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Drug-induced liver injury: Interactions between drug properties and host factors

  • Author Footnotes
    † These authors equally contributed to the manuscript.
    Minjun Chen
    Footnotes
    † These authors equally contributed to the manuscript.
    Affiliations
    Division of Bioinformatics and Biostatistics, National Center for Toxicological Research, US Food and Drug Administration, Jefferson, AR, United States
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  • Author Footnotes
    † These authors equally contributed to the manuscript.
    Ayako Suzuki
    Footnotes
    † These authors equally contributed to the manuscript.
    Affiliations
    Gastroenterology, Central Arkansas Veterans Healthcare System, Little Rock, AR, United States

    Department of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, United States
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  • Jürgen Borlak
    Affiliations
    Center of Pharmacology and Toxicology, Hannover Medical School, Hannover, Germany
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  • Raúl J. Andrade
    Correspondence
    Corresponding author. Address: Departamento de Medicina, Facultad de Medicina, Boulevard Louis Pasteur 32, 29071 Malaga, Spain. Tel.: +34 952 134242; fax: +34 952 131511.
    Affiliations
    Unidad de Gestión Clínica de Enfermedades Digestivas, Servicio de Farmacología Clínica, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Málaga, Spain

    Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
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  • M Isabel Lucena
    Affiliations
    Unidad de Gestión Clínica de Enfermedades Digestivas, Servicio de Farmacología Clínica, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Málaga, Spain

    Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
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  • Author Footnotes
    † These authors equally contributed to the manuscript.
Open AccessPublished:April 22, 2015DOI:https://doi.org/10.1016/j.jhep.2015.04.016

      Summary

      Idiosyncratic drug-induced liver injury (DILI) is a common cause for drug withdrawal from the market and although infrequent, DILI can result in serious clinical outcomes including acute liver failure and the need for liver transplantation. Eliminating the iatrogenic “harm” caused by a therapeutic intent is a priority in patient care. However, identifying culprit drugs and individuals at risk for DILI remains challenging. Apart from genetic factors predisposing individuals at risk, the role of the drugs’ physicochemical and toxicological properties and their interactions with host and environmental factors need to be considered. The influence of these factors on mechanisms involved in DILI is multi-layered. In this review, we summarize current knowledge on 1) drug properties associated with hepatotoxicity, 2) host factors considered to modify an individuals’ risk for DILI and clinical phenotypes, and 3) drug-host interactions. We aim at clarifying knowledge gaps needed to be filled in as to improve risk stratification in patient care. We therefore broadly discuss relevant areas of future research. Emerging insight will stimulate new investigational approaches to facilitate the discovery of clinical DILI risk modifiers in the context of disease complexity and associated interactions with drug properties, and hence will be able to move towards safety personalized medicine.

      Abbreviations:

      DILI (drug-induced liver injury), HLA (human leucocyte antigen), DAMPs (the damage associated molecular pattern molecules), ADMET (absorption, distribution, metabolism, excretion and toxicity), GST (glutathione-S-transferase), ROS (reactive oxygen species), JNK (c-Jun N-terminal kinase), Nrf-2 (nuclear factor erythroid 2-related factor 2), Keap-1 (Kelch-like ECH-associated protein 1), mtDNA (mitochondrial DNA), MPT (mitochondrial permeability transition), BSEP (bile salt export pump), ATP (adenosine triphosphate), P-gp (P-glycoprotein), MRP (multidrug resistance-associated protein), NAT2 (N-acetyltransferase 2), CYP450 (cytochrome P450), GSTM1 (glutathione S-transferase Mu 1), GSTT1 (glutathione S-transferase theta 1), NSAIDs (non-steroidal anti-inflammatory drugs), GSH (gluthatione), POLG (polymerase (DNA directed), gamma), FXR (farnesoid X receptor), LPS (lipopolysaccharides), MELD (Model for end-stage liver disease), PARP-1 (Poly-(ADP-Ribose) Polymerase-1), NAFLD (non-alcoholic fatty liver disease), SOD2 (superoxide dismutase 2), GPX1 (glutathione peroxidase), NASH (nonalcoholic steatohepatitis), UDPGT (UDP-glucuronosyltransferase), NRTIs (nucleoside reverse transcriptase Inhibitors), PPARγ (peroxisome proliferator-activated receptor gamma), APC (antigen-presenting cell), MHC (major histocompatibility complex)

      Keywords

      Introduction

      Drug-induced hepatotoxicity is one of the major concerns in medical practice. Although it is relatively uncommon, drug-induced liver injury (DILI) is the leading cause of acute liver failure in the US and a major reason for liver transplantation [
      • Reuben A.
      • Koch D.G.
      • Lee W.M.
      Drug-induced acute liver failure: results of a US multicenter, prospective study.
      ]. Many marketed drugs, herbs and dietary supplements have a potential to cause liver injury. In preclinical studies, about 50% of candidate compounds present hepatic effects at supra-therapeutic dose and face drug attrition [
      • Amacher D.E.
      Serum transaminase elevations as indicators of hepatic injury following the administration of drugs.
      ]. DILI is also a major cause for drug failure in clinical trials and frequently results in regulatory actions and drug withdrawal [
      • Watkins P.B.
      Drug safety sciences and the bottleneck in drug development.
      ,
      • Chen M.
      • Zhang J.
      • Wang Y.
      • Liu Z.
      • Kelly R.
      • Zhou G.
      • et al.
      Liver Toxicity Knowledge Base (LTKB) – A systems approach to a complex endpoint.
      ].
      The incidence of DILI in general populations is about 14–19 per 100,000 inhabitants [
      • Sgro C.
      • Clinard F.
      • Ouazir K.
      • Chanay H.
      • Allard C.
      • Guilleminet C.
      • et al.
      Incidence of drug-induced hepatic injuries: a French population-based study.
      ,
      • Bjornsson E.S.
      • Bergmann O.M.
      • Bjornsson H.K.
      • Kvaran R.B.
      • Olafsson S.
      Incidence, presentation, and outcomes in patients with drug-induced liver injury in the general population of Iceland.
      ], while frequency estimated in a healthcare system is around 30–33 per 100,000 persons [
      • Shin J.
      • Hunt C.M.
      • Suzuki A.
      • Papay J.I.
      • Beach K.J.
      • Cheetham T.C.
      Characterizing phenotypes and outcomes of drug-associated liver injury using electronic medical record data.
      ]. The reported incidence and severity of DILI varies among drugs [
      • Bjornsson E.S.
      • Bergmann O.M.
      • Bjornsson H.K.
      • Kvaran R.B.
      • Olafsson S.
      Incidence, presentation, and outcomes in patients with drug-induced liver injury in the general population of Iceland.
      ,
      • Shin J.
      • Hunt C.M.
      • Suzuki A.
      • Papay J.I.
      • Beach K.J.
      • Cheetham T.C.
      Characterizing phenotypes and outcomes of drug-associated liver injury using electronic medical record data.
      ], suggesting that drug properties have a role in DILI risk determination. Conversely, drugs with DILI potential cause liver injury only in a small portion of patients indicating that host factors play a major role in DILI development.
      DILI is classified into intrinsic vs. idiosyncratic liver injury, reflecting a dominant role of drug toxicity (dose-dependent) vs. host factors (no dose dependence) in liver injury. With a few exceptions (i.e., acetaminophen), most of DILI experienced in humans are considered idiosyncratic. However, inflammatory stress may influence the dose-response curve towards sensitization for toxicity at therapeutic doses, making the two DILI types less distinct [
      • Roth R.A.
      • Ganey P.E.
      Intrinsic versus idiosyncratic drug-induced hepatotoxicity – Two villains or one?.
      ]. Indeed, around 10% of acetaminophen-induced acute liver failure cases occurred at recommended dosage, suggesting host factors modify individual risks of acetaminophen liver injury [
      • Larson A.M.
      • Polson J.
      • Fontana R.J.
      • Davern T.J.
      • Lalani E.
      • Hynan L.S.
      • et al.
      Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study.
      ,
      • Gulmez S.E.
      • Larrey D.
      • Pageaux G.P.
      • Lignot S.
      • Lassalle R.
      • Jove J.
      • et al.
      Transplantation for acute liver failure in patients exposed to NSAIDs or paracetamol (acetaminophen): the multinational case-population SALT study.
      ]. Besides, drug dosage is a well-known determinant of idiosyncratic DILI [
      • Lammert C.
      • Einarsson S.
      • Saha C.
      • Niklasson A.
      • Bjornsson E.
      • Chalasani N.
      Relationship between daily dose of oral medications and idiosyncratic drug-induced liver injury: search for signals.
      ,
      • Chen M.
      • Borlak J.
      • Tong W.
      High lipophilicity and high daily dose of oral medications are associated with significant risk for drug-induced liver injury.
      ]. Thus, the two entities may rather coincide in human DILI.
      The current mechanistic understanding of DILI is depicted in Fig. 1. The key mechanisms in DILI are two-fold: 1) drug/metabolite exposure to a threshold level, determined by the dose and drug handling of the liver, and 2) the adaptive immune response or “alarm-signalling” by the damage associated molecular pattern molecules (DAMPs) [
      • Kaplowitz N.
      Avoiding idiosyncratic DILI: two is better than one.
      ]. Cellular damage occurs at an intricate balance between toxic drug exposure and defence mechanisms. Once cells are damaged, innate and adaptive responses kick-in and play a significant role in driving tissue inflammation and injury. The degree of local tissue inflammation and injury, in a balance with tissue repair, influences overall tissue damage and determines clinical outcome. Drug exposure and properties of administered drugs play primary roles at the initial stages of cellular damage while host factors drive ‘host responses’ to toxic insults with the induction of cellular repair programs.
      Figure thumbnail gr1
      Fig. 1Current mechanistic understanding in the initiation and progression events relevant to idiosyncratic drug-induced liver injury. Two mechanistic cascades, (A) Sterile inflammation caused by drug-induced cytotoxicity vs. (B) Immune response via antigen presenting cells (APCs) and/or helper T-cells. Drugs/reactive metabolites exert direct toxicity or form adducts leading to haptenization. Cells respond by activating adaptive pathways. Injured hepatocytes release “danger signals”, such as the damage associated molecular patterns molecules (DAMPs) which favour the release of pro-inflammatory cytokines to induce a T/B-cell response against hepatocytes. The HLA associations discovered in GWAS suggest that the adaptive immune response is an upstream event. The innate immune system can either co-stimulate the adaptive immunity or modulate the degree of inflammation and regeneration.
      Figure thumbnail fx3

