Drug-Induced Liver Injury: Insights from Genetic Studies

• Ballet F : Hepatotoxicity in drug development: Detection, significance and solutions.J. Hepatol.26(Suppl. 2) , 26–36 (1997).
   PubMed Web of Science ®Google Scholar
• Watkins PB , WhitcombRW: Hepatic dysfunction associated with troglitazone.N. Engl. J. Med.338(13) , 916–917 (1998).
   PubMed Web of Science ®Google Scholar
• Lee WM : Acute liver failure in the United States.Semin. Liver Dis.23(3) , 217–226 (2003).
   PubMed Web of Science ®Google Scholar
• Temple R : Policy developments in regulatory approval.Stat. Med.21(19) , 2939–2948 (2002).
   PubMed Web of Science ®Google Scholar
• Gunawan B , KaplowitzN: Clinical perspectives on xenobiotic-induced hepatotoxicity.Drug Metab. Rev.36(2) , 301–312 (2004).
   PubMed Web of Science ®Google Scholar
• Lucena MI , AndradeRJ, KaplowitzN et al.: Phenotypic characterization of idiosyncratic drug-induced liver injury: the influence of age and sex.Hepatology49(6) , 2001–2009 (2009).
   PubMed Web of Science ®Google Scholar
• Chalasani N , FontanaR, BonkovskyMD et al.: Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States.Gastroenterology135(6) , 1924–1934 (2008).
   PubMed Web of Science ®Google Scholar
• Zimmerman HJ : Hepatotoxicity. The Adverse Effects of Drugs and Other Chemicals on the Liver (2nd Edition). Lippincott Williams & Wilkins, PA, USA (1999).
   Google Scholar
• Park BK , KitteringhamNR, MaggsJL, PirmohamedM, WilliamsDP: The role of metabolic activation in drug-induced hepatotoxicity.Annu. Rev. Pharmacol. Toxicol.45 , 177–202 (2005).
   PubMed Web of Science ®Google Scholar
• Sgro C , ClinardF, OuazirK et al.: Incidence of drug-induced hepatic injuries: a French population-based study.Hepatology36(2) , 451–455 (2002).
   PubMed Web of Science ®Google Scholar
• Meier Y , CavallaroM, RoosM et al.: Incidence of drug-induced liver injury in medical inpatients.Eur. J. Clin. Pharmacol.61(2) , 135–143 (2005).
   PubMed Web of Science ®Google Scholar
• Seguin B , UetrechtJ: The danger hypothesis applied to idiosyncratic drug reactions.Curr. Opin. Allergy Clin. Immunol.3(4) , 235–242 (2003).
   PubMed Web of Science ®Google Scholar
• Lammert C , EinarssonS, SahaC, NiklassonA, BjornssonE, ChalasaniN: Relationship between daily dose of oral medications and idiosyncratic drug-induced liver injury: search for signals.Hepatology47(6) , 2003–2009 (2008).
   PubMed Web of Science ®Google Scholar
• Uetrecht J : Idiosyncratic drug reactions: current understanding.Annu. Rev. Pharmacol. Toxicol.47 , 513–539 (2007).
   PubMed Web of Science ®Google Scholar
• De Abajo FJ , MonteroD, MadurgaM, Garcia Rodriguez LA: Acute and clinically relevant drug-induced liver injury: a population based case–control study. Br. J. Clin. Pharmacol.58(1) , 71–80 (2004).
   PubMed Web of Science ®Google Scholar
• Senior JR : What is idiosyncratic hepatotoxicity? What is it not?Hepatology47(6) , 1813–1815 (2008).
   PubMed Web of Science ®Google Scholar
• Boelsterli UA , LimPL: Mitochondrial abnormalities. A link to idiosyncratic drug hepatotoxicity?Toxicol. Appl. Pharmacol.220(1) , 92–107 (2007).
   PubMed Web of Science ®Google Scholar
• Kaplowitz N : Idiosyncratic drug hepatotoxicity.Nat. Rev. Drug Discov.4(6) , 489–499 (2005).
