Far Maco Cine Tica i

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Drug Induced Liver Injury: The Role of DrugMetabolism and Transport

Alberto Corsini, PhD 1 and Michele Bortolini, MD, PhD 2

AbstractManystudies havepinpointedthe significant contribution of livermediated drug metabolism andtransport to thecomplexity of druginduced liverinjury(DILI). Phase I cytochrome P450 (CYP450) enzymes canlead to altered drug metabolism andformationof toxicmetabolites,whilst Phase II enzymes arealso associated with DILI.Theemergingroleofhepatic transporters in regulating themovementof endogenous andexogenous chemicals(e.g., bile acidsanddrugs) acrosscellularand tissuemembranes is critical indetermining thepathophysiology ofliverdisease as well asdrug toxicityandefficacy. Geneticand environmental factors can have a significant impact on drug metabolism and transporter proteins, consequently increasing the risk of DILI insusceptible individuals. The assessment of these factors therefore represents an important approach for predicting and preventing DILI, by betterunderstanding thepharmacological profileof a specificdrug. Thisreview focuses on themechanismsof DILIassociated withdrug metabolismand hepatic

transport, and how they can be influenced by underlying factors.

Keywordsdruginduced liver injury, drug metabolism, hepatic transporter, susceptibility

In the Westernworld, drug induced liver injury (DILI) nowaccounts for the majority of acute liver failure cases. 1,2 It isalso responsible for the market withdrawal or restricted useof many drugs, and is therefore a major concern to thehealthcare and pharmaceutical industries. 3

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The liver plays a crucial role in determining the toxicity

of drugs due to its key role in the metabolism, transport,and clearance of foreign substances. In fact, drugs whosemetabolism is predominantly ( > 50%) hepatic are morefrequently associated with adverse hepatic events compared to drugs that do not undergo signi cant hepaticmetabolism. 6

Most cases of drug induced liver failure in the United States and the United Kingdom are the result of intrinsicdrug reactions caused by acetaminophen (paracetamol)overdose. 2,7,8 On the other hand, hepatotoxicity associated with most drugs is considered idiosyncratic, 2 occurring insusceptible individuals. Idiosyncratic drug reactions are

therefore rarer and may not be detected during drugdevelopment programs. It is often only after a drug has beenlaunched onto themarket andexposedto a wider populationthat the potential for causing idiosyncratic DILI is realized.

Many drugs including NSAIDs, antibiotics, anticon-vulsants, and herbal remedies have been associated withidiosyncratic DILI. 9,10 However, estimating the frequencyof drug induced hepatotoxicity is challenging due tofactors confounding the accurate diagnosis of DILI. In aUK study, almost half of reported cases of hepatic adversedrug reactions were subsequently found to be unrelated to the administered drug. 11,12 Genetic, epigenetic, and

environmental factors have an important in uence on an

individual s susceptibility to developing DILI. Other clinical risk factors including older age, female sex, the presence of certain diseases or treatment with certainconcomitant drug therapies, have also been described. 9,10

The metabolism of a parent drug into toxic reactivemetabolite(s) and their accumulation within the hepato-

cyte to critical levels appears to be the most accredited hypothesis to explain damage initiation in many DILIcases. 13 Several mechanisms resulting in DILI have been proposed, 14 including the inhibition/induction of drugmetabolism pathways, movement of endogenous and exogenous compounds in and out of the hepatocyte,cellular homeostasis, mitochondrial function, and theactivation of cell death. 15 Altogether, the wide range of targeted structures and cell types, the diversity of themechanisms involved, and the importance of individualrisk factors currently hamper a clear approach for preventing and predicting DILI. This article reviews the

The Journal of Clinical Pharmacology53(5) 463474The Author(s) 2013DOI: 10.1002/jcph.23

1Dipartimento di Scienze Farmacologiche e Biomolecolari, Universitdegli Studi di Milano, Milan, Italy2Safety Risk Management, F. HoffmannLa Roche, Basel, Switzerland

Submitted for publication 15 May 2012; accepted 17 July 2012.

Corresponding Author:Alberto Corsini, Dipartimento di Scienze Farmacologiche e Biomole-colari, Universit degli Studi di Milano, Milan, Italy.Email: [email protected] Neither author is a Fellow of the American College of Clinical

Pharmacology (FCP).

Commentary


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current understanding of hepatic metabolism and transport of drugs in relation to DILI.

Hepatic Drug MetabolismGenerally, drug metabolism leads to the breakdown and safe elimination of a parent drug through a detoxi cation pathway. However, under certain conditions thesereactions may result in the generation and build up of harmful reactive metabolites that are more toxic than the parent drug.

Drug metabolism may be described as encompassingtwo phases: Phase I bioactivation/toxi cation reactionsand Phase II detoxi cation reactions.

During Phase I reactions, biotransformation of the parent drug involves the addition of functional hydroxyl,carboxyl, amino, or thiol groups necessary to complete thesubsequent phase of detoxi cation, and which makes thecompound more hydrophilic. The principal metabolicenzymes associated with Phase I reactions are members of the cytochrome P450 (CYP450) superfamily, whichcontribute to the metabolism of a wide range of xenobiotics and endogenous compounds. Studies havedemonstrated that the CYP450 isoenzymes, CYP1A2,2C9, 2C19, 2D6, and 3A4 are involved in the metabolismof most clinically available drugs. CYP3A4 has thehighest abundance of all CYP450 enzymes in the humanliver, although its expression levels vary widely betweenindividuals. 16 With very broad substrate speci city,CYP3A4 metabolizes roughly half of clinically used

drugs. 17

22

Phase II reactions involve conjugation with smallendogenous substances, which further increase hydrophi-licity, enabling metabolites to be exported into thesinusoidal circulation for renal clearance, or into bile.Metabolic enzymes involved in Phase II reactions includeuridine diphosphate glucuronosyltransferase (UGT), N

acetyltransferase 2 (NAT2), and glutathione S transferase(GST), which conjugate glucuronic acid, acetate, and glutathione (GSH), respectively. 23

Reactive Metabolite Mechanisms of DILI

An association between hepatic drug metabolism and DILI has been demonstrated, 6 supporting the hypothesisthat the formation and accumulation of reactive metab-olites beyond a critical threshold can result inhepatotoxicity. 13

The CYP450 enzymes play a major role in theformation of reactive metabolites, and their hepaticexpression is concentrated in the centrilobular region,which is consistent with typical histological ndings of centrilobular necrosis seen in serious, acute DILI cases.This suggests that the CYP450 enzymes may befunctionally important and that reactive metabolites may

also be potentially involved in DILI pathogenesis.24

Phase II enzymes, including UGTs, GSTs, NATs, and sulfotransferases (SULTs), can also catalyze the formationof reactive metabolites. 25

35 For example, carboxylic acid

containing drugs, which have been associated with drugtoxicity, can undergo glucuronidation by several hepaticUGT isoforms. This results in the formation of reactiveacyl glucuronides that may covalently bind to endogenous proteins, potentially contributing to the toxicity of thedrug. 32,33,36,37

Reactive metabolites can irreversibly bind to and modify many cellular components including enzymes,mitochondrial proteins, RNA, DNA, and lipids. Themechanisms through which they can cause hepatocellular damage are varied. For example, reactive metabolites can bind to hepatic proteins to form adducts, which can result in an immune response. 27 They can also directly inhibit functional hepatocellular mechanisms, such as the bile salt ef ux pump (BSEP), which may result in hepatic injurythrough the build up of toxic BSEP substrates.

Furthermore, reactive metabolites can lead to thedepletion of GSH, which may result in oxidative stress, asobserved in acetaminophen induced hepatic necrosis.Acetaminophen is mainly metabolized by glucuronidationand sulfation pathways. However, a small proportion of the drug is metabolized by CYP3A4, CYP2E1, and CYP1A2 to form the reactive metabolite, N acetyl p

benzoquinoneimine (NAPQI). This is normally rapidlydetoxi ed by conjugation to GSH and safely eliminated from the liver. However, overdose of acetaminophenresults in GSH depletion and the accumulation of NAPQI,

which binds to cellular proteins and leads to oxidativestress reactions, dysfunction of mitochondria and DNAdamage. 38

Hepatic Transporter ProteinsHepatic transporter proteins play a crucial role in both thein ux and ef ux of xenobiotics and endogenous compounds into and out of the cell (see Figure 1).