      Drug properties related to DILI risk in humans

      Drugs within a therapeutic class differ regarding their hepatic liability, suggesting that physicochemical and toxicological drug properties affect DILI risk. Typical examples are thiazolidinediones, of which troglitazone was withdrawn from market due to fatal hepatotoxicity, while rosiglitazone and pioglitazone were less harmful to the liver. Among drug properties, factors contributing to initial cell damage include surpassing a threshold dose, physicochemical characteristics, reactive metabolites formation, oxidative stress, mitochondrial hazard and inhibition of hepatic transporters.

      Threshold dose

      Idiosyncratic DILI is considered dose-independent; most DILI cases occur at therapeutic dose in an individual despite being well tolerated in the general populations. However, in preclinical testing, hepatotoxicity is often predicted at high drug exposure leading to several stress responses in hepatocytes [
      • Kaplowitz N.
      • DeLeve L.D.
      Drug-induced liver disease.
      ]. The conventional concept of dose independency is being challenged [
      • Senior J.R.
      What is idiosyncratic hepatotoxicity? What is it not?.
      ]. Uetrecht firstly suggested that idiosyncratic DILI was rarely observed with drugs given at daily doses of ⩽10 mg [
      • Uetrecht J.P.
      New concepts in immunology relevant to idiosyncratic drug reactions: the “danger hypothesis” and innate immune system.
      ] and many drugs withdrawn from market or issued with a boxed warning (e.g. nimesulide, bosentan) due to hepatotoxicity, were prescribed at daily doses ⩾50 or 100 mg [
      • Walgren J.L.
      • Mitchell M.D.
      • Thompson D.C.
      Role of metabolism in drug-induced idiosyncratic hepatotoxicity.
      ,
      • Stepan A.F.
      • Walker D.P.
      • Bauman J.
      • Price D.A.
      • Baillie T.A.
      • Kalgutkar A.S.
      • et al.
      Structural alert/reactive metabolite concept as applied in medicinal chemistry to mitigate the risk of idiosyncratic drug toxicity: a perspective based on the critical examination of trends in the top 200 drugs marketed in the United States.
      ]. Moreover, DILI patients in large cohorts from Spain and Iceland [
      • Bjornsson E.S.
      • Bergmann O.M.
      • Bjornsson H.K.
      • Kvaran R.B.
      • Olafsson S.
      Incidence, presentation, and outcomes in patients with drug-induced liver injury in the general population of Iceland.
      ,
      • Andrade R.J.
      • Lucena M.I.
      • Fernández M.C.
      • Pelaez G.
      • Pachkoria K.
      • García-Ruiz E.
      • et al.
      Drug-induced liver injury: an analysis of 461 incidences submitted to the Spanish registry over a 10-year period.
      ] and 81% of non-acetaminophen DILI patients undergoing liver transplantation in the United States received medications with daily doses of ⩾50 mg [
      • Reuben A.
      • Koch D.G.
      • Lee W.M.
      Drug-induced acute liver failure: results of a US multicenter, prospective study.
      ]. Therefore, a significant association between daily dose and poor DILI outcome (i.e. liver failure, transplantation and death) exists and was also found in a systematic survey based on pharmaceutical databases [
      • Lammert C.
      • Einarsson S.
      • Saha C.
      • Niklasson A.
      • Bjornsson E.
      • Chalasani N.
      Relationship between daily dose of oral medications and idiosyncratic drug-induced liver injury: search for signals.
      ]. These evidences suggest that surpassing a threshold dose is associated with an increased risk of triggering liver injury among the treated patients. Daily dose alone is, however, inadequate to reliably predict DILI risk from individual drugs because a majority of compounds needs ⩾50 mg to achieve efficacy [
      • Stephens C.
      • Andrade R.J.
      • Lucena M.I.
      Mechanisms of drug-induced liver injury.
      ].

      Lipophilicity

      A drug’s physicochemical property is known to affect cellular uptakes and ADMET (absorption, distribution, metabolism, excretion and toxicity). Chen et al. [
      • Chen M.
      • Borlak J.
      • Tong W.
      High lipophilicity and high daily dose of oral medications are associated with significant risk for drug-induced liver injury.
      ] explored the impact of lipophilicity in combination with daily dose and found oral medications at high daily doses (⩾100 mg) and a lipophilicity of logP ⩾3 to be significantly associated with severe DILI. Their study demonstrated that both factors could individually predict hepatotoxicity, while the “rule-of-two”, which combines dose and lipophilicity, performs better than daily dose alone, thus increasing the positive predictive value from 85% to 96% while decreasing the negative predictive value from 55% to 39%. Higher lipophilicity could enhance DILI risk by facilitating drug uptake from blood into hepatocytes, which conditions hepatic metabolism and may result in a greater amount of reactive metabolites, subsequently leading to an interaction with mitochondrial membranes and hepatocanalicuar transport [
      • Kaplowitz N.
      Avoiding idiosyncratic DILI: two is better than one.
      ,
      • Will Y.
      • Dykens J.
      Mitochondrial toxicity assessment in industry-a decade of technology development and insight.
      ]. Besides lipophilicity, other physiochemical properties as molecular weight and total polar surface area associate with in vivo toxicological outcomes [
      • Hughes J.D.
      • Blagg J.
      • Price D.A.
      • Bailey S.
      • Decrescenzo G.A.
      • Devraj R.V.
      • et al.
      Physiochemical drug properties associated with in vivo toxicological outcomes.
      ,
      • Chen M.
      • Bisgin H.
      • Tong L.
      • Hong H.
      • Fang H.
      • Borlak J.
      • et al.
      Toward predictive models for drug-induced liver injury in humans: are we there yet?.
      ].

      Formation of reactive metabolites

      Several lines of evidence suggests that the formation of reactive metabolites play a central role in the pathogenesis of idiosyncratic DILI [
      • Knowles S.R.
      • Uetrecht J.
      • Shear N.H.
      Idiosyncratic drug reactions: the reactive metabolite syndromes.
      ]. Reactive metabolites can covalently bind proteins to form drug-protein adducts that might trigger immune-mediated reactions or exert direct toxicity [
      • Pessayre D.
      • Fromenty B.
      • Berson A.
      • Robin M.-A.
      • Lettéron P.
      • Moreau R.
      • et al.
      Central role of mitochondria in drug-induced liver injury.
      ,
      • Faulkner L.
      • Meng X.
      • Park B.K.
      • Naisbitt D.J.
      The importance of hapten–protein complex formation in the development of drug allergy.
      ]. Cholestasis may also be a consequence of the canalicular secretion of reactive metabolites or disintegration of labile glutathione and/or glucuronide conjugates thereby damaging cholangiocytes or triggering an immune response. However, for a given drug, there is no clear-cut correlation between the potential to form reactive metabolites in experimental conditions and the actual incidence of hepatotoxicity in humans [
      • Park B.
      • Laverty H.
      • Srivastava A.
      • Antoine D.
      • Naisbitt D.
      • Williams D.
      Drug bioactivation and protein adduct formation in the pathogenesis of drug-induced toxicity.
      ]. Obach et al. [
      • Obach R.S.
      • Kalgutkar A.S.
      • Soglia J.R.
      • Zhao S.X.
      Can in vitro metabolism-dependent covalent binding data in liver microsomes distinguish hepatotoxic from nonhepatotoxic drugs? An analysis of 18 drugs with consideration of intrinsic clearance and daily dose.
      ] measured the formation of reactive metabolites in vitro and found that metabolism-dependent covalent binding with liver microsomes cannot distinguish hepatotoxic and non-hepatotoxic drugs. Another experimental study tested approximately 100 Merck drug candidates and found no correlation between liver toxicity observed from in vivo animal studies and the extent of covalent binding [
      • Park B.K.
      • Boobis A.
      • Clarke S.
      • Goldring C.E.P.
      • Jones D.
      • Kenna J.G.
      • et al.
      Managing the challenge of chemically reactive metabolites in drug development.
      ]. Within a given drug class, specific chemical structures can render the compound distinctly hepatotoxic. For instance, ebroditine, an antiulcer drug pharmacologically related to famotidine, carries a bromobenzene ring which undergoes metabolic activation to reactive epoxides [
      • Andrade R.J.
      • Lucena M.I.
      • Martin-Vivaldi R.
      • Fernandez M.C.
      • Nogueras F.
      • Pelaez G.
      • et al.
      Acute liver injury associated with the use of ebrotidine, a new H2-receptor antagonist.
      ]. Likewise, temafloxacin and trovafloxacin share a unique difluorinated side chain that does not occur in other quinolones with much less hepatotoxicity [
      • Lucena M.I.
      • Andrade R.J.
      • Rodrigo L.
      • Salmerón J.
      • Alvarez A.
      • Lopez-Garrido M.
      • et al.
      Trovafloxacin-induced acute hepatitis.
      ].