   PubMed Web of Science ®Google Scholar
• DeLeve LD : Risk factors for drug-induced liver disease. In: Drug-Induced Liver Disease. Kaplowitz N, DeLeve LD (Eds)., Informa Healthcare, NY, USA, 291–305 (2007).
   Google Scholar
• Andrade RJ , LucenaMI, Martín-VivaldiR et al.: Acute liver injury associated with the use of ebrotidine, a new H2-receptor antagonist.J. Hepatol.31(4) , 641–646 (1999).
   PubMed Web of Science ®Google Scholar
• Lucena MI , AndradeRJ, RodrigoL et al.: Trovafloxacin-induced acute hepatitis.Clin. Infect. Dis.30(2) , 400–401 (2000).
   PubMed Web of Science ®Google Scholar
• Lucena MI , CarvajalA, AndradeRJ, VelascoA: Antidepressant-induced hepatotoxicity.Expert. Opin. Drug. Saf.2(3) , 249–262 (2003).
   PubMedGoogle Scholar
• Andrade RJ , LucenaMI, AlcantaraR, FraileJM: Bentazepam-associated chronic liver disease.Lancet343(8901) , 860 (1994).
   PubMed Web of Science ®Google Scholar
• Spahn-Langguth H , LiC, BenetLZ: Mechanistic role of acyl glucuronides. In: Drug-Induced Liver Disease. Kaplowitz N, DeLeve LD (Eds)., Informa Healthcare, NY, USA, 125–157 (2007).
   Google Scholar
• Berson A , De Beco V, Letteron P et al.: Steatohepatitis-inducing drugs cause mitochondrial dysfunction and lipid peroxidation in rat hepatocytes. Gastroenterology114(4) , 764–774 (1998).
   PubMed Web of Science ®Google Scholar
• Pessayre D , BersonA, FromentyB, MansouriA: Mitochondria in steatohepatitis.Semin. Liver. Dis.21(1) , 57–69 (2001).
   PubMed Web of Science ®Google Scholar
• Pessayre D , HaouziD, FauD, RobinMA, MansouriA, BersonA: Withdrawal of life support, altruistic suicide, fratricidal killing and euthanasia by lymphocytes: different forms of drug-induced hepatic apoptosis.J. Hepatol.31(4) , 760–770 (1999).
   PubMed Web of Science ®Google Scholar
• Kaplowitz N : Liver biology and pathobiology.Hepatology43(Suppl. 1) , S235–S238 (2006).
   PubMedGoogle Scholar
• Fujimoto K , KumagaiK, ItoK et al.: Sensitivity of liver injury in heterozygous Sod2 knockout mice treated with troglitazone or acetaminophen.Toxicol. Pathol.37(2) , 193–200 (2009).
   PubMed Web of Science ®Google Scholar
• Aithal GP : Genetic basis of idiosyncratic hepatotoxicity. In: Hepatotoxicity. Andrade RJ (Ed.), Permanyer Publications, Barcelona, Spain, 39–55 (2007).
   Google Scholar
• Christensen K , MurrayJC: What genome-wide association studies can do for medicineN. Engl. J. Med.356(11) , 1094–1096 (2007).
   PubMed Web of Science ®Google Scholar
• Daly AK , DayCP: Candidate gene case–control association studies: advantages and potential pitfalls.Br. J. Clin. Pharmacol.52(5) , 489–499 (2001).
   PubMed Web of Science ®Google Scholar
• Risch NJ : Searching for genetic determinants in the new millennium.Nature405(6788) , 847–856 (2000).
   PubMed Web of Science ®Google Scholar
• Maddrey WC : Drug-induced hepatotoxicity.J. Clin. Gastroenterol.39(4 Suppl. 2) , S83–S89 (2005).
   PubMed Web of Science ®Google Scholar
• Pirmohamed M : Genetic factors in the predisposition to drug-induced hypersensitivity reactions.AAPS J.8(1) , E20–E26 (2006).
   PubMed Web of Science ®Google Scholar
• Gillette JR : Keynote address: man, mice, microsomes, metabolites, and mathematics 40 years after the revolution.Drug Metab. Rev.27(1–2) , 1–44 (1995).