Influx Transport Basolateral in ux transporters are responsible for the

hepatic uptake of xenobiotics and conjugated bile acidsfrom the liver sinusoids. Members of the solute carrier (SLC) superfamily carry out this function, and are believed to play a major role in therapeutic ef cacy and adverse drug reactions, including hepatotoxicity, throughthe regulation of transport across both cellular and tissuemembranes. This superfamily includes transporters in-volved in sodium dependent pathways, such as sodiumtaurocholate co transporting polypeptides (NTCP/ SLC10A1), and transporters involved in sodium indepen-dent pathways, such as members of the organic aniontransporter (OAT) and organic anion transporting poly-

peptide (OATP/SLCO) families.15,39 41

OATPs mediate

464 The Journal of Clinical Pharmacology / Vol 53 No 5 (2013)


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the uptake of a wide range of endogenous compounds and xenobiotics, and human OATP1B1 and OATP1B3 have been associated with the transport of many drugs. 42

46

Efflux Transport Transporters located at the apical membrane are responsible for the ef ux of both drug metabolites and bileconstituents, such as bile salts, into the bile canaliculus.The ATP binding cassette B1 protein (ABCB1), alsoknown as multidrug resistance type 1 protein (MDR1) and

P glycoprotein (P gp), is a well characterized canalicular transporter with broad substrate speci city that has beenassociated with cellular resistance to many drugs. 15,39,47,48

Numerous similar transporters have been identi ed and grouped into the ATP binding cassette (ABC) transporter superfamily. These include further proteins encoded bythe ABCB genes, such as MDR3 ( ABCB4) and BSEP( ABCB11), and members of the multidrug resistance

associated protein (MRP) family, encoded by ABCC genes, which are multi speci c transporters for different organic anions. Ef ux transporters located at the baso-lateral surface of the hepatocyte, such as MRP3 and

MRP4, play a role in the elimination of drug metabolitesinto the sinusoid for urinary excretion via the kidneys.

Transporter Proteins Associated With DILIStudies have indicated a potential role of hepatictransporter proteins in DILI. In both rats and mice,expression levels of uptake transporters are reduced and export transporters increased, on exposure to hepatotoxiccompounds including acetaminophen and carbon tetra-chloride (CCL 4).

49 52 Furthermore, acetaminophen induc-tion of MRP3 and MRP4 is associated with a reduction inacetaminophen induced hepatotoxicity on subsequent

exposure to higher doses.53

These data suggest that the

liver is able to regulate expression levels of transporters to prevent the accumulation of hepatotoxins in the hepato-cyte and subsequent cellular damage.

It is becoming increasingly evident that the inhibitionof hepatic transporter proteins by parent drugs or their metabolites is also a mechanism for cholestatic forms of DILI. As the transporter systems are responsible for thetransverse of biliary components across the hepatocellular membrane, their functional disruption can lead to harmfulintracellular accumulation of cholephilic compounds and

subsequent cholestatic liver injury.54

The hepatic uptake transporters OATP1B1 (OATP C)and OATP1B3 (OATP8) have been shown to play a part indetermining the hepatotoxic effects of troglitazone, a drugthat was used to treat type 2 diabetes mellitus before itswithdrawal from the market. The sulfate conjugate, M 1, isthe major metabolite of troglitazone and is transported byOATP1B1, which, if malfunctioning, results in theintracellular accumulation of this metabolite. In fact,subjects with impaired liver function have higher systemicconcentrations and a longer half life of M 1.55 AlthoughM 1 itself is pharmacologically inactive and devoid of

cytotoxic effects, its impaired hepatic excretion may lead tohepatotoxicity. Interestingly, M 1 inhibits OATP1B1 and OATP1B3, as well as BSEP1. As these transporters are alsoinvolved in the movement of bile salts and bilirubin acrossthe basolateral membrane and the canalicular membranerespectively, the inhibitory action of M 1 may disrupt thenormal hepatic in ux and ef ux transport of theseendogenous molecules leading to intrahepatic cholestasisand contributing to troglitazone induced liver injury. 56

Other BSEP inhibitors that can induce cholestatic DILIinclude bosentan and cyclosporin A. 57

59 Furthermore,cyclosporin A disrupts bile acid metabolism through

the competitive inhibition of the other canalicular

Figure 1. Key proteins involved in drug metabolism and transport.

Corsini and Bortolini 465


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transporters, MRP2 and ABCB1. 60 MRP2 has widesubstrate speci city for xenobiotics and endogenoussubstances, and is responsible for the excretion of pravastatin and methotrexate. Therefore, these two drugsmay also competitively inhibit this transporter leading toaccumulation of bile constituents and drugs in hepato-cytes, favoring hepatic injury. 61,62

Hepatic transporter proteins are also responsible for themovement of unconjugated bilirubin into the hepatocyteand to the intracellular microsomes for conjugation toglucuronic acid, and of conjugated bilirubin into the bilecanaliculus. HMG CoA reductase inhibitors, such asrosuvastatin and pitavastatin, competitively inhibit OATP1B1 transporters, which are involved in unconju-gated bilirubin uptake, and may be a cause of unconjugat-ed hyperbilirubinemia. 61

Some drugs may have effects on multiple drug

metabolizing and/or hepatic transporter proteins, withsome prominent examples shown in Table 1.

Factors Increasing Susceptibility to DILIIdiosyncratic DILI only occurs in a minority of patients,and is unpredictable based on the pharmacological actionof the drug. Therefore, other risk factors must be involved that render an individual susceptible, with idiosyncratic

DILI appearing to result from interactions betweendifferent mechanisms.

Both environmental and genetic factors can have anin uence on an individual s susceptibility to DILI. Age,female gender, alcohol use, and malnutrition have beenassociated with an increased risk of developing hepato-cellular injury. 65 This section focuses on the complexeffects of genetic variation, drug induced immunoallergichepatitis, drug drug interactions (DDIs) and underlyingdisease as factors that in uence drug metabolism and transport mechanisms associated with DILI (see Figure 2).

Genetic Susceptibility in IndividualsGenetic variation appears to be a key susceptibility factor for DILI in certain individuals. Associations betweenhepatotoxicity and gene polymorphisms have beenidenti ed in several components of DILI mechanistic pathways. Searches for genetic biomarkers of DILI havemainly concentrated on the identi cation of singlenucleotide polymorphisms (SNPs) within drug metabo-lism and transporter genes. 66 It should be noted, however,that a de nitive association between genotype and hepatotoxicity can be confounded by several factors,including a lack of statistical power due to lowobservationfrequency and dif culties in establishing a con dent diagnosis of DILI. Gene expression may also be affected by environmental factors. 67

CYP450. Numerous polymorphisms have been identi-ed within the CYP450 isoenzymes, and such variation

may contribute to the differences observed in drug

responses among individuals. However, a strong correla-tion between speci c CYP genotypes and DILI has not been established and only a few polymorphisms have beenassociated with hepatotoxicity.

Functional polymorphisms have been found inCYP2C9 and CYP2C19 , some of which have beenassociated with drug induced hepatotoxicity in small/ single case studies. 68

71 However, in a larger studyutilizing a Spanish registry of DILI patients, polymorphisms in these isoforms were not found to be associated with DILI, and therefore genetic variation in CYP2C9 and CYP2C19 may not be a DILI risk factor. 70

CYP2D6 is highly polymorphic with allelic variantsencoding enzymes with differing levels of activity, and it has been associated with hepatotoxicity due to severaldrugs, including antidepressants and herbal products. 72

76

Inter ethnic differences in CYP2D6 have been identi ed that demonstrate a relationship between genotype and enzyme activity; CYP2D6 gene duplications have beenfound in ultra rapid metabolizers, and SNPs have been found in poor metabolizers, affecting drug ef cacyand potential favoring hepatotoxicity (reviewed byBertilsson et al. 77 ).

A potential association between the CYP2E1 genotype,

which varies substantially between ethnic groups, and the

Table 1. Examples of Drugs With In Vivo Actions on Multiple DrugMetabolism and Transporter Proteins (Primarily Based on Refs.63,64 )

Drug Hepatic Protein (Effect)

Cyclosporin CYP3A (weak inhibitor)BSEP (inhibitor)ABCB1 (inhibitor)MRP2 (inhibitor)OATP1B1 (inhibitor)OATP1B3 (inhibitor)

Rifampin CYP3A (strong inducer/inhibitor)CYP2B6 (moderate inducer)CYP2C8 (moderate inducer/inhibitor)CYP2C9 (moderate inducer)CYP2C19 (moderate inducer)ABCB1 (inducer)OATP1B1 (inhibitor/substrate)

OATP1B3 (inhibitor/substrate)Ritonavir CYP3A (inhibitor)CYP2D6 (weak inhibitor)ABCB1 (inhibitor)OATP1B1 (inhibitor)OATP1B3 (inhibitor)

Troglitazone (no longer marketed ) CYP3A (inducer)BSEP (inhibitor)OATP1B1 (inhibitor)OATP1B3 (inhibitor)

Bosentan CYP3A (moderate inducer)CYP2C9 (weak inducer)BSEP (inhibitor)OATP1B1 (substrate)