      Oxidative stress

      Oxidative damage in the liver could be a consequence of cytosolic oxidant stress after drug metabolism or could arise from oxidant stress directly generated in mitochondria and the subsequent inflammatory cell response by injured hepatocytes. Oxidative stress is caused by an imbalance of reactive oxygen species (ROS) formation (c-Jun N-terminal kinase, JNK) and its detoxification by antioxidant defence systems (Nrf2/Keap1) [
      • Jaeschke H.
      • McGill M.R.
      • Ramachandran A.
      Oxidant stress, mitochondria, and cell death mechanisms in drug-induced liver injury: lessons learned from acetaminophen hepatotoxicity.
      ]. The balance of products of oxidative stress, protective cellular defence and cytokines modulating inflammation may be critical for DILI susceptibility, severity and extent of injury. Increased ROS can directly damage DNA, proteins, enzymes, and lipids in cells and tissues and induce immune-mediated liver damage. Some drugs (e.g. valproic acid) can induce enhanced generation of ROS by interrupting the homeostasis of mitochondria respiratory chain and triggering JNK signalling pathway, to subsequently activate mitochondrial permeability and death of hepatocytes [
      • Jaeschke H.
      • McGill M.R.
      • Ramachandran A.
      Oxidant stress, mitochondria, and cell death mechanisms in drug-induced liver injury: lessons learned from acetaminophen hepatotoxicity.
      ]. Recent reports suggest drug-induced oxidative stress also significantly correlate with DILI risk. Xu et al. identified ROS generation along with mitochondrial damage and intracellular glutathione depletion, as most important indicators contributing to hepatotoxicity as determined by high content imaging in primary human hepatocyte cultures [
      • Xu J.J.
      • Henstock P.V.
      • Dunn M.C.
      • Smith A.R.
      • Chabot J.R.
      • de Graaf D.
      Cellular imaging predictions of clinical drug-induced liver injury.
      ].

      Mitochondrial liability

      Mitochondrial dysfunction plays a critical role in the pathogenesis of DILI by alteration of metabolic pathways and damage to mitochondrial components [
      • Jaeschke H.
      • McGill M.R.
      • Ramachandran A.
      Oxidant stress, mitochondria, and cell death mechanisms in drug-induced liver injury: lessons learned from acetaminophen hepatotoxicity.
      ,
      • Boelsterli U.A.
      • Lim P.L.
      Mitochondrial abnormalities – A link to idiosyncratic drug hepatotoxicity?.
      ]. Drugs such as stavudine and amiodarone can induce steatosis/steatohepatitis by severely altering mitochondrial function. Mitochondrial damage could trigger hepatic necrosis and/or apoptosis, leading to activation of cell death signalling pathways such as JNK when a critical mitochondrial death threshold is surpassed [
      • Boelsterli U.A.
      • Lim P.L.
      Mitochondrial abnormalities – A link to idiosyncratic drug hepatotoxicity?.
      ,
      • Han D.
      • Dara L.
      • Win S.
      • Than T.A.
      • Yuan L.
      • Abbasi S.Q.
      • et al.
      Regulation of drug-induced liver injury by signal transduction pathways: critical role of mitochondria.
      ]. This view challenges the traditional paradigm, indicating that cell death is rather an active process involving mitochondria thereby determining the fate of cells as opposed to overwhelming biochemical injury [
      • Han D.
      • Dara L.
      • Win S.
      • Than T.A.
      • Yuan L.
      • Abbasi S.Q.
      • et al.
      Regulation of drug-induced liver injury by signal transduction pathways: critical role of mitochondria.
      ]. Specifically, drugs can impair mitochondrial respiration (valproic acid) and/or β-oxidation (aspirin, tamoxifen), trigger mitochondrial membrane disruption (diclofenac) and damage mtDNA (tacrine) [
      • Dykens J.A.
      • Will Y.
      The significance of mitochondrial toxicity testing in drug development.
      ,
      • Labbe G.
      • Pessayre D.
      • Fromenty B.
      Drug-induced liver injury through mitochondrial dysfunction: mechanisms and detection during preclinical safety studies.
      ,
      • Chen M.
      • Tung C.-W.
      • Shi Q.
      • Guo L.
      • Shi L.
      • Fang H.
      • et al.
      A testing strategy to predict risk for drug-induced liver injury in humans using high-content screen assays and the ‘rule-of-two’ model.
      ]. Interestingly, Porceddu et al. [
      • Porceddu M.
      • Buron N.
      • Roussel C.
      • Labbe G.
      • Fromenty B.
      • Borgne-Sanchez A.
      Prediction of liver injury induced by chemicals in human with a multiparametric assay on isolated mouse liver mitochondria.
      ] reported a significant association between loss of mitochondrial integrity and the potential to cause DILI, based on the analysis of 124 chemicals/drugs.

      Inhibition of BSEP and other hepatobiliary transporters

      Hepatobiliary transporters, and particularly the canalicular adenosine triphosphate (ATP)-dependent bile salt export pump (BSEP), are responsible for the biliary excretion of several organic compounds including bile acids. An impaired function of BSEP determines the accumulation of cytotoxic bile acids in hepatocytes leading to the induction of oxidative stress and/or apoptosis and necrosis by FAS-mediated pathways [
      • Pauli-Magnus C.
      • Meier P.J.
      Hepatobiliary transporters and drug-induced cholestasis.
      ]. Drugs and/or metabolites with capacity to inhibit BSEP in vitro have potential to cause DILI as has been shown by Morgan et al. using BSEP-inverted vesicles [
      • Morgan R.E.
      • Trauner M.
      • van Staden C.J.
      • Lee P.H.
      • Ramachandran B.
      • Eschenberg M.
      • et al.
      Interference with bile salt export pump function is a susceptibility factor for human liver injury in drug development.
      ]. Although this approach enables preclinical drug testing with some drugs shown to be potent BSEP inhibitors and have either been withdrawn from the market (troglitazone) or received warnings (imatinib) for hepatotoxicity, others (pioglitazone, simvastatin) have a low potential for DILI risk. Hence, BSEP inhibitory potency alone is insufficient for determining DILI risk and additional factors should be considered. Recently, Aleo et al. demonstrated that drugs which carry a more serious DILI risk influence both BSEP and mitochondrial activities [
      • Aleo M.D.
      • Luo Y.
      • Swiss R.
      • Bonin P.D.
      • Potter D.M.
      • Will Y.
      Human drug-induced liver injury severity is highly associated to dual inhibition of liver mitochondrial function and bile salt export pump.
      ]. Mitochondrial dysfunction would result in impaired ATP production, and in conjunction with BSEP inhibition, might explain the synergistic link between mitochondria and ATP-dependent transporters such as BSEP in DILI.
      The hepatic canalicular transporter P-glycoprotein (P-gp) is a well-known determinant in multidrug resistance in chemotherapy [
      • Wu C.-P.
      • Hsieh C.-H.
      • Wu Y.-S.
      The emergence of drug transporter-mediated multidrug resistance to cancer chemotherapy.
      ]. Other hepatobiliary transporters of the multidrug resistance protein (MRP) family are also involved in the excretion of conjugated organic anions, bilirubin and drug metabolites. Recent studies suggest that the consideration of MRP2/3/4 inhibition could improve the correlation with DILI risk in humans as compared with BSEP inhibition alone [
      • Köck K.
      • Ferslew B.C.
      • Netterberg I.
      • Yang K.
      • Urban T.J.
      • Swaan P.W.
      • et al.
      Risk factors for development of cholestatic drug-induced liver injury: inhibition of hepatic basolateral bile acid transporters multidrug resistance-associated proteins 3 and 4.
      ], suggesting that defects in transporters function modify drug disposition. Owing to the fact that hepatocytes are highly polarized and transporters function either bi- or mono-directional, the host and drug interactions may lead to different phenotypes of DILI (i.e. cholestasis, hepatocellular, steatosis).