   PubMed Web of Science ®Google Scholar
• Pessayre D : Role of reactive metabolites in drug-induced hepatitis.J. Hepatol.23(Suppl. 1) , 16–24 (1995).
   PubMed Web of Science ®Google Scholar
• Williams DP , KitteringhamNR, NaisbittDJ, PirmohamedM, SmithDA, ParkBK: Are chemically reactive metabolites responsible for adverse reactions to drugs?Curr. Drug Metab.3(4) , 351–366 (2002).
   PubMedGoogle Scholar
• Walgren JL , MitchellMD, ThompsonDC: Role of metabolism in drug-induced idiosyncratic hepatotoxicity.Crit. Rev. Toxicol.35(4) , 325–361 (2005).
   PubMed Web of Science ®Google Scholar
• Phillips KA , VeenstraDL, OrenE, LeeJK, SadeeW: Potential role of pharmacogenomics in reducing adverse drug reactions: a systematic review.JAMA286(18) , 2270–2279 (2001).
   PubMed Web of Science ®Google Scholar
• Xu C , LiCY, KongAN: Induction of Phase I, II and III drug metabolism/transport by xenobiotics.Arch. Pharm. Res.28(3) , 249–268 (2005).
   PubMed Web of Science ®Google Scholar
• Andrade RJ , CamargoR, LucenaMI, Gonzalez-GrandeR: Causality assessment in drug-induced hepatotoxicity.Expert Opin. Drug Saf.3(4) , 329–344 (2004).
   PubMedGoogle Scholar
• Larrey D : Epidemiology and individual susceptibility to adverse drug reactions affecting the liver.Semin. Liver Dis.22(2) , 145–155 (2002).
   PubMed Web of Science ®Google Scholar
• Egger T , DormannH, AhneG et al.: Cytochrome p450 polymorphisms in geriatric patients: impact on adverse drug reactions – a pilot study.Drugs Aging22(3) , 265–272 (2005).
   PubMed Web of Science ®Google Scholar
• Kirchheiner J , RootsI, GoldammerM, RosenkranzB, BrockmollerJ: Effect of genetic polymorphisms in cytochrome p450 (CYP) 2C9 and CYP2C8 on the pharmacokinetics of oral antidiabetic drugs: clinical relevance.Clin. Pharmacokinet.44(12) , 1209–1225 (2005).
   PubMed Web of Science ®Google Scholar
• Larrey D : Hepatotoxicity of herbal remedies.J. Hepatol.26(Suppl. 1) , 47–51 (1997).
   PubMedGoogle Scholar
• Horsmans Y , LannesD, PessayreD, LarreyD: Possible association between poor metabolism of mephenytoin and hepatotoxicity caused by Atrium, a fixed combination preparation containing phenobarbital, febarbamate and difebarbamate.J. Hepatol.21(6) , 1075–1079 (1994).
   PubMed Web of Science ®Google Scholar
• Seybold U , LandauerN, HillebrandS, GoebelFD: Senna-induced hepatitis in a poor metabolizer.Ann. Intern. Med.141(8) , 650–651 (2004).
   PubMed Web of Science ®Google Scholar
• Miners JO , BirkettDJ: Cytochrome P4502C9: an enzyme of major importance in human drug metabolism.Br. J. Clin. Pharmacol.45(6) , 525–538 (1998).
   PubMed Web of Science ®Google Scholar
• Scordo MG , AklilluE, YasarU, DahlML, SpinaE, Ingelman-SundbergM: Genetic polymorphism of cytochrome P450 2C9 in a Caucasian and a black African population.Br. J. Clin. Pharmacol.52(4) , 447–450 (2001).
   PubMed Web of Science ®Google Scholar
• De Morais SM , WilkinsonGR, BlaisdellJ, MeyerUA, NakamuraK, GoldsteinJA: Identification of a new genetic defect responsible for the polymorphism of (S)-mephenytoin metabolism in Japanese.Mol. Pharmacol.46(4) , 594–598 (1994).