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risk of developing DILI has also been demonstrated.Interestingly, the wild type CYP2E1 genotype correlated with an increased susceptibility to antituberculosis drug

induced hepatotoxicity (ATDH) compared to variant genotypes in some studies. 78

81 However, this associationwas not established in other studies, 82

87 although it wasfound that the wild type CYP2E1 genotype increased theseverity of hepatotoxicity 85 and raised the risk of ATDHwhen combined with a slow acetylator NAT2 genotype. 82

Bose et al. 83 also showed that the combination of a slowacetylator NAT2 genotype anda variant CYP2E1 genotypein particular affected the frequency of ATDH in Indian

patients.CYP2B6 is also polymorphic, and variants of this gene

have been associated with ticlopidine induced hepatotox-icity in Japanese patients when combined with the humanleukocyte antigen HLA A*3303 haplotype. 88 Orientalshave a higher frequency of both the HLA A*3303 alleleand a variant CYP2B6 allele compared to Caucasians. Thismay explain ethnic variability in ticlopidine induced hepatotoxicity, which is a frequent adverse reaction inJapanese patients, but rare in Caucasians. 88

UGTs. The UGT superfamily catalyzes glucuronida-tion reactions, which aid the removal of drugs and

endogenous compounds such as bilirubin and bile acids.89

There are many isoforms of UGT, which are encoded by19 genes in humans. 23

UGT1A1 plays a key role in the metabolism of bilirubin, and mutations found in the UGT1A1 gene areresponsible for Gilbert s syndrome and a risk factor for hyperbilirubinemia. Drugs that are metabolized byUGT1A1 (e.g., irinotecan, estradiol, and buprenorphine)or inhibit its function (e.g., indinavir and ketoconazole)have increased hepatotoxic potential in patients with amutant UGT1A1 genotype. Furthermore, UGT1A1 poly-morphisms have been associated with an increased risk of ATDH 90 and combinations of certain UGT1A1, UGT1A3,

and UGT1A7 genetic variants have been implicated inatazanavir and indinavir induced hyperbilirubinemia. 91,92

Another polymorphic UGT isoform, UGTB7, has beenassociated with diclofenac induced liver injury throughincreased glucuronidation activity. 93

NAT2. NAT2 is highly polymorphic and some variantshave been identi ed as slow or rapid acetylators.Isoniazid, an antituberculosis drug, is initially metabolized by NAT2 prior to oxidation by CYP2E1. Although rapid acetylators have been associated with isoniazid induced liver necrosis in the past, 94 subsequent studies haveindicated a strong correlation of slow acetylators with

hepatotoxicity caused by such antituberculosis

Figure 2. Factors affecting susceptibility of individuals to DILI through drug metabolism and transport disturbances.



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drugs. 79,95 100 In the absence of ef cient acetylation, it is

possible that drug metabolism is achieved throughalternative CYP mediated pathways, resulting in thegeneration of toxic metabolites. Slow acetylators havealso been associated with sulfonamide induced liver injury. 101

GST. GST is a Phase II conjugation enzyme that has animportant role in the prevention of oxidative stress.Human cytosolic GSTM1 and GSTT1 are expressed polymorphically and have been associated with DILI. Anincreased prevalence of the GSTM1 null genotype and theGSTT1 null genotype has been found in patients withATDH in some studies, 102

104 though other studies havefailed to demonstrate a signi cant association. 81,86,105,106

The GSTM1 null genotype has also been shown to be arisk factor for carbamazepine induced hepatotoxicity, 107

and, furthermore, the double GSTT1 GSTM1 null geno-type has been associated with troglitazone , tacrine ,antibacterial , and NSAID induced DILI. 108 112

MnSOD. Manganese superoxide dismutase (MnSOD)also has an important role in the defense against cellular oxidative stress. Certain allelic variations of MnSOD mayincrease susceptibility to hepatocellular DILI by variousdrugs, including antituberculosis drugs. 102 However,these MnSOD allelic variants have been associated inthe Spanish DILI registry with an increased risk of cholestatic and mixed DILI from certain types of drugmetabolites. 113 It is predicted that these variants mayresult in an increase of MnSOD levels and therefore therelevance of the polymorphisms is uncertain. However,

an accumulation of hydrogen peroxide from increased MnSOD activity has been suggested as a potentialmechanism for DILI susceptibility. 102,113

ABC Transporters. Mutations in the ABC transportersMDR3 ( ABCB4), MRP2 ( ABCC2) and BSEP ( ABCB11),which are located at the canalicular hepatocyte membrane,have been associated with DILI. Separate non synony-mous mutations in ABCB4 have been found in a patient with hepatocellular DILI taking amoxicillin clavulanicacid, and in a patient with cholestatic DILI takingrisperidone. 114 Mutations in ABCC2 have been associated with herbal induced hepatocellular and cholestatic liver

injury in Korean patients;115

one of these variants mayresult in a lower transport activity of MRP2 and has beenfound in patients with diclofenac hepatotoxicity. 93

Furthermore, genetic variations of ABCC2 result inDubin Johnson syndrome, an autosomal disease that causes conjugated hyperbilirubinemia. A common geneticvariant of ABCB11 has been associated with both drug

induced hepatocellular and drug induced cholestatic liver injury. 114,116 This 1331T > C (V444A) polymorphism inexon 13 is also a susceptibility factor for estrogen induced cholestasis. 117

SLC Transporters. The SLC transporter, OATP1B1, is

responsible for the in ux of many drugs that are known to

cause hepatotoxicity, including troglitazone, rifampin, bosentan, methotrexate, and statins. 40 Polymorphisms inthe corresponding SLCO1B1 gene have been associated with drug hypersensitivity. For example, several SNPsidenti ed in this gene result in altered function, whichaffects levels of statins, methotrexate, and irinotecan that may contribute to severe drug toxicities. 40,118 121 Inaddition, a SNP at position 388 (A > G) has beenassociated with an increased risk of hyperbilirubinemia inneonates. 122 Furthermore, the identi cation of OATP1B1and OATP1B3 co de ciencies in Rotor syndrome fami-lies suggests that drugs inhibiting these transporters could increase the risk of drug induced conjugated hyperbilirubinemia, which may have implications for DILIsusceptibility in patients de cient in SLCO1B1 and SLCO1B3 .123

Adaptive Immunological Mechanisms of DILIThe adaptive immune system has been implicated as amechanism of DILI for several drugs, as indicated by thetime of presentation, allergic symptoms and the presenceof certain immune cells in biopsy samples. It ishypothesized that the drug metabolite, or parent drug, binds to hepatic proteins to form a neoantigen, and activates the immune system to generate antibodiesagainst the modi ed and/or native protein. 124,125 Thismechanism has been associated with diclofenac induced hepatotoxicity, 126 and the presence of autoantibodiesagainst the CYP450 enzymes have been reported in casesof hepatitis induced by several drugs including halothane,

tienilic acid, dihydralazine, and anticonvulsant drugs. 9,13,127

An alternative theory, called the p i concept, suggeststhat a drug stimulates an immune response through direct interaction with T cell receptors. 128,129 This mechanismwas originally proposed for sulfamethoxazole (SMX) after T cells recognizing SMX itself were identi ed in allergicindividuals. 130,131

Despite this evidence of the adaptive immune system asa mechanism of DILI, its role in the progression to drug

induced hepatotoxicity is not fully understood. The liver is by nature tolerant in its response to antigens through the

ineffective stimulation of T

cell reactions by hepaticantigen presenting cells. 132

137 This may, however, just explain the rarity of idiosyncratic DILI, and susceptibleindividuals could represent a breakdown in antigentolerance of the liver.

DrugDrug InteractionsPotential DDIs are an important consideration, particular-ly in the treatment of older patients who may have multiplechronic conditions requiring concomitant therapies. DDIscan alter a drug s toxicity pro le and therefore potentiallyresult in hepatotoxicity. However, causality assessment in

DILI cases can be challenging and the last prescribed drug



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cannot be assumed to be the culprit or the only responsibleagent. 12

The inhibition and induction of drug metabolizingenzymes are important causes of DDIs. A build up of drugs or their metabolites can be potentially toxic throughcompetitive inhibition and lead to a greater risk of adverseevents. Alternatively, a reduction in drug concentrationthrough enzyme induction can result in a loss of ef cacy.

CYPs have a fundamental role in general drugmetabolism, especially the major human hepatic and intestinal CYP3A4 isoform. Therefore, the identi cationof drugs that are CYP3A inducers, inhibitors or substratesis informative for potential toxicity/ef cacy when use isintended in combination with another drug known to affect CYP3A.

