducts with plasma proteins and hepatocellular proteins. In hepatocytes co-cultured with lymphocytes, these NSAID-altered proteins can become antigenic. Thus, long-lived, drug-altered proteins may act as immunogens and produce cytotoxic T-cell-mediated or antibody-dependent, cell-mediated toxicity in susceptible patients. Alternatively, individual abnormalities in metabolism or disposition of some NSAIDs may lead to the formation or accumulation of toxic metabolites. Additional work with transgenic animal models is needed to permit better understanding of the general and specific risk factors involved in the pathogenesis of the idiosyncratic liver injuries related to NSAIDs and other drugs.     

结直肠癌化疗所致肝损伤的影响因素及保肝药的合理性研究

目的 调查笔者所在医院结直肠恶性肿瘤患者化疗后肝损伤情况及保肝药的使用情况,分析可能影响肝损伤的有关因素,并评价不同化疗方案所致肝损伤的特点及使用保肝药的规范性。方法 对笔者所在医院2017年6月1日-2018年5月31日期间接受化疗的200例结直肠癌患者用药情况进行回顾性分析,记录患者的个人信息、化疗方案及使用保肝药的情况,分析相关因素并评价保肝药使用合理性。结果 从性别、年龄、体表面积、肿瘤类型、肿瘤分期、疗程、是否饮酒、化疗中出现的不良反应来分析与肝损伤可能有关的因素,发现肿瘤分期、疗程、化疗中出现中重度消化道反应与肝损伤有一定联系。从给药指征、重复给药、给药时机、疗程及用药禁忌等方面综合评价保肝药合理性,155例使用过保肝药的患者中,140例应用保肝药与说明书或指南推荐用法相符。结论 不同化疗方案的肝损伤程度之间的差异无统计学意义,肿瘤分期和化疗疗程是肝损伤的影响因素。此外临床医师应更加规范的使用保肝药。     

The hepatotoxicity of Polygonum multiflorum: The emerging role of the immune-mediated liver injury

Herbal and dietary supplements(HDS)-induced liver injury has been a great concern all over the world.Polygonum multiflorum Thunb.,a well-known Chinese herbal medicine,is recently drawn increasing attention because of its hepatotoxicity.According to the clinical and experimental studies,P.multiflorum-induced liver injury(PM-DILI)is considered to be immune-mediated idiosyncratic liver injury,but the role of immune response and the underlying mechanisms are not completely elucidated.Previous studies focused on the direct toxicity of PM-DILI by using animal models with intrinsic drug-induced liver injury(DILI).However,most epidemiological and clinical evidence demonstrate that PM-DILI is immune-mediated idiosyncratic liver injury.The aim of this review is to assess current epidemiological,clinical and experimental evidence about the possible role of innate and adaptive immunity in the idiosyncratic hepatotoxicity of P.multiflorum.The potential effects of factors associated with immune tolerance,including immune checkpoint molecules and regulatory immune cells on the individual’s susceptibility to PM-DILI are also discussed.We conclude by giving our hypothesis of possible immune mechanisms of PM-DILI and providing suggestions for future studies on valuable biomarkers identification and proper immune models establishment.     

Models of hepatotoxicity and the underlying cellular,biochemical and immunological mechanism(s): A critical discussion

Liver is a primary organ involved in biotransformation of food and drugs. Hepatic diseases are a major worldwide problem. Hepatic disorders are mainly caused by toxic chemicals (alcohol), xenobiotics (carbon tetrachloride, chlorinated hydrocarbons and gases CO₂ and O₂) anticancer (azathioprine, doxorubicin, cisplatin), immunosuppressant (cyclosporine), analgesic anti-inflammatory (paracetamol, thioacetamide), anti-tubercular (isoniazid, rifampicin) drugs, biologicals (Bacillus-Calmette–Guerin vaccine), radiations (gamma radiations), heavy metals (cadmium, arsenic), mycotoxin (aflatoxin), galactosamine, lipopolysaccharides, etc. Various risk factors for hepatic injury include concomitant hepatic diseases, age, gender, alcoholism, nutrition and genetic polymorphisms of cytochrome P₄₅₀ enzymes have also been emphasized.The present review enumerates various in vivo animal models and in vitro methods of hepatic injury using diverse toxicants, their probable metabolic pathways, and numerous biochemical changes viz. serum biomarkers enzymes, liver function, oxidative stress associated events like free radicals formation, lipid peroxidation, enzyme antioxidants and participation of cytokines (tumour necrosis factor-α, transforming growth factor-β, tumour necrosis factor-related apoptosis inducing ligand), and other biomolecules (Fas and C-jun N-terminal kinase) are also discussed. The underlying cellular, molecular, immunological, and biochemical mechanism(s) of action responsible for liver damage (toxicity) are also been discussed. This review should be immensely useful for researchers especially for phytochemists, pharmacologists and toxicologists working on hepatotoxicity, hepatotoxic chemicals and drugs, hepatoprotective agents and drug research organizations involved especially in phytopharmaceuticals and other natural products.     