   PubMed Web of Science ®Google Scholar
• Kirchheiner J , BrockmollerJ: Clinical consequences of cytochrome P450 2C9 polymorphisms.Clin. Pharmacol. Ther.77(1) , 1–16 (2005).
   PubMed Web of Science ®Google Scholar
• Larrey D , PageauxGP: Genetic predisposition to drug-induced hepatotoxicity.J. Hepatol.26(Suppl. 2) , 12–21 (1997).
   PubMed Web of Science ®Google Scholar
• Sevilla-Mantilla C , OrtegaL, AgundezJA, Fernandez-GutierrezB, LaderoJM, Diaz-RubioM: Leflunomide-induced acute hepatitis.Dig. Liver Dis.36(1) , 82–84 (2004).
   PubMedGoogle Scholar
• Morin S , LoriotMA, PoirierJM et al.: Is diclofenac a valuable CYP2C9 probe in humans?Eur. J. Clin. Pharmacol.56(11) , 793–797 (2001).
   PubMed Web of Science ®Google Scholar
• Aithal GP , DayCP, LeathartJB, DalyAK: Relationship of polymorphism in CYP2C9 to genetic susceptibility to diclofenac-induced hepatitis.Pharmacogenetics10(6) , 511–518 (2000).
   PubMedGoogle Scholar
• Yasar U , EliassonE, Forslund-BergengrenC et al.: The role of CYP2C9 genotype in the metabolism of diclofenac in vivo and in vitro.Eur. J. Clin. Pharmacol.57(10) , 729–735 (2001).
   PubMed Web of Science ®Google Scholar
• Bort R , MaceK, BoobisA et al.: Hepatic metabolism of diclofenac: role of human CYP in the minor oxidative pathways.Biochem. Pharmacol.58(5) , 787–796 (1999).
   PubMed Web of Science ®Google Scholar
• Daly AK , AithalGP, LeathartJBS, SwainsburyRA, DangTS, DayCP: Genetic susceptibility to diclofenac-induced hepatotoxicity: contribution of UGT2B7, CYP2C8, and ABCC2 genotypes.Gastroenterology132(1) , 272–281 (2007).
   PubMed Web of Science ®Google Scholar
• Kirchheiner J , KudliczD, MeiselC et al.: Influence of CYP2C9 polymorphisms on the pharmacokinetics and cholesterol-lowering activity of (-)-3S,5R-fluvastatin and (+)-3R,5S-fluvastatin in healthy volunteers.Clin. Pharmacol. Ther.74(2) , 186–194 (2003).
   PubMed Web of Science ®Google Scholar
• Goldstein JA , FalettoMB, Romkes-SparksM et al.: Evidence that CYP2C19 is the major (S)-mephenytoin 4´-hydroxylase in humans.Biochemistry33(7) , 1743–1752 (1994).
   PubMed Web of Science ®Google Scholar
• Andersson T , RegardhCG, LouYC, ZhangY, DahlML, BertilssonL: Polymorphic hydroxylation of S-mephenytoin and omeprazole metabolism in Caucasian and Chinese subjects.Pharmacogenetics2(1) , 25–31 (1992).
   PubMedGoogle Scholar
• Baumann P : Pharmacogenetics of antidepressant metabolism. Value of the debrisoquin test.Encephale12(4) , 143–148 (1986).
   PubMedGoogle Scholar
• Ward SA , WalleT, WalleUK, WilkinsonGR, BranchRA: Propranolol‘s metabolism is determined by both mephenytoin and debrisoquin hydroxylase activities.Clin. Pharmacol. Ther.45(1) , 72–79 (1989).
   PubMed Web of Science ®Google Scholar
• Bertilsson L : Geographical/interracial differences in polymorphic drug oxidation. Current state of knowledge of cytochromes P450 (CYP) 2D6 and 2C19.Clin. Pharmacokinet.29(3) , 192–209 (1995).
   PubMed Web of Science ®Google Scholar
• Allabi AC , GalaJL, DesagerJP, HeusterspreuteM, HorsmansY: Genetic polymorphisms of CYP2C9 and CYP2C19 in the Beninese and Belgian populations.Br. J. Clin. Pharmacol.56(6) , 653–657 (2003).