Numerous drugs have been identi ed as CYP3A4inhibitors, including antibiotics, antidepressants, calciumchannel blockers, steroids, and antiretrovirals. Proteaseinhibitor (PI) and non nucleoside reverse transcriptaseinhibitor (NNRTI) antiretroviral drugs can inhibit or induce CYP3A4. Therefore the potential for hepatotoxicityshould be considered carefully in the co administration of PIs, and combinations like amprenavir ritonavir should beavoided due to competition in CYP3A4 metabolism. This isalso important in liver transplant recipients who commonlyreceive calcineurin inhibitor based immunosuppressionregimens using cyclosporin or tacrolimus, which aremetabolized by CYP3A4. Nel navir has been shown toaffect tacrolimus levels in a human immunode ciency virus(HIV) positive liver transplant recipient, and this may be an

effect of PIs in general. The administration of bothtacrolimus and nel navir to transplant patients requires asubstantial reduction in tacrolimus dosing to achieveappropriate levels of the drug and prevent overdosing. 138

Rifampin and rifabutin are the most potent CYP3A4inducers and their co administration can signi cantlyreduce a drug s ef cacy. 22,139 However, rifampin canacutely inhibit both CYP3A4 and CYP2C8, counteractingits inducing effect, as demonstrated in the metabolism of the antidiabetic drug, repaglinide. 140

It is also important to mention that potential immuneresponses which lead to autoantibody production against

CYPs will also cause the partial or complete loss of CYPcatalytic activity. This effect could result in DDIs and adverse drug reactions. 27

Besides having an effect on drug metabolizingenzymes, DDIs can in uence the function of transporter proteins, another route to alter the drug s ef cacy and potential to cause toxicity. 39,141,142 As mentioned before,the hepatotoxic effect of troglitazone, 56,58 cyclosporine, 59

and bosentan 57 are related, at least in part, by their inhibitory effect on transporter proteins.

ABCB1shares many substrates with CYP3A4and theymay function together in a detoxi cation pathway that can

affect the concentration and ef cacy of many drugs. Like

CYP3A4, ABCB1 is induced by several drugs includingantiretrovirals, and inhibited by many drugs includingcyclosporin, indinavir, and erythromycin. 143 Furthermore,ABCB1 can modify the levels of these overlappingsubstrates, thereby affecting their inductive and inhibitoryaction on CYP3A4.

Inhibition of OATP1B1 is also a recognized DDImechanism, with cyclosporin signi cantly increasingconcentrations of statins through the inhibition of OATP1B1 as well as ABCB1 and CYP3A4. 39,40 A recent study has given insight into how cyclosporin mediated inhibition of OATP1B1 and/or OATP1B3 may result inconjugated hyperbilirubinemia. 123 In addition, rifampininhibits both OATP1B1 and OATP1B3 in vitro , an effect also observed in vivo when administered intravenouslyimmediately before the victim drug. 144,145

Underlying DiseaseLiver disease has been shown to alter the expression of drug transporter proteins, not only in the liver itself but also in other organs. 146 When a patient has underlyingliver disease, the pharmacokinetics of a drug can beimpaired. However, it is dif cult to predict how the actionof a drug will be affected, and hence what adaptationsshould be made to a dosing regimen. 147

The risk of DILI and recommendations for using potentially hepatotoxic agents in patients with chronicliver disease have been comprehensively discussed in areview of published data. 148 Pre existing liver disease,however, is not in general deemed to increase a subject s

susceptibility to DILI, and most drugs can be used safelyin these patients. 149,150 Nevertheless, it is important to bear in mind that a diminished liver reserve, or theimpaired ability of the liver to recover, could worsen theconsequences of DILI. 151

To assess the risk of DILI in chronic liver diseases suchas hepatitis B and C and interpret the causative role of agiven drug regimen, the impairment of drug pharmacoki-netics, risk of drug interactions, and potential confoundingfactors should always be considered. Such factors include

uctuations in aminotransferase levels over the naturalcourse of the disease 152,153 or, particularly in HIV co

infected subjects, concomitant antiviral regimens that caninduce generally mild hepatocellular injury or unconju-gated hyperbilirubinemia, 91,92 or ares of hepatitis viralreactivation. 154

158

Herbal remedies are commonly used by patients withchronic hepatitis C, 159,160 and may produce interactionswith hepatic drug metabolizing enzymes. 161,162 Anexample is St. John s Wort ( Hypericum perforatum L.)which can modify CYP3A isoenzyme activity and,consequently, the metabolism of several immunosuppres-sive agents such as cyclosporine and tacrolimus. 162

It has been demonstrated in both rats and humans that

non

alcoholic fatty liver disease (NAFLD), characterized



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by mitochondrial dysfunction, can signi cantly increasethe risk of DILI, 163,164 making obese and diabetic patientsmore susceptible to liver damage induced by drugs.

Cancer patients are also at an increased risk for DILI, asthe ef cacy and toxicity of many antineoplastic drugs arein uenced by disturbances in drug metabolizing and transporter pathways. The hepatotoxic potential of chemotherapeutic agents may increase in oncology patients with liver disease, and the severity of toxichepatitis can be variable. 165 Other non chemotherapeuticdrugs may also increase the susceptibility of cancer patients to hepatotoxicity. Drugs such as antimicrobialsare commonly used in the long term care of oncology patients, which may cause DILI that is dif cult todistinguish from liver injury resulting from concurrent antineoplastic therapies. 166

DiscussionThe liver represents the major target organ for many drugsand toxins because of its unique role in drug metabolism,detoxi cation, and bioactivation. 167

The elucidation of the metabolic and transport path-ways through which drugs are processed in the liver hasled to a better understanding of potential DILI mecha-nisms. Many studies, spanning from laboratory based experimental research to clinical case studies, have pin

pointed the signi cant contribution of liver mediated drugmetabolism and clearance to the complexity of DILI. Infact, drugs with more than 50% hepatic metabolism are

more likely to cause DILI than those with lesser hepaticmetabolism. 6 This is well documented by a series of drugs(e.g., paracetamol, 38 troglitazone, 58 cyclosporin 59 ) inwhich their hepatotoxicity was caused by impaired hepaticmetabolism and transport.

The rarity of idiosyncratic DILI suggests a complex process involving the interplay of several metabolic and transport mechanisms, as well as genetic or environmentalfactors, which in turn can increase an individual ssusceptibility to DILI. Indeed, genetic polymorphisms of drug metabolizing and drug transporter proteins areincreasingly recognized as important factors causing inter

individual variation in drug response and drug (hepato)toxicity. However, an identi ed genetic polymorphism isunlikely to be solely responsible for a particular phenotype,and interaction with other variant genes and environmentalfactors should be taken into consideration. 67 Sequencevariations of enhancers have been shown to affect theexpression levels of hepatic transporter proteins associated withvarious drugs, supporting evidence that generegulatorysequences signi cantlycontribute to therisk of idiosyncraticDILI. 168 Advances in genetic research should lead to amore comprehensive understanding of how an individual sgenotype may increase their susceptibility to liver injury

from certain drugs.

Finally, clinical assessments of individual patientsshould be conducted to address the relationship betweenDILI and the pharmacokinetics of a drug. These should include the evaluation of environmental factors, such asethanol consumption, and underlying diseases, such asliver disorders or cancer. Concomitant drug therapyshould also be assessed, including use of over the counter drugs and herbal or homeopathic remedies, to avoid relevant DDIs.

The detailed assessment of drug metabolism and transport, therefore, represents an important approachfor a better understanding of the pharmacological pro leof a speci c drug and for managing risks associated with its potential to cause liver injury in susceptible patients.

Financial Disclosure

This work was supported

nancially by F. Hoffmann

La RocheLtd. A. Corsini has consultancy agreements with, and hasreceived research funding from, pharmaceutical companiesincluding F. Hoffman La Roche. M. Bortolini is a full timeemployee of F. Hoffmann La Roche.

References1. Lee WM. Acute liver failure in the United States. Semin Liver Dis.

2003;23(3):217 226.2. Ostapowicz G, Fontana RJ, Schiodt FV, et al. Results of a

prospective study of acute liver failure at 17 tertiary care centers inthe United States. Ann Intern Med. 2002;137(12):947 954.

3. Garcia Cortes M, Stephens C, Lucena MI, Fernandez Castaner A,

Andrade RJ. Causality assessment methods in drug induced liver injury: strengths and weaknesses. J Hepatol. 2011;55(3):683 691.

4. Kaplowitz N. Drug induced liver disorders: implications for drugdevelopment and regulation. Drug Saf. 2001;24(7):483 490.

5. Temple RJ, Himmel MH. Safety of newly approved drugs:implications for prescribing. JAMA. 2002;287(17):2273 2275.

6. Lammert C, Bjornsson E, Niklasson A, Chalasani N. Oralmedications with signi cant hepatic metabolism at higher risk for hepatic adverse events. Hepatology. 2010;51(2):615 620.

7. Bernal W, Cross TJ, Auzinger G, et al. Outcome after wait listingfor emergency liver transplantation in acute liver failure: a singlecentre experience. J Hepatol. 2009;50(2):306 313.

8. Russo MW, Galanko JA, Shrestha R, Fried MW, Watkins P. Liver transplantation for acute liver failure from drug induced liver injuryin the United States. Liver Transpl. 2004;10(8):1018 1023.