      Host factors modifying DILI risks and clinical phenotypes

      Host factors contributing to individual susceptibility and clinical phenotypes of DILI have not been systematically investigated. In this section, we will provide cross-disciplinary view over host factors influencing key mechanistic components of DILI, classified into four categories: drug handling, toxicological responses, inflammation and immune responses, and imbalance of tissue damage and induction of repair processes.

      Host factors influencing drug handling

      Factors that modify the level of exposure to the reactive metabolites and/or alter the disposition of the drug may critically influence the development of DILI. In individual cases, drug therapy adjustments appear to change a drug’s hepatotoxic potential; e.g. reducing the dose of mianserin [
      • Otani K.
      • Kaneko S.
      • Tasaki H.
      • Fukushima Y.
      Hepatic injury caused by mianserin.
      ] and prolonged dose intervals of gefitinib [
      • Seki N.
      • Uematsu K.
      • Shibakuki R.
      • Eguchi K.
      Promising new treatment schedule for gefitinib responders after severe hepatotoxicity with daily administration.
      ] eliminated risk of hepatotoxicity while atorvastatin dose escalation increased the risk of hepatotoxicity [
      • Carrascosa M.F.
      • Salcines-Caviedes J.R.
      • Lucena M. Isabel
      • Andrade R.J.
      Acute liver failure following atorvastatin dose escalation: is there a threshold dose for idiosyncratic hepatotoxicity?.
      ]. These observations underpin the need of surpassing a threshold dose to induce DILI in a unique susceptible individual [
      • Carrascosa M.F.
      • Salcines-Caviedes J.R.
      • Lucena M. Isabel
      • Andrade R.J.
      Acute liver failure following atorvastatin dose escalation: is there a threshold dose for idiosyncratic hepatotoxicity?.
      ]. Inter-individual differences in drug tissue concentration are further influenced by oral bioavailability, volume of distribution, visceral blood flow, drug metabolism, nutritional status, excretion/transport, age and genetic and epigenetic factors.
      Aging is known to influence the pharmacokinetics of drugs due to decreased renal function and cytochrome-mediated hepatic metabolism, while reduced conjugation reactions seem to be restricted to older frail patients [
      • Mitchell S.J.
      • Hilmer S.N.
      Drug-induced liver injury in older adults.
      ]. Hence, older age likely enhances DILI susceptibility. This concept, however, has not been supported by data from large national DILI registries. In the Spanish DILI Registry 46% of DILI patients were ⩾60 years of age and the US Drug-Induced Liver Injury Network (DILIN) reported 18.5% of DILI patients to be 65 years or older [
      • Lucena M.I.
      • Andrade R.J.
      • Kaplowitz N.
      • García-Cortes M.
      • Fernández M.C.
      • Romero-Gomez M.
      • et al.
      Phenotypic characterization of idiosyncratic drug-induced liver injury: the influence of age and sex.
      ,
      • Chalasani N.
      • Fontana R.J.
      • Bonkovsky H.L.
      • Watkins P.B.
      • Davern T.
      • Serrano J.
      • et al.
      Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States.
      ]. In a population-based study done in Iceland, a relationship between DILI incidence and increasing age was observed, probably related to a greater exposure to polypharmacy in older subjects [
      • Bjornsson E.S.
      • Bergmann O.M.
      • Bjornsson H.K.
      • Kvaran R.B.
      • Olafsson S.
      Incidence, presentation, and outcomes in patients with drug-induced liver injury in the general population of Iceland.
      ]. Apparently, the type of liver injury differed with age with younger patients presenting more frequently hepatocellular damage as compared to cholestatic/mixed injury seen in the old [
      • Lucena M.I.
      • Andrade R.J.
      • Kaplowitz N.
      • García-Cortes M.
      • Fernández M.C.
      • Romero-Gomez M.
      • et al.
      Phenotypic characterization of idiosyncratic drug-induced liver injury: the influence of age and sex.
      ,
      • Hunt C.M.
      • Yuen N.A.
      • Stirnadel-Farrant H.A.
      • Suzuki A.
      Age-related differences in reporting of drug-associated liver injury: data-mining of WHO Safety Report Database.
      ]. The risk of developing valproic acid-induced hepatotoxicity with fatal outcomes is higher in children below the age of two [
      • Dreifuss F.
      • Santilli N.
      • Langer D.
      • Sweeney K.
      • Moline K.
      • Menander K.
      Valproic acid hepatic fatalities A retrospective review.
      ]. Hepatotoxicity induced by isoniazid appears to be more frequent in older patients. A retrospective study in 3377 adults receiving isoniazid therapy demonstrated that the DILI incidence was about two-fold amongst 35–49 years old and almost five-fold in ⩾50 years old patients as compared to the 25–34 years old ones [
      • Fountain F.F.
      • Tolley E.
      • Chrisman C.R.
      • Self T.H.
      Isoniazid hepatotoxicity associated with treatment of latent tuberculosis infection A 7-year evaluation from a public health tuberculosis clinic.
      ].
      Furthermore, gene expression of drug metabolizing enzymes and transporters vary significantly among individuals, being influenced by genetic variants, epigenetic alterations, age, gender, hormones, nutrition, alcohol, and co-medications [
      • Eichelbaum M.
      • Ingelman-Sundberg M.
      • Evans W.E.
      Pharmacogenomics and individualized drug therapy.
      ]. Genetic polymorphisms of drug metabolizing enzymes are estimated to influence the clinical outcome in 20–25% of all drug therapies [
      • Eichelbaum M.
      • Ingelman-Sundberg M.
      • Evans W.E.
      Pharmacogenomics and individualized drug therapy.
      ]. Some racial differences in DILI caused by anti-tuberculosis drugs have been attributed to variants of drug metabolizing genes coding for NAT2, CYP2E1, GSTM1 and GSTT1 [
      • Du H.
      • Chen X.
      • Fang Y.
      • Yan O.
      • Xu H.
      • Li L.
      • et al.
      Slow N-acetyltransferase 2 genotype contributes to anti-tuberculosis drug-induced hepatotoxicity: a meta-analysis.
      ]. Thus, polymorphisms of drug metabolizing enzymes and transporters are considered as one of the key contributors in an individual’s DILI risk [
      • Urban T.J.
      • Daly A.K.
      • Aithal G.P.
      Genetic basis of drug-induced liver injury: present and future.
      ].
      Gender, pubertal development, sex hormones, pregnancy and growth hormone levels also influence drug metabolizing enzymes [
      • Waxman D.J.
      • Holloway M.G.
      Sex differences in the expression of hepatic drug metabolizing enzymes.
      ]. For instance, men have a higher clearance rate of acetaminophen than women due to higher glucuronidation rates, while CYP3A4, a major drug metabolizing enzyme, is expressed at a higher rate in women [
      • Hunt C.M.
      • Westerkam W.R.
      • Stave G.M.
      Effect of age and gender on the activity of human hepatic CYP3A.
      ]. Furthermore, cytokines released in systemic infection inflammation significantly represses activities of cytochrome P450 monooxygenases and transporters [
      • Morgan E.T.
      Regulation of cytochromes P450 during inflammation and infection.
      ,
      • Theken K.N.
      • Deng Y.
      • Kannon M.A.
      • Miller T.M.
      • Poloyac S.M.
      • Lee C.R.
      Activation of the acute inflammatory response alters cytochrome P450 expression and eicosanoid metabolism.
      ]. Consequently, in patients with systemic inflammatory response syndrome, detoxification processes may significantly decrease possibly requiring dose adjustment.
      Lifestyle, disease conditions, and co-medications also modify individual’s drug handling capability. Alcohol and high fat diets are known to induce CYPs 2E1 and 4A. Alcohol-induced increase in CYP2E1 has been associated with an increased risk of acetaminophen-induced liver injury in humans, which is explained by an increased generation of the reactive metabolite N-acetyl-p-benzoquinone imine (NAPQI) [
      • Seeff L.B.
      • Cuccherini B.A.
      • Zimmerman H.J.
      • Adler E.
      • Bendjamin S.B.
      Acetaminophen hepatotoxicity in alcoholics A therapeutic misadventure.
      ]. Malnutrition and cellular senescence could result in decreased xenobiotic clearance and subsequently lead to slower drug elimination and higher drug plasma levels. Additionally, several marketed drugs are known to inhibit/induce specific drug metabolizing enzymes and transporters [
      • Yu K.
      • Geng X.
      • Chen M.
      • Zhang J.
      • Wang B.
      • Ilic K.
      • et al.
      High daily dose and being a substrate of cytochrome P450 enzymes are two important predictors of drug-induced liver injury.
      ], which potentially alter reactive metabolite formation, drug conjugation, and/or drug elimination, and therefore modifying an individual’s DILI risk [
      • Seeff L.B.
      • Cuccherini B.A.
      • Zimmerman H.J.
      • Adler E.
      • Bendjamin S.B.
      Acetaminophen hepatotoxicity in alcoholics A therapeutic misadventure.
      ,
      • Yu K.
      • Geng X.
      • Chen M.
      • Zhang J.
      • Wang B.
      • Ilic K.
      • et al.
      High daily dose and being a substrate of cytochrome P450 enzymes are two important predictors of drug-induced liver injury.
      ].