   PubMed Web of Science ®Google Scholar
• Chang M , DahlML, TybringG, GotharsonE, BertilssonL: Use of omeprazole as a probe drug for CYP2C19 phenotype in Swedish Caucasians: comparison with S-mephenytoin hydroxylation phenotype and CYP2C19 genotype.Pharmacogenetics5(6) , 358–363 (1995).
   PubMedGoogle Scholar
• Brosen K , de Morais SM, Meyer UA, Goldstein JA: A multifamily study on the relationship between CYP2C19 genotype and S-mephenytoin oxidation phenotype. Pharmacogenetics5(5) , 312–317 (1995).
   PubMedGoogle Scholar
• Pachkoria K , LucenaMI, Ruiz-CabelloF, CrespoE, CabelloMR, AndradeRJ: Genetic polymorphisms of CYP2C9 and CYP2C19 are not related to drug-induced idiosyncratic liver injury (DILI).Br. J. Pharmacol.150(6) , 808–815 (2007).
   PubMed Web of Science ®Google Scholar
• Dorado P , BereczR, CaceresMC, GonzalezI, CobaledaJ, LlerenaA: Determination of debrisoquine and 4-hydroxydebrisoquine by high-performance liquid chromatography: application to the evaluation of CYP2D6 genotype and debrisoquine metabolic ratio relationship.Clin. Chem. Lab. Med.43(3) , 275–279 (2005).
   PubMed Web of Science ®Google Scholar
• Marez D , LegrandM, SabbaghN et al.: Polymorphism of the cytochrome P450 CYP2D6 gene in a European population: characterization of 48 mutations and 53 alleles, their frequencies and evolution.Pharmacogenetics7(3) , 193–202 (1997).
   PubMedGoogle Scholar
• Bertilsson L , DahlML, DalenP, Al-ShurbajiA: Molecular genetics of CYP2D6: clinical relevance with focus on psychotropic drugs.Br. J. Clin. Pharmacol.53(2) , 111–122 (2002).
   PubMed Web of Science ®Google Scholar
• Morgan MY , ReshefR, ShahRR, OatesNS, SmithRL, SherlockS: Impaired oxidation of debrisoquine in patients with perhexiline liver injury.Gut25(10) , 1057–1064 (1984).
   PubMed Web of Science ®Google Scholar
• Watson RG , OlomuA, ClementsD, WaringRH, MitchellS, EliasE: A proposed mechanism for chlorpromazine jaundice – defective hepatic sulphoxidation combined with rapid hydroxylation.J. Hepatol.7(1) , 72–78 (1988).
   PubMed Web of Science ®Google Scholar
• Maurer HH , KraemerT, SpringerD, StaackRF: Chemistry, pharmacology, toxicology, and hepatic metabolism of designer drugs of the amphetamine (ecstasy), piperazine, and pyrrolidinophenone types: a synopsis.Ther. Drug Monit.26(2) , 127–131 (2004).
   PubMed Web of Science ®Google Scholar
• Caccia S : Metabolism of the newer antidepressants. An overview of the pharmacological and pharmacokinetic implications.Clin. Pharmacokinet.34(4) , 281–302 (1998).
   PubMed Web of Science ®Google Scholar
• Otani K , KanekoS, TasakiH, FukushimaY: Hepatic injury caused by mianserin.Br. Med. J.299(6697) , 519 (1989).
   PubMedGoogle Scholar
• Yasui N , OtaniK, KanekoS et al.: Inhibition of trazodone metabolism by thioridazine in humans.Ther. Drug Monit.17(4) , 333–335 (1995).
   PubMed Web of Science ®Google Scholar
• Hull M , JonesR, BendallM: Fatal hepatic necrosis associated with trazodone and neuroleptic drugs.Br. Med. J.309(6951) , 378 (1994).
   PubMedGoogle Scholar
• Inoue K , InazawaJ, NakagawaH et al.: Assignment of the human cytochrome P-450 nifedipine oxidase gene (CYP3A4) to chromosome 7 at band q22.1 by fluorescence in situ hybridization.Jpn. J. Hum. Genet.37(2) , 133–138 (1992).