9. Andrade RJ,Robles M,UlzurrunE, LucenaMI. Drug induced liver injury: insights from genetic studies. Pharmacogenomics. 2009;10(9):1467 1487.

10. Russmann S, Kullak Ublick GA, Grattagliano I. Current conceptsof mechanisms in drug induced hepatotoxicity. Curr Med Chem.2009;16(23):3041 3053.

11. Aithal GP, Rawlins MD, Day CP. Accuracy of hepatic adversedrug reaction reporting in one English health region. BMJ. 1999;319(7224):1541.

12. Shapiro MA, Lewis JH. Causality assessment of drug induced hepatotoxicity: promises and pitfalls. Clin Liver Dis. 2007;11(3):477 505.

13. Stirnimann G, Kessebohm K, Lauterburg B. Liver injury caused bydrugs: an update. Swiss Med Wkly. 2010;140:w13080. http://www.

smw.ch/content/smw

2010

13080/. Accessed May 9, 2012.



9/12

14. Kenne K, Skanberg I, Glinghammar B, et al. Prediction of drug

induced liver injury in humans by using in vitro methods: the caseof ximelagatran. Toxicol In Vitro. 2008;22(3):730 746.

15. Giacomini KM, Sugiyama Y. Membrane transporters and drugresponse. In: Brunton LL, Chabner B, Knollman B, eds. Goodman& Gilman s Pharmacological Basis of Therapeutics . 12th ed. NewYork: McGraw Hill; 2011: 89.

16. Dai D, Tang J, Rose R, et al. Identi cation of variants of CYP3A4and characterization of their abilities to metabolize testosterone and chlorpyrifos. J Pharmacol Exp Ther. 2001;299(3):825 831.

17. Aoyama T, Yamano S, Waxman DJ, et al. Cytochrome P 450hPCN3, a novel cytochrome P 450 IIIA gene product that isdifferentially expressed in adult human liver. cDNA and deduced amino acid sequence and distinct speci cities of cDNA expressed hPCN1 and hPCN3 for the metabolism of steroid hormones and cyclosporine. J Biol Chem. 1989;264(18):10388 10395.

18. Guengerich FP. Cytochrome P 450 3A4: regulation and role indrug metabolism. Annu Rev Pharmacol Toxicol. 1999;39:1 17.

19. Rebbeck TR, Jaffe JM, Walker AH, Wein AJ, Malkowicz SB.Modi cation of clinical presentation of prostate tumors by a novelgenetic variant in CYP3A4. J Natl Cancer Inst. 1998;90(16):1225

1229.20. Shimada T, Gillam EM, Sandhu P, Guo Z, Tukey RH, GuengerichFP. Activation of procarcinogens by human cytochrome P450enzymes expressed in Escherichia coli . Simpli ed bacterialsystems for genotoxicity assays. Carcinogenesis. 1994;15(11):2523 2529.

21. Thummel KE, O Shea D, Paine MF, et al. Oral rst passelimination of midazolam involves both gastrointestinal and hepatic CYP3A mediated metabolism. Clin Pharmacol Ther.1996;59(5):491 502.

22. Zhou SF, Xue CC, Yu XQ, Li C, Wang G. Clinically important drug interactions potentially involvingmechanism based inhibitionof cytochrome P450 3A4 and the role of therapeutic drugmonitoring. Ther Drug Monit. 2007;29(6):687 710.

23. Gonzalez FJ, Coughtrie M, Tukey RH. Drug metabolism. In:

Brunton LL, Chabner B, Knollman B, eds. Goodman & Gilman s Pharmacological Basis of Therapeutics . 12th ed. New York:McGraw Hill; 2011: 123 144.

24. Andrade RJ, Robles M, Lucena MI. Rechallenge in drug induced liverinjury: the attractivehazard. Expert Opin Drug Saf. 2009;8(6):709 714.

25. Glatt H. Sulfation and sulfotransferases 4: bioactivation of mutagens via sulfation. FASEB J. 1997;11(5):314 321.

26. Strange RC, Spiteri MA, Ramachandran S, Fryer AA. Glutathione

S transferase family of enzymes. Mutat Res. 2001;482(1 2):21 26.

27. Zhou S, Chan E, Duan W, Huang M, Chen YZ.Drug bioactivation,covalent binding to target proteins and toxicity relevance. Drug Metab Rev. 2005;37(1):41 213.

28. Glatt H, Engelke CE, Pabel U, et al. Sulfotransferases: genetics and role in toxicology. Toxicol Lett. 2000;112 113:341 348.

29. Glatt H. Sulfotransferases in the bioactivation of xenobiotics. Chem Biol Interact. 2000;129(1 2):141 170.

30. Glatt H, Boeing H, Engelke CE, et al. Human cytosolicsulphotransferases: genetics, characteristics, toxicological aspects. Mutat Res. 2001;482(1 2):27 40.

31. Hinson JA, Forkert PG. Phase II enzymes and bioactivation. Can J Physiol Pharmacol. 1995;73(10):1407 1413.

32. Ritter JK. Roles of glucuronidation and UDP glucuronosyltrans-ferases in xenobiotic bioactivation reactions. Chem Biol Interact.2000;129(1 2):171 193.

33. Sallustio BC, Sabordo L, Evans AM, Nation RL. Hepaticdisposition of electrophilic acyl glucuronide conjugates. Curr Drug Metab. 2000;1(2):163 180.

34. Spahn Langguth H, Dahms M, Hermening A. Acyl glucuronides:covalent binding and its potential relevance. Adv Exp Med Biol.1996;387:313 328.

35. van Bladeren PJ. Glutathione conjugation as a bioactivationreaction. Chem Biol Interact. 2000;129(1 2):61 76.

36. Boelsterli UA. Xenobiotic acyl glucuronides and acyl CoAthioesters as protein reactive metabolites with the potential tocause idiosyncratic drug reactions. Curr Drug Metab. 2002;3(4):439 450.

37. Shipkova M, Armstrong VW, Oellerich M, Wieland E. Acylglucuronide drug metabolites: toxicological and analytical impli-cations. Ther Drug Monit. 2003;25(1):1 16.

38. Antoine DJ, Williams DP, Park BK. Understanding the role of reactive metabolites in drug induced hepatotoxicity: state of thescience. Expert Opin Drug Metab Toxicol. 2008;4(11):1415 1427.

39. Giacomini KM, Huang SM, Tweedie DJ, et al. Membranetransporters in drug development. Nat Rev Drug Discov. 2010;9(3):215 236.

40. Kalliokoski A, Niemi M. Impact of OATP transporters on pharmacokinetics. Br J Pharmacol. 2009;158(3):693 705.

41. Lee EJ, Lean CB, Limenta LM. Role of membrane transporters in

the safety pro le of drugs. Expert Opin Drug Metab Toxicol.2009;5(11):1369 1383.42. Abe T, Unno M, Onogawa T, et al. LST 2, a human liver speci c

organic anion transporter, determines methotrexate sensitivityin gastrointestinal cancers. Gastroenterology. 2001;120(7):1689 1699.

43. Hagenbuch B, Meier PJ. Organic anion transporting polypeptidesof the OATP/SLC21 family: phylogenetic classi cation as OATP/ SLCO superfamily, new nomenclature and molecular/functional properties. P ugers Arch. 2004;447(5):653 665.

44. HagenbuchB, GuiC. Xenobiotic transporters of thehumanorganicanion transporting polypeptides (OATP) family. Xenobiotica.2008;38(7 8):778 801.

45. Konig J, Cui Y, Nies AT, Keppler D. A novel human organic aniontransporting polypeptide localized to the basolateral hepatocyte

membrane. Am J Physiol Gastrointest Liver Physiol. 2000;278(1):G156 G164.

46. Konig J, Cui Y, Nies AT, Keppler D. Localization and genomicorganization of a new hepatocellular organic anion transporting polypeptide. J Biol Chem. 2000;275(30):23161 23168.

47. Johnstone RW, Tainton KM, Rue i AA, et al. P glycoprotein doesnot protect cells against cytolysis induced by pore forming proteins. J Biol Chem. 2001;276(20):16667 16673.

48. Marzolini C, Paus E, Buclin T, Kim RB. Polymorphisms in humanMDR1 (P glycoprotein): recent advances and clinical relevance.Clin Pharmacol Ther. 2004;75(1):13 33.

49. Aleksunes LM, Slitt AM, Cherrington NJ, Thibodeau MS,Klaassen CD, Manautou JE. Differential expression of mousehepatic transporter genes in response to acetaminophen and carbontetrachloride. Toxicol Sci. 2005;83(1):44 52.

50. Geier A, Kim SK, Gerloff T, et al. Hepatobiliary organic aniontransporters are differentially regulated in acute toxic liver injuryinduced by carbon tetrachloride. J Hepatol. 2002;37(2):198 205.