      Host factors modifying toxicological responses

      Drugs initiate cellular damage through diverse mechanisms: reactive metabolite formation, which leads to covalent binding to cellular proteins, oxidative stress, endoplasmic reticulum stress, mitochondrial injury, DNA damage, epigenetic modifications, and/or inhibition of bile acid excretion (Fig. 1). Various patients’ host factors may influence toxicological responses and modify the risks of developing cellular damage.
      Specifically, risk of inducing cellular damage through reactive metabolites is affected by cellular detoxification mechanisms. Patients with genetic defects in GST were reported to have an increased risk of developing DILI caused by anti-tuberculosis drugs [
      • Huang Y.-S.
      • Su W.-J.
      • Huang Y.-H.
      • Chen C.-Y.
      • Chang F.-Y.
      • Lin H.-C.
      • et al.
      Genetic polymorphisms of manganese superoxide dismutase, NAD (P) H: quinone oxidoreductase, glutathione S-transferase M1 and T1, and the susceptibility to drug-induced liver injury.
      ], NSAIDs and antibacterials [
      • Lucena M.I.
      • Andrade R.J.
      • Martínez C.
      • Ulzurrun E.
      • García-Martín E.
      • Borraz Y.
      • et al.
      Glutathione S-transferase m1 and t1 null genotypes increase susceptibility to idiosyncratic drug-induced liver injury.
      ]. Slow acetylators of NAT2 were also associated with moderate to severe DILI related to anti-tuberculosis drugs [
      • Ng C.-S.
      • Hasnat A.
      • Al Maruf A.
      • Ahmed M.U.
      • Pirmohamed M.
      • Day C.P.
      • et al.
      N-acetyltransferase 2 (NAT2) genotype as a risk factor for development of drug-induced liver injury relating to antituberculosis drug treatment in a mixed-ethnicity patient group.
      ]. Thus, at a given amount of reactive metabolite formation, those with diminished cellular detoxification are at a higher risk of developing DILI.
      Induction of cellular oxidative stress is another major toxicological insult caused by drugs. The degree of drug-induced oxidative insult may be modified by host’s pre-existing increased cellular oxidants, increased substrates for oxidative reactions (e.g., steatosis, lipid peroxidation), and/or decreased anti-oxidants. Patients with functional polymorphisms in mitochondrial superoxide dismutase and glutathione peroxidase have a higher risk of developing DILI, especially for those culprit drugs that are hazardous for mitochondria and/or form highly reactive intermediates [
      • Huang Y.-S.
      • Su W.-J.
      • Huang Y.-H.
      • Chen C.-Y.
      • Chang F.-Y.
      • Lin H.-C.
      • et al.
      Genetic polymorphisms of manganese superoxide dismutase, NAD (P) H: quinone oxidoreductase, glutathione S-transferase M1 and T1, and the susceptibility to drug-induced liver injury.
      ,
      • Lucena M.I.
      • García-Martín E.
      • Andrade R.J.
      • Martínez C.
      • Stephens C.
      • Ruiz J.D.
      • et al.
      Mitochondrial superoxide dismutase and glutathione peroxidase in idiosyncratic drug-induced liver injury.
      ]. Other host factors influencing cellular oxidative stress are listed in Table 1 [
      • Pessayre D.
      • Fromenty B.
      • Berson A.
      • Robin M.-A.
      • Lettéron P.
      • Moreau R.
      • et al.
      Central role of mitochondria in drug-induced liver injury.
      ,
      • Aruoma O.I.
      Free radicals, oxidative stress, and antioxidants in human health and disease.
      ,
      • Zawia N.H.
      • Lahiri D.K.
      • Cardozo-Pelaez F.
      Epigenetics, oxidative stress, and Alzheimer disease.
      ]. A female-specific susceptibility to oxidative stress in idiosyncratic DILI has been reported [
      • Lucena M.I.
      • Andrade R.J.
      • Kaplowitz N.
      • García-Cortes M.
      • Fernández M.C.
      • Romero-Gomez M.
      • et al.
      Phenotypic characterization of idiosyncratic drug-induced liver injury: the influence of age and sex.
      ].
      Table 1Overview of drug/host factors influencing specific mechanisms involved in idiosyncratic drug-induced liver injury.
      *Drugs of very low bioavailability were associated with few DILI reports (e.g., acarbose).
      +Drugs that were withdrawn from markets worldwidely or in some countries.
      Host factors influencing mitochondrial functions are listed in Table 1 [
      • Pessayre D.
      • Fromenty B.
      • Berson A.
      • Robin M.-A.
      • Lettéron P.
      • Moreau R.
      • et al.
      Central role of mitochondria in drug-induced liver injury.
      ,
      • Finsterer J.
      • Segall L.
      Drugs interfering with mitochondrial disorders.
      ,
      • Kirchner H.
      • Osler M.E.
      • Krook A.
      • Zierath J.R.
      Epigenetic flexibility in metabolic regulation: disease cause and prevention?.
      ]. In normal mitochondrial biology, significant amount of ROS is produced and usually appropriately detoxified [
      • Dai D.F.
      • Chiao Y.A.
      • Marcinek D.J.
      • Szeto H.H.
      • Rabinovitch P.S.
      Mitochondrial oxidative stress in aging and healthspan.
      ]. However, mitochondrial aging, partly due to accumulated oxidative mitochondrial DNA damage [
      • Labbe G.
      • Pessayre D.
      • Fromenty B.
      Drug-induced liver injury through mitochondrial dysfunction: mechanisms and detection during preclinical safety studies.
      ], may be affected by other host factors such as over-nutrition (e.g., obesity, insulin resistance, diabetes, and NASH) and alcohol [
      • Labbe G.
      • Pessayre D.
      • Fromenty B.
      Drug-induced liver injury through mitochondrial dysfunction: mechanisms and detection during preclinical safety studies.
      ,
      • Fromenty B.
      Drug-induced liver injury in obesity.
      ]. Damaged mitochondrial DNA is repaired and maintained by mitochondrial DNA polymerase γ, encoded by the nuclear gene POLG. A recent gene-association study showed that about 50% of cases with valproate-induced liver injury were heterozygous for POLG substitution mutations and its odds ratio was estimated as high as 24 [
      • Stewart J.D.
      • Horvath R.
      • Baruffini E.
      • Ferrero I.
      • Bulst S.
      • Watkins P.B.
      • et al.
      Polymerase γ Gene POLG determines the risk of sodium valproate-induced liver toxicity.
      ]. Individuals with carnitine deficiency were also associated with an increased risk of valproate-induced liver injury [
      • Felker D.
      • Lynn A.
      • Wang S.
      • Johnson D.E.
      Evidence for a potential protective effect of carnitine-pantothenic acid co-treatment on valproic acid-induced hepatotoxicity.
      ] while carnitine appears to be protective against valproate-induced liver injury and improve survival in severe cases.
      Inhibition of bile acid transporter leads to intrahepatocellular bile acid accumulation while inhibition of phosphatidyl choline excretion (MDR2/3) alters bile composition and leads to cholangiocyte injury [
      • Rodrigues A.D.
      • Lai Y.
      • Cvijic M.E.
      • Elkin L.L.
      • Zvyaga T.
      • Soars M.G.
      Drug-induced perturbations of the bile acid pool, cholestasis, and hepatotoxicity: mechanistic considerations beyond the direct inhibition of the bile salt export pump.
      ]. As shown in Table 1, hepatic transporters are influenced by genetic variations, co-medications, bacterial endotoxins and the farconoid xenosensing receptor (FXR), which functions as a bile acid sensor and acts as a key regulator of metabolic processes [
      • Pauli-Magnus C.
      • Meier P.J.
      Hepatobiliary transporters and drug-induced cholestasis.
      ].
      Bile acids salts are anionic detergents and highly toxic to the cells. In bile, mixed micelle formation with cholesterol, phospholipids, bile pigments, proteins, and inorganic electrolytes protects cholangiocytes from the toxic detergent effect of bile acid salts. Dysfunction of MDR3/ABCB4 (phosphatidyl choline translocation across canaliculus membranes, regulated by FXR) has been associated with clinical cholestasis, presumably via inhibition of micelle formation, releasing free bile acids salts in bile [
      • de Vree J.M.
      • Jacquemin E.
      • Sturm E.
      • Cresteil D.
      • Bosma P.J.
      • Aten J.
      • et al.
      Mutations in the MDR3 gene cause progressive familial intrahepatic cholestasis.
      ]. Patients with primary biliary cirrhosis and extrahepatic bile obstruction have decreased biliary bicarbonate secretion measured by positron emission tomography [
      • Prieto J.
      • García N.
      • Martí-Climent J.M.
      • Peñuelas I.
      • Richter J.A.
      • Medina J.F.
      Assessment of biliary bicarbonate secretion in humans by positron emission tomography.
      ,
      • Yoshikado T.
      • Takada T.
      • Yamamoto T.
      • Yamaji H.
      • Ito K.
      • Santa T.
      • et al.
      Itraconazole-induced cholestasis: involvement of the inhibition of bile canalicular phospholipid translocator MDR3/ABCB4.
      ], suggesting a potential susceptibility to drugs influencing bile components (i.e., itraconazole) [
      • Yoshikado T.
      • Takada T.
      • Yamamoto T.
      • Yamaji H.
      • Ito K.
      • Santa T.
      • et al.
      Itraconazole-induced cholestasis: involvement of the inhibition of bile canalicular phospholipid translocator MDR3/ABCB4.
      ].