   PubMedGoogle Scholar
• Nelson DR , KoymansL, KamatakiT et al.: P450 superfamily: update on new sequences, gene mapping, accession numbers and nomenclature.Pharmacogenetics6(1) , 1–42 (1996).
   PubMedGoogle Scholar
• Hsieh KP , LinYY, ChengCL et al.: Novel mutations of CYP3A4 in Chinese.Drug Metab. Dispos.29(3) , 268–273 (2001).
   PubMed Web of Science ®Google Scholar
• Klees TM , SheffelsP, ThummelKE, KharaschED: Pharmacogenetic determinants of human liver microsomal alfentanil metabolism and the role of cytochrome P450 3A5.Anesthesiology102(3) , 550–556 (2005).
   PubMed Web of Science ®Google Scholar
• Staudinger JL , GoodwinB, JonesSA et al.: The nuclear receptor PXR is a lithocholic acid sensor that protects against liver toxicity.Proc. Natl Acad. Sci. USA98(6) , 3369–3374 (2001).
   PubMed Web of Science ®Google Scholar
• Gnerre C , BlattlerS, KaufmannMR, LooserR, MeyerUA: Regulation of CYP3A4 by the bile acid receptor FXR: evidence for functional binding sites in the CYP3A4 gene.Pharmacogenetics14(10) , 635–645 (2004).
   PubMedGoogle Scholar
• Kostrubsky VE , SzakacsJG, JefferyEH et al.: Role of CYP3A in ethanol-mediated increases in acetaminophen hepatotoxicity.Toxicol. Appl. Pharmacol.143(2) , 315–323 (1997).
   PubMed Web of Science ®Google Scholar
• Lakehal F , DansettePM, BecquemontL et al.: Indirect cytotoxicity of flucloxacillin toward human biliary epithelium via metabolite formation in hepatocytes.Chem. Res. Toxicol.14(6) , 694–701 (2001).
   PubMed Web of Science ®Google Scholar
• Andrade RJ , SalmeronFJ, LucenaMI: Drug hepatotoxicity. In: The Clinician‘s Guide to Liver Disease. Reddy KR, Faust T (Eds)., Slack Incorporated, NJ, USA, 321–343 (2005).
   Google Scholar
• Kassahun K , PearsonPG, TangW et al.: Studies on the metabolism of troglitazone to reactive intermediates in vitro and in vivo. Evidence for novel biotransformation pathways involving quinone methide formation and thiazolidinedione ring scission.Chem. Res. Toxicol.14(1) , 62–70 (2001).
   PubMed Web of Science ®Google Scholar
• Ricaurte B , GuirguisA, TaylorHC, ZabriskieD: Simvastatin-amiodarone interaction resulting in rhabdomyolysis, azotemia, and possible hepatotoxicity.Ann. Pharmacother.40(4) , 753–757 (2006).
   PubMed Web of Science ®Google Scholar
• Lucena MI , AndradeRJ, ViciosoL, GonzalezFJ, PachkoriaK, Garcia-MunozB: Prolonged cholestasis after raloxifene and fenofibrate interaction: a case report.World J. Gastroenterol.12(32) , 5244–5246 (2006).
   PubMed Web of Science ®Google Scholar
• Chen B , ZhangWX, CaiWM: The influence of various genotypes on the metabolic activity of NAT2 in a Chinese population.Eur. J. Clin. Pharmacol.62(5) , 355–359 (2006).
   PubMed Web of Science ®Google Scholar
• Gross M , KruisselbrinkT, AndersonK et al.: Distribution and concordance of N-acetyltransferase genotype and phenotype in an American population.Cancer Epidemiol. Biomarkers Prev.8(8) , 683–892 (1999).
   PubMed Web of Science ®Google Scholar
• Evans DA : N-acetyltransferase.Pharmacol. Ther.42(2) , 157–234 (1989).
   PubMed Web of Science ®Google Scholar
• Weber WW , HeinDW: N-acetylation pharmacogenetics.Pharmacol. Rev.37(1) , 25–79 (1985).