51. Ghanem CI, Gomez PC, Arana MC, et al. Effect of acetaminophenon expression and activity of rat liver multidrug resistance

associated protein 2 and P glycoprotein. Biochem Pharmacol.2004;68(4):791 798.

52. Song IS, Lee YM, Chung SJ, Shim CK. Multiple alterations of canalicular membrane transport activities in rats with CCl(4)

induced hepatic injury. Drug Metab Dispos. 2003;31(4):482 490.53. Aleksunes LM, Campion SN, Goedken MJ, Manautou JE.

Acquired resistance to acetaminophen hepatotoxicity is associated with induction of multidrug resistance associated protein 4 (Mrp4)in proliferating hepatocytes. Toxicol Sci. 2008;104(2):261 273.



10/12

54. Pauli Magnus C, Meier PJ. Hepatobiliary transporters and drug

induced cholestasis. Hepatology. 2006;44(4):778 787.55. Ott P, Ranek L, Young MA. Pharmacokinetics of troglitazone, a

PPAR gamma agonist, in patients with hepatic insuf ciency. Eur J Clin Pharmacol. 1998;54(7):567 571.

56. Nozawa T, Sugiura S, Nakajima M, et al. Involvement of organicanion transporting polypeptides in the transport of troglitazonesulfate: implications for understanding troglitazone hepatotoxicity. Drug Metab Dispos. 2004;32(3):291 294.

57. Fattinger K, Funk C, Pantze M, et al. The endothelin antagonist bosentan inhibits the canalicular bile salt export pump: a potentialmechanism for hepatic adverse reactions. Clin Pharmacol Ther.2001;69(4):223 231.

58. Funk C, Ponelle C, Scheuermann G, Pantze M. Cholestatic potential of troglitazone as a possible factor contributing totroglitazone induced hepatotoxicity: in vivo and in vitrointeractionat the canalicular bile salt export pump (Bsep) in the rat. Mol Pharmacol. 2001;59(3):627 635.

59. Stieger B, Fattinger K, Madon J, Kullak Ublick GA, Meier PJ.Drug and estrogen induced cholestasis through inhibition of thehepatocellular bile salt export pump (Bsep) of rat liver.

Gastroenterology. 2000;118(2):422

430.60. Akashi M, Tanaka A, Takikawa H. Effect of cyclosporin A on the biliary excretion of cholephilic compounds in rats. Hepatol Res.2006;34(3):193 198.

61. AhYM,KimYM,KimMJ,et al. Drug induced hyperbilirubinemiaand the clinical in uencing factors. Drug Metab Rev. 2008;40(4):511 537.

62. Kato R, Nishide M, Kozu C, et al. Is cyclosporine A transport inhibitedby pravastatin via multidrugresistantprotein2? Eur J Clin Pharmacol. 2010;66(2):153 158.

63. FDA/Guidance for industry: drug interaction studies studydesign, data analysis, implications for dosing, and labelingrecommendations. Draft guidance. Food and Drug AdministrationWeb site. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM292362.pdf. February 2012.

Accessed May 9, 2012.64. FDA/Drugs/Development resources page. Drug development and

drug interactions: table of substrates, inhibitors and inducers. Food and Drug Administration Web site. http://www.fda.gov/Drugs/ DevelopmentApprovalProcess/DevelopmentResources/DrugInter-actionsLabeling/ucm093664.htm. Updated September 16, 2011.Accessed May 9, 2012.

65. DeLeve L, Kaplowitz N. Prevention and therapy of drug induced hepatic injury. In: Wolfe MM, ed. Therapy of Digestive Disorders .Philadelphia: WB Saunders, Harcourt, Brace; 2000: 334 348.

66. Au JS, Navarro VJ, Rossi S. Review article: drug induced liver injury its pathophysiology and evolving diagnostictools. Aliment Pharmacol Ther. 2011;34(1):11 20.

67. Meyer UA, Gut J. Genomics and the prediction of xenobiotictoxicity. Toxicology 2002;181 182:463 466.

68. Larrey D, Pageaux GP. Genetic predisposition to drug induced hepatotoxicity. J Hepatol. 1997;26(Suppl. 2):12 21.

69. LarreyD. Epidemiologyand individual susceptibility to adverse drugreactions affecting the liver. Semin Liver Dis. 2002;22(2):145 155.

70. Pachkoria K, Lucena MI, Ruiz Cabello F, Crespo E, Cabello MR,Andrade RJ. Genetic polymorphisms of CYP2C9 and CYP2C19are not related to drug induced idiosyncratic liver injury (DILI). Br J Pharmacol. 2007;150(6):808 815.

71. Sevilla Mantilla C, Ortega L, Agundez JA, Fernandez Gutierrez B,Ladero JM, Diaz Rubio M. Le unomide induced acute hepatitis. Dig Liver Dis. 2004;36(1):82 84.

72. CacciaS. Metabolism of thenewerantidepressants. An overview of the pharmacological and pharmacokinetic implications. Clin Pharmacokinet. 1998;34(4):281 302.

73. Maurer HH, Kraemer T, Springer D, Staack RF. Chemistry, pharmacology, toxicology, and hepatic metabolism of designer drugs of the amphetamine (ecstasy), piperazine, and pyrrolidino- phenone types: a synopsis. Ther Drug Monit. 2004;26(2):127 131.

74. MorganMY, ReshefR, Shah RR, Oates NS, Smith RL,Sherlock S.Impaired oxidation of debrisoquine in patients with perhexilineliver injury. Gut. 1984;25(10):1057 1064.

75. Otani K, Kaneko S, Tasaki H, Fukushima Y. Hepatic injury caused by mianserin. BMJ. 1989;299(6697):519.

76. Seybold U, Landauer N, Hillebrand S, Goebel FD. Senna induced hepatitis in a poormetabolizer. AnnIntern Med. 2004;141(8):650 651.

77. Bertilsson L, Dahl ML,Dalen P, Al Shurbaji A. Moleculargeneticsof CYP2D6: clinical relevance with focus on psychotropic drugs. Br J Clin Pharmacol. 2002;53(2):111 122.

78. Huang YS, Chern HD, Su WJ, et al. Cytochrome P450 2E1genotype and the susceptibility to antituberculosis drug induced hepatitis. Hepatology. 2003;37(4):924 930.

79. Sun F, Chen Y, Xiang Y, Zhan S. Drug metabolising enzyme polymorphisms and predisposition to anti tuberculosis drug

induced liver injury: a meta analysis. Int J Tuberc Lung Dis.2008;12(9):994 1002.

80. Vuilleumier N, Rossier MF, Chiappe A, et al. CYP2E1 genotypeand isoniazid induced hepatotoxicity in patients treated for latent tuberculosis. Eur J Clin Pharmacol. 2006;62(6):423 429.

81. Wang T, Yu HT, Wang W, Pan YY, He LX, Wang ZY. Genetic polymorphisms of cytochrome P450 and glutathione S transferaseassociated with antituberculosis drug induced hepatotoxicity inChinese tuberculosis patients. J Int Med Res. 2010;38(3):977 986.

82. An HR, Wu XQ, Wang ZY, Zhang JX, Liang Y. NAT2 and CYP2E1 polymorphisms associated with antituberculosis drug

induced hepatotoxicity in Chinese patients. Clin Exp Pharmacol Physiol. 2012;39(6):535 543.

83. Bose PD, Sarma MP, Medhi S, Das BC, Husain SA, Kar P. Role of polymorphic N acetyl transferase2 and cytochrome P4502E1 genein antituberculosis treatment induced hepatitis. J Gastroenterol Hepatol. 2011;26(2):312 318.

84. Cho HJ, Koh WJ, Ryu YJ, et al. Genetic polymorphisms of NAT2and CYP2E1 associated with antituberculosis drug induced hepatotoxicity in Korean patients with pulmonary tuberculosis.Tuberculosis (Edinb). 2007;87(6):551 556.

85. Lee SW, Chung LS, Huang HH, Chuang TY, Liou YH, Wu LS. NAT2 and CYP2E1 polymorphisms and susceptibility to rst lineanti tuberculosis drug induced hepatitis. Int J Tuberc Lung Dis.2010;14(5):622 626.

86. Tang SW, Lv XZ, Zhang Y, et al., CYP2E1, GSTM1 and GSTT1genetic polymorphisms and susceptibility to antituberculosis drug

induced hepatotoxicity: a nested case control study. J Clin PharmTher. 2012;37(5):588 593.

87. Teixeira RL, Morato RG, Cabello PH, et al. Genetic poly-morphisms of NAT2, CYP2E1 and GST enzymes and theoccurrence of antituberculosis drug induced hepatitis in BrazilianTB patients. Mem Inst Oswaldo Cruz. 2011;106(6):716 724.