      Host factors modulating inflammation and immune responses

      Innate/adaptive immune response plays a key role in inducing inflammation and determining the degree of ‘injury’ (Fig. 1). Host factors known to modulate inflammation and immune response which, in turn, may influence DILI susceptibility will be discussed below.
      Several genetic variants in the HLA regions were identified as risk factors for DILI [
      • Urban T.J.
      • Daly A.K.
      • Aithal G.P.
      Genetic basis of drug-induced liver injury: present and future.
      ]. Carriers of the HLA-B57:01 genotype are at an 80-fold increased risk of flucloxacillin-induced DILI [
      • Daly A.K.
      • Donaldson P.T.
      • Bhatnagar P.
      • Shen Y.
      • Pe’er I.
      • Floratos A.
      • et al.
      HLA-B5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin.
      ]. DILI caused by other drugs (e.g. lumiracoxib, lapatanib, ticlopidine, amoxicillin-clavulanate and ximelagatran) are also associated with HLA genotypes [
      • Stephens C.
      • Andrade R.J.
      • Lucena M.I.
      Mechanisms of drug-induced liver injury.
      ]. Even causal drugs not accompanied by hypersensitivity features show the association with the HLA haplotypes, suggesting an important role of the immune system in DILI [
      • Stephens C.
      • Andrade R.J.
      • Lucena M.I.
      Mechanisms of drug-induced liver injury.
      ].
      Gender and sex hormones are well-known to influence inflammation and immune response. An immune-mediated DILI model showed gender bias in immune response and inflammation; more severe hepatitis, more antibody production, and a higher level of pro-inflammatory hepatic cytokines in females vs. males [
      • Cho J.
      • Kim L.
      • Li Z.
      • Rose N.R.
      • Talor M.V.
      • Njoku D.B.
      Sex bias in experimental immune-mediated, drug-induced liver injury in BALB/c mice: suggested roles for Tregs, estrogen, and IL-6.
      ]. Indeed, females with DILI are at a higher risk of developing acute liver failure or requiring liver transplantation [
      • Andrade R.J.
      • Lucena M.I.
      • Fernández M.C.
      • Pelaez G.
      • Pachkoria K.
      • García-Ruiz E.
      • et al.
      Drug-induced liver injury: an analysis of 461 incidences submitted to the Spanish registry over a 10-year period.
      ,
      • Lucena M.I.
      • Andrade R.J.
      • Kaplowitz N.
      • García-Cortes M.
      • Fernández M.C.
      • Romero-Gomez M.
      • et al.
      Phenotypic characterization of idiosyncratic drug-induced liver injury: the influence of age and sex.
      ]. In halothane-induced DILI, estrogens reduce liver injury in mice while progesterone exacerbates the damage possibly by modulating inflammation and immune response. Indeed, increased hepatic neutrophils and up-regulated hepatic mRNA levels of pro-inflammatory cytokines were noted with progesterone pre-treatment whereas estradiol resulted in the opposite effects [
      • Toyoda Y.
      • Miyashita T.
      • Endo S.
      • Tsuneyama K.
      • Fukami T.
      • Nakajima M.
      • et al.
      Estradiol and progesterone modulate halothane-induced liver injury in mice.
      ].
      Racial differences in inflammation and immune response are also known. African-Americans are at a higher risk of developing chronic DILI (defined as persistent liver alteration beyond six months of DILI recognition), while Asians are associated with earlier development of liver-related death or liver transplantation [
      • Fontana R.J.
      • Hayashi P.H.
      • Gu J.
      • Reddy K.R.
      • Barnhart H.
      • Watkins P.B.
      • et al.
      Idiosyncratic drug-induced liver injury is associated with substantial morbidity and mortality within 6 months from onset.
      ]. Potential race-associated genetic variants enhancing inflammation or adaptive immune response are warranted future investigations.
      Immune and inflammatory responses are also influenced by medications co-administered at the time of drug exposure. Previous data-mining using a large spontaneous adverse event reporting system discovered latent associations between reduced reporting frequency of liver events and various co-reported medications. Among the identified medications, anti-inflammatory agents and immunosuppressants were disproportionally prevalent [
      • Suzuki A.
      • Yuen N.A.
      • Ilic Katarina
      • Hunt Christine M.
      Drug-induced liver injury (DILI) modulated by concomitant use of targeted drug classes: an analysis of 303 drugs associated with hepatotoxicity.
      ,
      • Suzuki A.
      • Yuen N.A.
      • Ilic Katarina
      • Hunt Christine M.
      Concomitant medications impact reporting frequency of drug-induced liver injury: data mining analysis using the WHO VigiBase™ database.
      ]. Despite the preliminary nature of these observations, the associations suggest that the concomitant use of anti-inflammatory and immunosuppressant agents may modulate host immune response and inflammation and impact DILI occurrence. Other host factors potentially influencing inflammation and immune response are listed in Table 1.
      The gut–liver axis plays a role in DILI. Increased intestinal permeability due to damaged intestinal mucosal barrier increases hepatic endotoxin influx, which in turn activates Kupffer cells and the production of pro-inflammatory cytokines, arachidonic acid metabolites and ROS in the liver [
      • Rizzardini M.
      • Zappone M.
      • Villa P.
      • Gnocchi P.
      • Sironi M.
      • Diomede L.
      • et al.
      Kupffer cell depletion partially prevents hepatic heme oxygenase 1 messenger RNA accumulation in systemic inflammation in mice: role of interleukin 1beta.
      ]. In experimental models, intestine-derived endotoxin or co-administration of LPS enhances liver injury induced by chemicals [
      • Deng X.
      • Stachlewitz R.F.
      • Liguori M.J.
      • Blomme E.A.
      • Waring J.F.
      • Luyendyk J.P.
      • et al.
      Modest inflammation enhances diclofenac hepatotoxicity in rats: role of neutrophils and bacterial translocation.
      ,
      • Shaw P.J.
      • Hopfensperger M.J.
      • Ganey P.E.
      • Roth R.A.
      Lipopolysaccharide and trovafloxacin coexposure in mice causes idiosyncrasy-like liver injury dependent on tumor necrosis factor-alpha.
      ], while decreased intestinal permeability reduced liver injury [
      • Wang L.K.
      • Wang L.W.
      • Li X.
      • Han X.Q.
      • Gong Z.J.
      Ethyl pyruvate prevents inflammatory factors release and decreases intestinal permeability in rats with D-galactosamine-induced acute liver failure.
      ]. Likely, a disrupted mucosal barrier induced by drugs (e.g. NSAID), alcohol abuse, or intestinal disorders as seen with celiac disease and inflammatory bowel disease, or acute enterocolitis can act synergistically enhancing liver damage caused by hepatotoxic drugs [
      • Kaplowitz N.
      • DeLeve L.D.
      Drug-induced liver disease.
      ].
      Whether pre-existing chronic liver diseases enhances the risk of hepatotoxicity is hampered by the fact that recrudescence of inflammation can go undistinguished from true injury induced by a drug. A few examples, however, suggest potential enhancement of drug hepatotoxicity by existing chronic inflammation (or chronic viral infection). A previous retrospective study showed that patients with pre-existing chronic liver injury are at an increased risk of acute liver injury following acetaminophen overdose [
      • Nguyen G.C.
      • Sam J.
      • Thuluvath P.J.
      Hepatitis C is a predictor of acute liver injury among hospitalizations for acetaminophen overdose in the United States: a nationwide analysis.
      ]. Severe DILI cases caused by anti-retroviral medications are more commonly observed among patients co-infected with hepatitis B and/or C virus [
      • Sulkowski M.S.
      Drug-induced liver injury associated with antiretroviral therapy that includes HIV-1 protease inhibitors.
      ]. Further, chronic hepatitis C virus infection, human immunodeficiency virus (HIV) infection, and autoimmune disease were associated with an increased risk of DILI caused by anti-tuberculosis drug therapy [
      • Lomtadze N.
      • Kupreishvili L.
      • Salakaia A.
      • Vashakidze S.
      • Sharvadze L.
      • Kempker R.R.
      • et al.
      Hepatitis C virus co-infection increases the risk of anti-tuberculosis drug-induced hepatotoxicity among patients with pulmonary tuberculosis.
      ,
      • Shu C.C.
      • Lee C.H.
      • Lee M.C.
      • Wang J.Y.
      • Yu C.J.
      • Lee L.N.
      Hepatotoxicity due to first-line anti-tuberculosis drugs: a five-year experience in a Taiwan medical centre.
      ].