The design and development of imidazothiazole–chalcone derivatives as potential anticancer drugs

Introduction: Imidazothiazole derivatives have long been therapeutically used for the treatment of various diseases. In recent years, the imidazothiazole and chalcone moieties have emerged as important pharmacophores in the development of antitumor agents. Imidazothiazole–chalcone conjugates can be accessed by covalently binding these two powerful pharamacophore units. These conjugates are known to exhibit a wide range of biological properties, including anticancer, antimicrobial, anti-inflammatory and immunosuppressive activities. Their promising biological profile and easy synthetic accessibility have triggered investigations directed at the design and development of new imidazothiazole–chalcone conjugate derivatives as potential chemotherapeutics.

Areas covered: The present review focuses on recent reports of the syntheses and anticancer properties of various imidazothiazoles, chalcones and imidazothiazole-linked chalcone conjugates. Furthermore, the authors discuss the structure–activity relationships (SAR) of imidazothiazoles and chalcones and their conjugates as new antitumor agents, as well as in vitro and in vivo evaluation, clinical use and their future therapeutic applications.

Expert opinion: A large number of imidazothiazoles, chalcones and a new series of imidazothiazole–chalcone conjugates possess potent anticancer activity that could be further developed as drug candidates. Imidazothiazole-based conjugates could also display synergistic effect, and still there is a need to use the drug combinations permitting lower dose and development of new generation of drugs. Despite encouraging observed results for their response to tumors in clinical studies, full characterization of their toxicity is further required for their clinical usage as safe drugs for the treatment of cancer.     

Thirty-day rat toxicity study reveals reversible liver toxicity of mifepristone (RU486) and metapristone

Objective: Mifepristone (RU486) is an oral first-line contraceptive used by hundreds of millions of women, and recently it was tested for anticancer activity in both genders worldwide. We are developing metapristone (the N-monodemethyl RU486) as a potential metastasis chemopreventive. The present acute and 30-d subacute toxicity study aimed at examining and compared in parallel the potential toxicity of the two drugs.

Methods: The single-dose acute toxicity and 30-d subacute toxicity studies were conducted in mice and rats, respectively, by gavaging metapristone or mifepristone at various doses. Blood samples and organs were collected for blood chemistry, hematology and histology analyses.

Results: Oral mifepristone (3000?mg/kg) caused 30% and 40% death in female and male mice, respectively, within 15 h post-dosing. In comparison, the same dose of metapristone produced 30% acute death in males only. Thirty-day oral administration of the two drugs to rats (12.5, 50 and 200?mg/kg/day) caused reversible hepatotoxicity that only occurred at 200?mg/kg/day group, evidenced by the elevated liver enzyme activity and liver organ weight.

Conclusion: The present study, for the first time, reveals reversible hepatotoxicity in rats caused by the 30-d consecutive administration at the high dose, and warns the potential hepatotoxicity caused by long-term administrations of high doses of mifepristone or metapristone in clinical trials but not by the acute single abortion doses.     

Interactions between oral antineoplastic agents and concomitant medication: a systematic review

Introduction: In recent years, the number of oral antitumoral agents has considerably increased. Oral administration increases the risk of interactions, because most oral anticancer drugs are taken on a daily basis. Interactions can increase exposure to antitumoral agents or cause treatment failure. Many antitumoral drugs undergo enzymatic metabolism by cytochrome P450. As some act as inducers or inhibitors of one or more isoenzymes, they can lead to decreases or increases in plasma concentrations of concomitant drugs. Hence, cytostatic drugs can act not only as victims but also as perpetrators. P-glycoprotein, an efflux transporter, can also be involved in pharmacokinetic interactions.

Areas covered: A Medline search was performed to summarize the available evidence of the most clinically relevant interactions between oral chemotherapy agents and other drugs. The search covered the period from 1966 until August 2012 for each antitumoral drug using the medical subject headings ‘Drug Interactions' OR ‘Pharmacokinetics'. While the present review is not exhaustive, it aims to increase clinicians' awareness of potential drug–drug interactions.

Expert opinion: As cancer patients are often polymedicated and treated by different physicians, the risk of drug interactions between antitumoral agents and other medications is high. More clinical interaction studies are encouraged to ensure appropriate antineoplastic pharmacokinetics in clinical practice.     