   PubMed Web of Science ®Google Scholar
• Agundez JA , OliveraM, MartinezC, LaderoJM, BenitezJ: Identification and prevalence study of 17 allelic variants of the human NAT2 gene in a white population.Pharmacogenetics6(5) , 423–428 (1996).
   PubMedGoogle Scholar
• Lin HJ , HanCY, LinBK, HardyS: Ethnic distribution of slow acetylator mutations in the polymorphic N-acetyltransferase (NAT2) gene.Pharmacogenetics4(3) , 125–134 (1994).
   PubMedGoogle Scholar
• Xie HG , XuZH, Ou-YangDS et al.: Meta-analysis of phenotype and genotype of NAT2 deficiency in Chinese populations.Pharmacogenetics7(6) , 503–514 (1997).
   PubMedGoogle Scholar
• Blum M , GrantDM, McBrideW, HeimH, MeyerUA: Human arylamine N-acetyltransferase genes: isolation, chromosomal localization and functional expression.DNA Cell Biol.9(3) , 193–203 (1990).
   PubMed Web of Science ®Google Scholar
• Hein DW , DollMA, RustanTD, FergusonRJ: Metabolic activation of N-hydroxyarylamines and N-hydroxyarylamides by 16 recombinant human NAT2 allozymes: effects of 7 specific NAT2 nucleic acid substitutions.Cancer Res.55(16) , 3531–3536 (1995).
   PubMed Web of Science ®Google Scholar
• Huang YS , ChernHD, SuWJ et al.: Polymorphism of the N-acetyltransferase 2 gene as a susceptibility risk factor for antituberculosis drug-induced hepatitis.Hepatology35(4) , 883–889 (2002).
   PubMed Web of Science ®Google Scholar
• Ellard GA : Variations between individuals and populations in the acetylation of isoniazid and its significance for the treatment of pulmonary tuberculosis.Clin. Pharmacol. Ther.19(5 Pt 2) , 610–625 (1976).
   PubMed Web of Science ®Google Scholar
• Lauterburg BH , SmithCV, ToddEL, MitchellJR: Pharmacokinetics of the toxic hydrazino metabolites formed from isoniazid in humans.J. Pharmacol. Exp. Ther.235(3) , 566–570 (1985).
   PubMed Web of Science ®Google Scholar
• Sharma SK , BalamuruganA, SahaPK, PandeyRM, MehraNK: Evaluation of clinical and immunogenetic risk factors for the development of hepatotoxicity during antituberculosis treatment.Am. J. Respir. Crit. Care Med.166(7) , 916–919 (2002).
   PubMed Web of Science ®Google Scholar
• Mitchell JR , ThorgeirssonUP, BlackM et al.: Increased incidence of isoniazid hepatitis in rapid acetylators: possible relation to hydranize metabolites.Clin. Pharmacol. Ther.18(1) , 70–79 (1975).
   PubMed Web of Science ®Google Scholar
• Mitchell JR , PotterWZ: Drug metabolism in the production of liver injury.Med. Clin. North Am.59(4) , 877–885 (1975).
   PubMed Web of Science ®Google Scholar
• Huang YS , ChernHD, SuWJ et al.: Cytochrome P450 2E1 genotype and the susceptibility to antituberculosis drug-induced hepatitis.Hepatology37(4) , 924–930 (2003).
   PubMed Web of Science ®Google Scholar
• Olomu AB , VickersCR, WaringRH et al.: High incidence of poor sulfoxidation in patients with primary biliary cirrhosis.N. Engl. J. Med.318(17) , 1089–1092 (1988).
   PubMed Web of Science ®Google Scholar
• Knowles SR , UetrechtJ, ShearNH: Idiosyncratic drug reactions: the reactive metabolite syndromes.Lancet356(9241) , 1587–1591 (2000).
   PubMed Web of Science ®Google Scholar
• Hayes JD , FlanaganJU, JowseyIR: Glutathione transferases.Annu. Rev. Pharmacol. Toxicol.45 , 51–88 (2005).