      Host factors modifying cell death, tissue injury and repair

      The balance between tissue injury and repair needs to be considered with impaired tissue repair worsening the condition leading to poor clinical outcome. This concept is supported by clinical studies, where the impact of co-medications on DILI outcome in patients with acetaminophen-associated liver injury was examined [
      • Suzuki A.
      • Yuen N.
      • Walsh J.
      • Papay J.
      • Hunt C.M.
      • Diehl A.M.
      Co-medications that modulate liver injury and repair influence clinical outcome of acetaminophen-associated liver injury.
      ,
      • Suzuki A.
      • Watkins P.
      • Kaplowitz N.
      • Hunt C.
      • Sanders C.
      • Diehl A.
      • et al.
      Co-medication with adrenoreceptor antagonists is associated with lower meld scores at admission in patients with acetaminophen-induced acute liver failure.
      ]. Briefly, co-medications with drugs which ameliorate liver injury and/or enhance liver repair in animal experiments (e.g., statins, fibrates, β-blockers, NSAIDs) were associated with a decreased likelihood of fatality (or lower MELD scores) among acetaminophen-associated liver injury while co-medications with drugs enhancing liver injury and/or impairing liver regeneration (i.e., sympathetic stimulants) were associated with an increased likelihood of fatality [
      • Suzuki A.
      • Yuen N.
      • Walsh J.
      • Papay J.
      • Hunt C.M.
      • Diehl A.M.
      Co-medications that modulate liver injury and repair influence clinical outcome of acetaminophen-associated liver injury.
      ,
      • Suzuki A.
      • Watkins P.
      • Kaplowitz N.
      • Hunt C.
      • Sanders C.
      • Diehl A.
      • et al.
      Co-medication with adrenoreceptor antagonists is associated with lower meld scores at admission in patients with acetaminophen-induced acute liver failure.
      ]. Potential beneficial impacts of lipid lowering drugs (i.e., statins, fibrates) and anti-inflammatory agents (e.g., NSAIDs, immunosuppressants) are associated with improved clinical outcomes in patients diagnosed with dyslipidemia and collagen diseases among DILI cases [
      • Suzuki A.
      • Watkins P.
      • Kaplowitz N.
      • Hunt C.
      • Sanders C.
      • Diehl A.
      • et al.
      Co-medication with adrenoreceptor antagonists is associated with lower meld scores at admission in patients with acetaminophen-induced acute liver failure.
      ,
      • Robles-Diaz M.
      • Lucena M.I.
      • Kaplowitz N.
      • Stephens C.
      • Medina-Caliz I.
      • Gonzalez-Jimenez A.
      • et al.
      Use of Hy’s law and a new composite algorithm to predict acute liver failure in patients with drug-induced liver injury.
      ].
      Epigenetic modifications of host chromatin may impair regeneration following injury [
      • Shukla V.
      • Cuenin C.
      • Dubey N.
      • Herceg Z.
      Loss of histone acetyltransferase cofactor transformation/transcription domain-associated protein impairs liver regeneration after toxic injury.
      ,
      • Murata K.
      • Hamada M.
      • Sugimoto K.
      • Nakano T.
      A novel mechanism for drug-induced liver failure: inhibition of histone acetylation by hydralazine derivatives.
      ]. Loss of histone acetylation results in impaired liver regeneration in mice after toxic injury [
      • Shukla V.
      • Cuenin C.
      • Dubey N.
      • Herceg Z.
      Loss of histone acetyltransferase cofactor transformation/transcription domain-associated protein impairs liver regeneration after toxic injury.
      ]. Impaired histone acetylation induced by todralazine (a hydralazine derivative) also results in impaired liver regeneration, which was correlated with clinical cases of drug-induced acute liver failure [
      • Murata K.
      • Hamada M.
      • Sugimoto K.
      • Nakano T.
      A novel mechanism for drug-induced liver failure: inhibition of histone acetylation by hydralazine derivatives.
      ]. Additionally, nutritional deficiencies cause epigenetic modifications, which potentially alter individual susceptibility to hepatotoxicity. Deficiencies of folic acids, vitamin B12, and choline induce methyl donor depletion, contributing to hypomethylation of genes in cellular metabolism and hepatocyte differentiation [
      • Brunaud L.
      • Alberto J.M.
      • Ayav A.
      • Gerard P.
      • Namour F.
      • Antunes L.
      • et al.
      Effects of vitamin B12 and folate deficiencies on DNA methylation and carcinogenesis in rat liver.
      ,
      • Zeisel S.H.
      Dietary choline deficiency causes DNA strand breaks and alters epigenetic marks on DNA and histones.
      ,
      • Pooya S.
      • Blaise S.
      • Moreno Garcia M.
      • Giudicelli J.
      • Alberto J.M.
      • Gueant-Rodriguez R.M.
      • et al.
      Methyl donor deficiency impairs fatty acid oxidation through PGC-1alpha hypomethylation and decreased ER-alpha, ERR-alpha, and HNF-4alpha in the rat liver.
      ]. Folic acid deficiency is associated with more severe liver damage in ethanol-fed micropigs [
      • Halsted C.H.
      • Villanueva J.A.
      • Devlin A.M.
      • Niemela O.
      • Parkkila S.
      • Garrow T.A.
      • et al.
      Folate deficiency disturbs hepatic methionine metabolism and promotes liver injury in the ethanol-fed micropig.
      ,
      • Villanueva J.A.
      • Esfandiari F.
      • White M.E.
      • Devaraj S.
      • French S.W.
      • Halsted C.H.
      S-adenosylmethionine attenuates oxidative liver injury in micropigs fed ethanol with a folate-deficient diet.
      ] while folic acid supplementation has been associated with a reduced reporting frequency of liver events across different agents with hepatotoxic potential in previous data-mining analyses [
      • Suzuki A.
      • Yuen N.A.
      • Ilic Katarina
      • Hunt Christine M.
      Drug-induced liver injury (DILI) modulated by concomitant use of targeted drug classes: an analysis of 303 drugs associated with hepatotoxicity.
      ,
      • Suzuki A.
      • Yuen N.A.
      • Ilic Katarina
      • Hunt Christine M.
      Concomitant medications impact reporting frequency of drug-induced liver injury: data mining analysis using the WHO VigiBase™ database.
      ].
      Age-related decline of mitochondrial function may also compromise energy supply for cellular metabolism and tissue regeneration [
      • Dai D.F.
      • Chiao Y.A.
      • Marcinek D.J.
      • Szeto H.H.
      • Rabinovitch P.S.
      Mitochondrial oxidative stress in aging and healthspan.
      ,
      • Schmucker D.L.
      • Sanchez H.
      Liver regeneration and aging: a current perspective.
      ]. In patients with hepatitis A, a likelihood of poor clinical outcomes increases with increased age [
      • Brown G.R.
      • Persley K.
      Hepatitis A epidemic in the elderly.
      ]. Decompensated cirrhosis is another factor of poor outcome. Such patients require specific care in the selection of medications, and drugs with significant hepatic metabolism should be avoided [
      • Lewis J.
      • Stine J.
      Review article: prescribing medications in patients with cirrhosis – A practical guide.
      ].
      Toxic insults can induce different forms for cell death. Unlike apoptosis, necrotic cell death leads to plasma membrane disturbance and subsequent releases of its cellular contents, which may induce an inflammatory response. Sexual dimorphism was observed in such cell death regulations in other systems [
      • Jog N.R.
      • Caricchio R.
      Differential regulation of cell death programs in males and females by Poly (ADP-Ribose) Polymerase-1 and 17beta estradiol.
      ,
      • Ortona E.
      • Matarrese P.
      • Malorni W.
      Taking into account the gender issue in cell death studies.
      ]. An immune-mediated nephritis mouse model evidenced more apoptosis in females but more necrosis in males. The observed gender-biased in cell death was partially mediated by estrogen and Poly-(ADP-Ribose) Polymerase-1 (PARP-1) [
      • Jog N.R.
      • Caricchio R.
      Differential regulation of cell death programs in males and females by Poly (ADP-Ribose) Polymerase-1 and 17beta estradiol.
      ]. In one recent clinical analysis of DILI cases, the frequency of apoptosis was increased in women at a given injury pattern [
      • Suzuki Ayako
      • Gu Jiezhun
      • Tillmann Hans
      • Bonkovsky Herbert
      • Fontana Robert
      • Kleiner David E.
      Association of gender and menopause with injury types and histological features of drug-induced liver injury.
      ]. Further investigations are warranted to delineate the suspected sex difference in cell death and its clinical relevance.