Bile acids and bile acid derivatives: use in drug delivery systems and as therapeutic agents

ABSTRACT

Introduction: Bile acids are biological surfactants and signaling molecules with important paracrine and endocrine functions. The enterohepatic organotropism of bile acids turns these facial amphiphiles into attractive drug delivery systems for selective drug targeting to the liver or to enhance drug bioavailability by improving intestinal absorption and metabolic stability.

Areas covered: Bile acid-based amphiphiles, in the form of mixed micelles, bilosomes, drug conjugates and hybrid lipid-polymer nanoparticles are critically discussed as delivery systems for anticancer drugs, antimicrobial agents and therapeutic peptides/proteins, including vaccines. Therapeutic applications of bile acid derivatives as cytotoxic and neuroprotective agents are also addressed.

Expert opinion: Bile acids play an important role in modulating cancer therapy and novel derivatives with cytotoxic activity not restricted to the gastrointestinal tract can be expected. Selective toxicity targeting the bacterial membrane remains an attractive area of research for further development of bile acid-based bactericidal agents. On the other hand, the neuroprotective properties of some bile acids offer therapeutic potential in neurodegenerative disorders. Bile acid-based nanoparticles are also a growing research area due to the unique characteristics and tunable properties of these nanosystems. Therefore, multifaceted pharmaceutical and biomedical applications of bile salts are to be expected in the near future.     

Hepatotoxicity reports in the FDA adverse event reporting system database: A comparison of drugs that cause injury via mitochondrial or other mechanisms

Drug-induced liver injury (DILI) is a leading reason for preclinical safety attrition and post-market drug withdrawals. Drug-induced mitochondrial toxicity has been shown to play an essential role in various forms of DILI, especially in idiosyncratic liver injury. This study examined liver injury reports submitted to the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) for drugs associated with hepatotoxicity via mitochondrial mechanisms compared with non-mitochondrial mechanisms of toxicity. The frequency of hepatotoxicity was determined at a group level and individual drug level. A reporting odds ratio (ROR) was calculated as the measure of effect. Between the two DILI groups, reports for DILI involving mitochondrial mechanisms of toxicity had a 1.43 (95% CI 1.42–1.45; P < 0.0001) times higher odds compared to drugs associated with non-mitochondrial mechanisms of toxicity. Antineoplastic, antiviral, analgesic, antibiotic, and antimycobacterial drugs were the top five drug classes with the highest ROR values. Although the top 20 drugs with the highest ROR values included drugs with both mitochondrial and non-mitochondrial injury mechanisms, the top four drugs (ROR values > 18: benzbromarone, troglitazone, isoniazid, rifampin) were associated with mitochondrial mechanisms of toxicity. The major demographic influence for DILI risk was also examined. There was a higher mean patient age among reports for drugs that were associated with mitochondrial mechanisms of toxicity [56.1 ± 18.33 (SD)] compared to non-mitochondrial mechanisms [48 ± 19.53 (SD)] (P < 0.0001), suggesting that age may play a role in susceptibility to DILI via mitochondrial mechanisms of toxicity. Univariate logistic regression analysis showed that reports of liver injury were 2.2 (odds ratio: 2.2, 95% CI 2.12–2.26) times more likely to be associated with older patient age, as compared with reports involving patients less than 65 years of age. Compared to males, female patients were 37% less likely (odds ratio: 0.63, 95% CI 0.61–0.64) to be subjects of liver injury reports for drugs associated with mitochondrial toxicity mechanisms. Given the higher proportion of severe liver injury reports among drugs associated with mitochondrial mechanisms of toxicity, it is essential to understand if a drug causes mitochondrial toxicity during preclinical drug development when drug design alternatives, more clinically relevant animal models, and better clinical biomarkers may provide a better translation of drug-induced mitochondrial toxicity risk assessment from animals to humans. Our findings from this study align with mitochondrial mechanisms of toxicity being an important cause of DILI, and this should be further investigated in real-world studies with robust designs.     

Tumor vasculature as target for therapeutic intervention

Importance of the field: Solid tumors rely on efficient oxygen and nutrients transport for their growth, development and survival. Many tumors can stimulate new blood vessel formation. Because this angiogenic vasculature is aberrant from normal host vasculature, several strategies have been explored that specifically target tumor blood vessels.

Areas covered in this review: Over the past decade, many molecules that act on tumor vasculature have been identified. They can be divided into three groups based on their mechanism of action: i) antiangiogenic molecules cause tumor growth arrest; ii) vasoactive agents induce hyperabnormalization of the tumor vasculature, improving conventional drug accumulation in the tumor; iii) vascular disrupting agents that cause blood vessel congestion, resulting in massive secondary tumor cell necrosis. Many investigational drugs from these classes are currently being evaluated to assess their role in tumor therapy.