88. Ariyoshi N, Iga Y, HirataK, et al. Enhanced susceptibility of HLA

mediated ticlopidine induced idiosyncratic hepatotoxicity byCYP2B6 polymorphism in Japanese. Drug Metab Pharmacokinet.2010;25(3):298 306.

89. Miners JO, McKinnon RA, Mackenzie PI. Genetic polymorphismsof UDP glucuronosyltransferases and their functional signi cance.Toxicology. 2002;181 182:453 456.

90. Chang JC, Liu EH, Lee CN, et al. UGT1A1 polymorphismsassociated with risk of induced liver disorders by anti tuberculosismedications. Int J Tuberc Lung Dis. 2012;16(3):376 378.

91. Lankisch TO, Moebius U, Wehmeier M, et al. Gilbert s diseaseand atazanavir: from phenotype to UDP glucuronosyltransferasehaplotype. Hepatology. 2006;44(5):1324 1332.



11/12

92. Lankisch TO, Behrens G, Ehmer U, et al. Gilbert s syndrome and hyperbilirubinemia in protease inhibitor therapy an extended haplotypeof genetic variants increases risk in indinavir treatment. J Hepatol. 2009;50(5):1010 1018.

93. Daly AK, Aithal GP, Leathart JB, Swainsbury RA, Dang TS, DayCP. Genetic susceptibility to diclofenac induced hepatotoxicity:contribution of UGT2B7, CYP2C8, and ABCC2 genotypes.Gastroenterology. 2007;132(1):272 281.

94. Mitchell JR,Zimmerman HJ,IshakKG, et al.Isoniazid liver injury:clinical spectrum, pathology, and probable pathogenesis. Ann Intern Med. 1976;84(2):181 192.

95. Dickinson DS, Bailey WC, Hirschowitz BI, Soong SJ, Eidus L,Hodgkin MM. Risk factors for isoniazid (NIH) induced liver dysfunction. J Clin Gastroenterol. 1981;3(3):271 279.

96. Gronhagen Riska C, HellstromPE,Froseth B. Predisposing factorsin hepatitis induced by isoniazid rifampin treatmentof tuberculosis. Am Rev Respir Dis. 1978;118(3):461 466.

97. Huang YS, Chern HD, Su WJ, et al. Polymorphism of the N acetyltransferase 2 gene as a susceptibility risk factor for antituberculosis drug induced hepatitis. Hepatology. 2002;35(4):883 889.

98. Pande JN, Singh SP, Khilnani GC, Khilnani S, Tandon RK. Risk factors for hepatotoxicity from antituberculosis drugs: a case

control study. Thorax. 1996;51(2):132 136.99. Parthasarathy R, Sarma GR, Janardhanam B, et al. Hepatic toxicity

in SouthIndian patients during treatmentof tuberculosis withshort

course regimens containing isoniazid, rifampicin and pyrazina-mide. Tubercle. 1986;67(2):99 108.

100. Wang PY, Xie SY, Hao Q, Zhang C, Jiang BF. NAT2 polymorphisms and susceptibility to anti tuberculosis drug

induced liver injury: a meta analysis. Int J Tuberc Lung Dis.2012;16(5):589 595.

101. Shear NH, Spielberg SP, Grant DM, Tang BK, Kalow W.Differences in metabolism of sulfonamides predisposing toidiosyncratic toxicity. Ann Intern Med. 1986;105(2):179 184.

102. Huang YS, Su WJ, Huang YH, et al. Genetic polymorphisms of

manganese superoxide dismutase, NAD(P)H: quinone oxidore-ductase,glutathione S transferase M1 and T1,and the susceptibilityto drug induced liver injury. J Hepatol. 2007;47(1):128 134.

103. Leiro V, Fernandez Villar A, Valverde D, et al. In uence of glutathione S transferase M1 and T1 homozygous null mutationson the risk of antituberculosis drug induced hepatotoxicity in aCaucasian population. Liver Int. 2008;28(6):835 839.

104. Roy B, Chowdhury A, Kundu S, et al. Increased risk of antituberculosis drug induced hepatotoxicity in individuals withglutathione S transferase M1 null mutation. J Gastroenterol Hepatol. 2001;16(9) 1033 1037.

105. Chatterjee S, Lyle N, Mandal A, Kundu S. GSTT1 and GSTM1gene deletions are not associated with hepatotoxicity caused byantitubercular drugs. J Clin Pharm Ther. 2010;35(4):465 470.

106. Kim SH, Kim SH, Yoon HJ, et al. GSTT1 and GSTM1 nullmutations and adverse reactions induced by antituberculosis drugsin Koreans. Tuberculosis (Edinb). 2010;90(1):39 43.

107. Ueda K, Ishitsu T, Seo T, et al. Glutathione S transferase M1 nullgenotype as a risk factor for carbamazepine induced mild hepatotoxicity. Pharmacogenomics. 2007;8(5):435 442.

108. Chalasani N, Bjornsson E. Risk factors for idiosyncratic drug

induced liver injury. Gastroenterology. 2010;138(7):2246 2259.109. Lucena MI, Andrade RJ, Martinez C, et al. Glutathione

S transferase m1 and t1 null genotypes increase susceptibility toidiosyncratic drug induced liver injury. Hepatology. 2008;48(2):588 596.

110. Simon T, Becquemont L, Mary Krause M, et al. Combined glutathione S transferase M1 and T1 genetic polymorphism and tacrine hepatotoxicity. Clin Pharmacol Ther. 2000;67(4):432 437.

111. Usui T, Hashizume T, Katsumata T, Yokoi T, Komuro S. In vitroinvestigation of the glutathione transferase M1 and T1 nullgenotypesas risk factors for troglitazone induced liverinjury. Drug Metab Dispos. 2011;39(7):1303 1310.

112. Watanabe I, Tomita A, Shimizu M, et al. A study to surveysusceptible genetic factors responsible for troglitazone associated hepatotoxicity in Japanese patients with type 2 diabetes mellitus.Clin Pharmacol Ther. 2003;73(5):435 455.

113. Lucena MI, Garcia Martin E, Andrade RJ, et al. Mitochondrialsuperoxide dismutase and glutathione peroxidase in idiosyncraticdrug induced liver injury. Hepatology. 2010;52(1):303 312.

114. Lang C, Meier Y, Stieger B, et al. Mutations and polymorphisms inthe bile salt export pump and the multidrug resistance protein 3associated with drug induced liver injury. Pharmacogenet Geno-mics. 2007;17(1):47 60.

115. Choi JH, Ahn BM, Yi J, et al. MRP2 haplotypes confer differentialsusceptibility to toxic liver injury. Pharmacogenet Genomics.2007;17(6):403 415.

116. Andrade RJ, Crespo E, Ulzurrun E, et al. Polymorphic bile salt export pump transporter is a major determinant of hepatocellular drug induced liver injury. Hepatology. 2008;48(Suppl. S1):468A.

Abstract 353.117. Meier Y, Zodan T, Lang C, et al. Increased susceptibility for intrahepatic cholestasis of pregnancy and contraceptive induced cholestasis in carriers of the 1331T > C polymorphism in the bilesalt export pump. World J Gastroenterol. 2008;14(1):38 45.

118. Konig J, Seithel A, Gradhand U, Fromm MF. Pharmacogenomicsof human OATP transporters. Naunyn Schmiedebergs Arch Pharmacol. 2006;372(6):432 443.

119. Link E, Parish S, Armitage J, et al. SLCO1B1 variants and statin

induced myopathy a genomewide study. N Engl J Med. 2008;359(8):789 799.

120. Takane H, Kawamoto K, Sasaki T, et al. Life threatening toxicitiesin a patient with UGT1A1 6/ 28 and SLCO1B1 15/ 15 genotypesafter irinotecan based chemotherapy. Cancer Chemother Pharma-col. 2009;63(6):1165 1169.

121. Trevino LR, Shimasaki N, Yang W, et al. Germline geneticvariation in an organic anion transporter polypeptide associated with methotrexate pharmacokinetics and clinical effects. J ClinOncol. 2009;27(35):5972 5978.

122. Huang MJ, Kua KE, Teng HC, Tang KS, Weng HW, Huang CS.Riskfactors for severe hyperbilirubinemia in neonates. Pediatr Res.2004;56(5):682 689.

123. van de Steeg E, Stranecky V, Hartmannova H, et al. CompleteOATP1B1 and OATP1B3 de ciency causes human Rotor syndrome by interrupting conjugated bilirubin reuptake into theliver. J Clin Invest. 2012;122(2):519 528.

124. Park BK, Pirmohamed M, Kitteringham NR. Role of drugdisposition in drug hypersensitivity: a chemical, molecular, and clinical perspective. Chem Res Toxicol. 1998;11(9):969 988.

125. Uetrecht JP. Newconcepts in immunology relevant to idiosyncraticdrug reactions:the danger hypothesis and innate immune system.Chem Res Toxicol. 1999;12(5):387 395.