      Drug-host interaction: what do we know and what should we know, and how should we approach it

      Both drug properties and host factors are multi-layered, influencing multiple mechanisms, and likely interact at multiple levels to determine DILI susceptibility, clinical phenotypes and outcome. Table 1 provides a structured summary of drug properties and host factors relevant to human DILI, which is organized based on mechanistic elements. Some combinations of drugs and host factors may exert additive interactions on DILI risks, which may explain clinical observations of high-risk populations for specific agents. A few examples with suggested mechanisms are provided in Table 2. A previous data-mining analysis showed that mitochondrial liability was more prevalent among the drugs with an increased pediatric reporting frequency, while cholestatic manifestation, high lipophilicity and biliary excretion were more common among the drugs associated with a higher reporting frequency in the elderly, which might be explained by interactions between specific drug properties and age-biased attributes [
      • Hunt C.M.
      • Yuen N.A.
      • Stirnadel-Farrant H.A.
      • Suzuki A.
      Age-related differences in reporting of drug-associated liver injury: data-mining of WHO Safety Report Database.
      ]. Drug-host interactions also appear to exist between specific drug properties and host genetic variants. Lucena et al. found that SOD2Ala/Ala genotype was associated with an increased risk of developing cholestatic/mixed injury induced by drugs with mitochondrial hazard [
      • Lucena M.I.
      • García-Martín E.
      • Andrade R.J.
      • Martínez C.
      • Stephens C.
      • Ruiz J.D.
      • et al.
      Mitochondrial superoxide dismutase and glutathione peroxidase in idiosyncratic drug-induced liver injury.
      ]. Ulzurrun et al. suggested positive interaction between drugs containing a carbocyclic system with aromatic rings (e.g. NSAIDs) and a genetic variant, ABCC11 c.133 CC in DILI susceptibility [
      • Ulzurrun E.
      • Stephens C.
      • Crespo E.
      • Ruiz-Cabello F.
      • Ruiz-Nuñez J.
      • Saenz-López P.
      • et al.
      Role of chemical structures and the 1331T> C bile salt export pump polymorphism in idiosyncratic drug-induced liver injury.
      ]. Lastly, sexual dimorphism (XX vs. XY) may contribute gender-specific susceptibility of neurons and splenocytes to different cytotoxic agents, suggesting gender bias in cellular toxicological responses [
      • Du L.
      • Bayir H.
      • Lai Y.
      • Zhang X.
      • Kochanek P.M.
      • Watkins S.C.
      • et al.
      Innate gender-based proclivity in response to cytotoxicity and programmed cell death pathway.
      ]. Whether hepatocytes or cholangiocytes exerts similar gender-biased toxicological responses requires future investigation.
      Table 2Specific drug-host interactions influencing risks of idiosyncratic drug-induced liver injury
      • Kaplowitz N.
      • DeLeve L.D.
      Drug-induced liver disease.
      .
      Collectively, a conceptual framework explaining the relevance of drug-host interactions in human DILI is depicted in Fig. 2. The proverb of “the blind men and the elephant” teaches us the manifold nature of truth; in the story, every one of the blind men touches different parts of the elephant and describes it differently without knowing that all stems from the same animal. Through this analogy, we intent to highlight the different mechanisms underlying human DILI. Future investigations targeting drug-host interactions in an integrative system analysis will favour unravelling the determinants that overlap and potentiate each other on DILI. In this regard, recent progress in differentiating induced pluripotent stem cells makes it possible to develop patient-specific hepatocytes as a “host dependent” assay system to investigate drug-host interactions [
      • Liang P.
      • Lan F.
      • Lee A.S.
      • Gong T.
      • Sanchez-Freire V.
      • Wang Y.
      • et al.
      Drug screening using a library of human induced pluripotent stem cell-derived cardiomyocytes reveals disease specific patterns of cardiotoxicity.
      ]. On the other hand, introducing advanced bioinformatics methodologies, machine learning [
      • Chen M.
      • Shi L.
      • Kelly R.
      • Perkins R.
      • Fang H.
      • Tong W.
      Selecting a single model or combining multiple models for microarray-based classifier development? – A comparative analysis based on large and diverse datasets generated from the MAQC-II project.
      ], topic modelling [
      • Bisgin H.
      • Chen M.
      • Wang Y.
      • Kelly R.
      • Fang H.
      • Xu X.
      • et al.
      A systems approach for analysis of high content screening assay data with topic modeling.
      ], network analysis [
      • Ding Y.
      • Chen M.
      • Liu Z.
      • Ding D.
      • Ye Y.
      • Zhang M.
      • et al.
      AtBioNet – An integrated network analysis tool for genomics and biomarker discovery.
      ] and deep learning techniques [
      • Hinton G.
      • Osindero S.
      • Teh Y.-W.
      A fast learning algorithm for deep belief nets.
      ] to clinical analysis will unmask hidden patterns/associations. Inter-disciplinary translation integrating preclinical knowledge, drug properties and clinical phenotype is of critical importance for a better understanding of human DILI. Development of standardized nomenclature, electronic form of knowledge base for hepatotoxic drugs and drug properties [
      • Chen M.
      • Vijay V.
      • Shi Q.
      • Liu Z.
      • Fang H.
      • Tong W.
      FDA-approved drug labeling for the study of drug-induced liver injury.
      ], ranking/classification of post-marketing safety profiles [
      • Suzuki A.
      • Andrade R.J.
      • Bjornsson E.
      • Lucena M.I.
      • Lee W.M.
      • Yuen N.A.
      • et al.
      Drugs associated with hepatotoxicity and their reporting frequency of liver adverse events in VigiBase: unified list based on international collaborative work.
      ], and bioinformatics infrastructure to support discovery-driven research will enhance the transferability of information and facilitate inter-disciplinary research in the field.
      Figure thumbnail gr2
      Fig. 2Conceptual framework explaining drug-host interactions in human DILI. Two key players in DILI, drug and host factors may interact in a multi-faceted manner at different functional pathways and determine individual susceptibility, clinical phenotype and outcome. Mechanisms involved in the initiation of cellular injury are likely drug specific and may occur as consequence of the interaction between specific drug properties and host-specific activities. Once injury is established host responses to the injury insult (i.e., immune response, inflammation, tissue injury and repair) are mainly determined by host factors. Such responses are likely modulated by various host factors such as age, gender, genetic factors, lifestyles, disease conditions and co-medications.

      Perspectives

      This review aimed at highlighting current knowledge on drug properties, host factors and drug-host interactions in human DILI and identifying knowledge gaps to stimulate future investigation. As individual risks and clinical phenotypes of DILI are likely determined by a multi-faceted interaction between drug properties and host factors, a new paradigm of DILI studies should be directed to address not only host factors or drug properties alone but their interactions. Developing new investigational approaches involving bioinformatics and computer science may become crucial in such future investigations. Indeed, preclinical safety assessment is currently based on the paradigm “high doses in healthy animals”. However, biological responses to drug treatment will inevitably differ in disease. Therefore, the utility of experimental models that simulate host conditions should be considered [
      • Chen M.
      • Borlak J.
      • Tong W.
      Predicting idiosyncratic drug-induced liver injury-some recent advances.
      ].
      Current knowledge is still limited and insufficient for accurate DILI risk prediction. Further investigations targeting drug-host interactions will enable establishing patient’s risk stratification and the development of a safety personalized medicine.

      Financial support

      This study was supported by the research grant P10-CTS-6470 , PI12-00620 , PI12-00378 and the Agencia Española del Medicamento y Productos Sanitarios ( AEMPS ). CIBERehd is funded by Instituto de Salud Carlos III .
      Author JB gratefully acknowledges support from The Virtual Liver Network (grant 031 6154 ) of the German Federal Ministry of Education and Research ( BMBF ). Part of this work was also funded by the Lower Saxony Ministry of Culture and Sciences and the Volkswagen Foundation , Germany to JB. Grant number: 25A.5-7251-99-3/00 .

      Conflict of interest

      The authors disclose the following: The views presented in this article do not necessarily reflect those of the U.S. Food and Drug Administration.
      The authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.

      Acknowledgement

      We appreciated Drs. Weida Tong, John Senior, and Mark Avigan for their comments and/or discussions. We also thank the discussions amongst the Liver Toxicity Knowledge Base (LTKB) interest group.

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