What the reader will gain: The underlying principle of each of the strategies is discussed, and the (pre)clinical results of the investigational drugs in this class are highlighted.

Take home message: To fully exploit the therapeutic potential of these drugs, it appears necessary to combine them with conventional anticancer agents, improve their selectivity for tumor vasculature, and develop biomarkers that predict the tumor sensitivity for these vascular strategies.     

Targeting the pregnane X receptor in liver injury

Introduction: The nuclear receptor pregnane X receptor (PXR) is a well-characterized hepatic xenobiotic sensor whose activation by chemically diverse compounds results in the induction of drug clearance pathways that rid the body of potentially toxic substances, thus conferring protection from foreign chemicals and endobiotics.

Areas covered: PXR activities are implicated in drug–drug interactions and endocrine disruption. Recent evidence supports a hepatoprotective role for PXR in chronic liver injury, inhibiting liver inflammation through suppression of the NF-κB pathway. However, PXR-mediated induction of CYP3A enhances APAP-induced acute liver injury by generating toxic metabolites. While these observations implicate PXR as a therapeutic target for liver injury, they also caution against PXR activation by pharmaceutical drugs.

Expert opinion: While evidence of PXR involvement in acute and chronic liver injuries identifies it as a possible therapeutic target, it raises additional concerns for all drug candidates. The in vitro and in vivo tests for human PXR activation should be incorporated into the FDA regulations for therapeutic drug approval to identify potential liver toxicities. In addition, PXR pharmacogenetic studies will facilitate the prediction of patient-specific drug reactivities and associated liver disorders.     

Clinical hepatotoxicity associated with antifungal agents

Introduction: Invasive fungal diseases (IFDs) are a leading cause of morbidity and mortality among immunocompromised patients with bone marrow failure syndromes, hematological malignancies, hematopoietic stem cell transplantation (HSCT), those admitted in intensive care units (ICUs) and those with prolonged febrile neutropenia. IFDs occur in a setting of multiple morbidities and are associated with case fatality rates between 30 and 70%. Along with the development of classes and compounds, the last two decades have seen substantial improvements in the prevention and management of these infections and an overall increased use of antifungal agents.

Areas covered: All antifungal agents, including amphotericin B formulations, echinocandins and the triazoles, may cause hepatic toxicity that ranges from mild and asymptomatic abnormalities in liver function tests to substantial liver injury and fulminant hepatic failure.

Expert opinion: The present article reviews incidence and severity of hepatotoxicity associated with different classes and agents to provide a better understanding of this specific end organ toxicity and safer use of antifungal agents A thorough understanding of the distribution, metabolism, elimination and drug-drug interactions of antifungal agents used for management of IFDs in combination with safety data from clinical trials, pharmacokinetic and pharmacodynamic studies may guide the use of antifungal treatment in patients at high risk for the development of hepatic dysfunction and in those with underlying liver damage due to cytotoxic therapy.     

A zebrafish phenotypic assay for assessing drug-induced hepatotoxicity

IntroductionNumerous studies have confirmed that zebrafish and mammalian toxicity profiles are strikingly similar and the transparency of larval zebrafish permits direct in vivo assessment of drug toxicity including hepatotoxicity in zebrafish.MethodsHepatotoxicity of 6 known mammalian hepatotoxic drugs (acetaminophen [APAP], aspirin, tetracycline HCl, sodium valproate, cyclophosphamide and erythromycin) and 2 non-hepatotoxic compounds (sucrose and biotin) were quantitatively assessed in larval zebrafish using three specific phenotypic endpoints of hepatotoxicity: liver degeneration, changes in liver size and yolk sac retention. Zebrafish liver degeneration was originally screened visually, quantified using an image-based morphometric analysis and confirmed by histopathology.ResultsAll the tested mammalian hepatotoxic drugs induced liver degeneration, reduced liver size and delayed yolk sac absorption in larval zebrafish, whereas the non-hepatotoxic compounds did not have observable adverse effect on zebrafish liver. The overall prediction success rate for hepatotoxic drugs and non-hepatotoxic compounds in zebrafish was 100% (8/8) as compared with mammalian results, suggesting that hepatotoxic drugs in mammals also caused similar hepatotoxicity in zebrafish.DiscussionLarval zebrafish phenotypic assay is a highly predictive animal model for rapidly in vivo assessment of compound hepatotoxicity. This convenient, reproducible animal model saves time and money for drug discovery and can serve as an intermediate step between cell-based evaluation and conventional animal testing of hepatotoxicity.