126. Boelsterli UA, Zimmerman HJ, Kretz Rommel A. Idiosyncraticliver toxicity of nonsteroidal antiin ammatory drugs: molecular mechanisms and pathology. Crit Rev Toxicol. 1995;25(3):207

235.127. Dansette PM, Bonierbale E, Minoletti C, Beaune PH, Pessayre D,

Mansuy D. Drug induced immunotoxicity. Eur J Drug Metab Pharmacokinet. 1998;23(4):443 451.

128. Pichler WJ. Pharmacological interaction of drugs with antigen

speci c immune receptors: the p i concept. Curr Opin Allergy Clin Immunol. 2002;2(4):301 305.

129. Pichler WJ. Direct T cell stimulations by drugs bypassing theinnate immune system. Toxicology 2005;209(2):95 100.



12/12

130. Burkhart C, von GS, Depta JP, et al. In uence of reduced glutathione on the proliferative response of sulfamethoxazole

speci c and sulfamethoxazole metabolite speci c human CD4 T cells. Br J Pharmacol. 2001;132(3):623 630.

131. Schnyder B, Burkhart C, Schnyder Frutig K, et al. Recognition of sulfamethoxazole and its reactive metabolites by drug speci cCD4 T cells from allergic individuals. J Immunol. 2000;164(12):6647 6654.

132. Ju C, McCoy JP, Chung CJ,Graf ML,Pohl LR. Tolerogenic role of Kupffer cells in allergic reactions. Chem Res Toxicol. 2003;16(12):1514 1519.

133. JuC,Pohl LR.Tolerogenic role of Kupffercellsin immune mediated adverse drug reactions. Toxicology. 2005;209(2):109 112.

134. Knolle PA, Schmitt E, Jin S, et al. Induction of cytokine productionin naive CD4( ) T cells by antigen presenting murine liver sinusoidal endothelial cells but failure to induce differentiationtoward Th1 cells. Gastroenterology. 1999;116(6):1428 1440.

135. LimmerA, Ohl J,KurtsC, etal. Ef cientpresentation of exogenousantigen by liver endothelialcellsto CD8 T cells results in antigen

speci c T cell tolerance. Nat Med. 2000;6(12):1348 1354.136. Pillarisetty VG, Shah AB, Miller G, Bleier JI, DeMatteo RP. Liver

dendritic cells are less immunogenic than spleen dendritic cells because of differences in subtype composition. J Immunol.2004;172(2):1009 1017.

137. You Q, Cheng L, Kedl RM, Ju C. Mechanism of T cell toleranceinduction by murine hepatic Kupffer cells. Hepatology. 2008;48(3):978 990.

138. Schvarcz R, Rudbeck G, Soderdahl G, Stahle L. Interaction between nel navir and tacrolimus after orthoptic liver transplanta-tion in a patient coinfected with HIV and hepatitis C virus (HCV).Transplantation. 2000;69(10):2194 2195.

139. Niemi M, Backman JT, Fromm MF, Neuvonen PJ, Kivisto KT.Pharmacokinetic interactions with rifampicin: clinical relevance.Clin Pharmacokinet. 2003;42(9):819 850.

140. Kajosaari LI, Laitila J, Neuvonen PJ, Backman JT. Metabolism of repaglinide by CYP2C8 andCYP3A4 in vitro:effect of brates and

rifampicin. Basic Clin Pharmacol Toxicol. 2005;97(4):249 256.141. Corsini A, Ceska R. Drug drug interactions with statins: will

pitavastatin overcome the statins Achilles heel? Curr Med ResOpin. 2011;27(8):1551 1562.

142. Poirier A, Funk C, Lave T, Noe J. New strategies to address drug

drug interactions involving OATPs. Curr Opin Drug Discov Dev.2007;10(1):74 83.

143. Corsini A, Bellosta S. Drug drug interaction with statins. Expert Rev Clin Pharmacol. 2008;1(1):105 113.

144. Lau YY, Huang Y, Frassetto L, Benet LZ. Effect of OATP1Btransporter inhibition on the pharmacokinetics of atorvastatin inhealthy volunteers. Clin Pharmacol Ther. 2007;81(2):194 204.

145. Vavricka SR, Van MJ, Ha HR, Meier PJ, Fattinger K. Interactionsof rifamycin SV and rifampicin with organic anion uptake systemsof human liver. Hepatology. 2002;36(1):164 172.

146. Ikemura K, Iwamoto T, Okuda M. Altered functions and expressions of drug transporters in liver, kidney and intestine indisorders of local and remote organs: possible role of oxidativestress in the pathogenesis. Expert Opin Drug Metab Toxicol. 2009;5(8):907 920.

147. Verbeeck RK. Pharmacokinetics and dosage adjustment in patientswith hepatic dysfunction. Eur J Clin Pharmacol. 2008;64(12):1147 1161.

148. Gupta NK, Lewis JH. Review article: the use of potentiallyhepatotoxic drugsin patients with liverdisease. Aliment Pharmacol Ther. 2008;28(9):1021 1041.

149. Lewis JH. The rational use of potentially hepatotoxic medicationsin patients with underlying liver disease. Expert Opin Drug Saf.2002;1(2):159 172.

150. Navarro VJ, Senior JR. Drug related hepatotoxicity. N Engl J Med.2006;354(7):731 739.

151. Amarapurkar DN. Prescribing medications in patients withdecompensated liver cirrhosis. Int J Hepatol. 2011;2011:519526.

152. Hadziyannis SJ, Sette H, Jr., Morgan TR, et al. Peginterferon

alpha2a and ribavirin combination therapy in chronic hepatitis C: arandomized study of treatment duration and ribavirin dose. Ann Intern Med. 2004;140(5):346 355.

153. Zeuzem S, Hultcrantz R, Bourliere M, et al. Peginterferon alfa 2b plus ribavirin for treatment of chronic hepatitis C in previouslyuntreated patients infected with HCV genotypes 2 or 3. J Hepatol.2004;40(6):993 999.

154. Dieterich DT, Robinson PA, Love J, Stern JO. Drug induced liver injury associated with the use of nonnucleoside reverse transcrip-tase inhibitors. Clin Infect Dis. 2004;38(Suppl. 2):S80 S89.

155. Inductivo

Yu I, Bonacini M. Highly active antiretroviral therapy

induced liver injury. Curr Drug Saf. 2008;3(1):4 13.156. Nunez M. Hepatotoxicity of antiretrovirals: incidence,mechanisms

and management. J Hepatol. 2006;44(Suppl. 1):S132 S139.157. Ogedegbe AO, Sulkowski MS. Antiretroviral associated liver

injury. Clin Liver Dis. 2003;7(2):475 499.158. Wit FW, Weverling GJ, Weel J, Jurriaans S, Lange JM. Incidence

of and risk factors for severe hepatotoxicity associated withantiretroviral combination therapy. J Infect Dis. 2002;186(1):23 31.

159. Detkova Z, Lefebvre A, Bastide C, et al. Herbal medicinesconsumption for chronic liver disease and functional intestinaldisorders: prospective study in 526 outpatients. Gastroenterology.2001;120: (5) (Suppl. 1):A228.

160. Seeff LB, Curto TM, Szabo G, et al. Herbal product use by

persons enrolled in the hepatitis C Antiviral Long Term Treatment Against Cirrhosis (HALT C) Trial. Hepatology. 2008;47(2):605 612.

161. Navarro VJ. Herbal and dietary supplement hepatotoxicity. Semin Liver Dis. 2009;29(4):373 382.

162. Stedman C. Herbal hepatotoxicity. Semin Liver Dis. 2002;22(2):195 206.

163. Donthamsetty S, Bhave VS, MitraMS, Latendresse JR, MehendaleHM. Nonalcoholic fatty liver sensitizes rats to carbon tetrachloridehepatotoxicity. Hepatology. 2007;45(2):391 403.

164. Tarantino G, Conca P, Basile V, et al. A prospective study of acutedrug induced liver injury in patients suffering from non alcoholicfatty liver disease. Hepatol Res. 2007;37(6):410 415.

165. Rodriguez Frias EA, Lee WM. Cancer chemotherapy I: hepatocel-lular injury. Clin Liver Dis. 2007;11(3):641 662, viii.

166. McDonald GB, Frieze D. A problem oriented approach to liver disease in oncology patients. Gut. 2008;57(7):987 1003.

167. Jaeschke H, Gores GJ, Cederbaum AI, Hinson JA, Pessayre D,Lemasters JJ. Mechanisms of hepatotoxicity. Toxicol Sci. 2002;65(2):166 176.

168. Kim MJ, Skewes Cox P, Fukushima H, et al. Functionalcharacterization of liver enhancers that regulate drug associated transporters. Clin Pharmacol Ther. 2011;89(4):571 578.


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