   PubMed Web of Science ®Google Scholar
• Ajith TA , HemaU, AswathyMS: Zingiber officinale Roscoe prevents acetaminophen induced acute hepatotoxicity by enhancing hepatic antioxidant status.Food Chem. Toxicol.45(11) , 2267–2272 (2007).
   PubMed Web of Science ®Google Scholar
• Gum SI , JoSJ, AhnSH et al.: The potent protective effect of wild ginseng (Panax ginseng C.A. Meyer) against benzo[a]pyrene-induced toxicity through metabolic regulation of CYP1A1 and GSTs.J. Ethnopharmacol.112(3) , 568–576 (2007).
   PubMed Web of Science ®Google Scholar
• Henderson CJ , WolfCR, KitteringhamN, PowellH, OttoD, ParkBK: Increased resistance to acetaminophen hepatotoxicity in mice lacking glutathione S-transferase Pi.Proc. Natl Acad. Sci. USA97(23) , 12741–12745 (2000).
   PubMed Web of Science ®Google Scholar
• Tanaka K , KiyosawaN, WatanabeK, ManabeS: Characterization of resistance to bromobenzene induced hepatotoxicity by microarray.J. Toxicol. Sci.32(2) , 129–134 (2007).
   PubMedGoogle Scholar
• Morishita K , MizukawaY, KasaharaT et al.: Gene expression profile in liver of differing ages of rats after single oral administration of acetaminophen.J. Toxicol. Sci.31(5) , 491–507 (2006).
   PubMedGoogle Scholar
• Zhao P , KalhornTF, SlatteryJT: Selective mitochondrial glutathione depletion byethanol enhances acetaminophen toxicity in rat liver.Hepatology36(2) , 326–335 (2002).
   PubMed Web of Science ®Google Scholar
• Chan K , HanXD, KanYW: An important function of Nrf2 in combating oxidative stress: detoxification of acetaminophen.Proc. Natl Acad. Sci. USA98(8) , 4611–4616 (2001).
   PubMed Web of Science ®Google Scholar
• Eaton DL , BammlerTK, KellyEJ: Interindividual differences in response to chemoprotection against aflatoxin-induced hepatocarcinogenesis: implications for human biotransformation enzyme polymorphisms.Adv. Exp. Med. Biol.500 , 559–576 (2001).
   PubMed Web of Science ®Google Scholar
• Dieckhaus CM , RollerSG, SantosWL, SofiaRD, MacdonaldTL: Role of glutathione S-transferases A1–1, M1–1, and P1–1 in the detoxification of 2-phenylpropenal, a reactive felbamate metabolite.Chem. Res. Toxicol.14(5) , 511–516 (2001).
   PubMed Web of Science ®Google Scholar
• Lo HW , Ali-OsmanF: Genetic polymorphism and function of glutathione-S-transferases in tumor drug resistance.Curr. Opin. Pharmacol.7(4) , 367–374 (2007).
   PubMed Web of Science ®Google Scholar
• Watanabe I , TomitaA, ShimizuM et al.: A study to survey susceptible genetic factors responsible for troglitazone-associated hepatotoxicity in Japanese patients with type 2 diabetes mellitus.Clin. Pharmacol. Ther.73(5) , 435–455 (2003).
   PubMed Web of Science ®Google Scholar
• Simon T , BecquemontL, Mary-KrauseM et al.: Combined glutathione-S-transferase M1 and T1 genetic polymorphism and tacrine hepatotoxicity.Clin. Pharmacol. Ther.67(4) , 432–437 (2000).
   PubMed Web of Science ®Google Scholar
• Green VJ , PirmohamedM, KitteringhamNR, KnappMJ, ParkBK: Glutathione S-transferase µ genotype (GSTM1*0) in Alzheimer‘s patients with tacrine transaminitis.Br. J. Clin. Pharmacol.39(4) , 411–415 (1995).
   PubMed Web of Science ®Google Scholar
• De Sousa M , PirmohamedM, KitteringhamNR, WoolfT, ParkBK: No association between tacrine transaminitis and the glutathione transferase θ genotype in patients with Alzheimer‘s disease.Pharmacogenetics8(4) , 353–355 (1998).
   PubMedGoogle Scholar
• Roy B , ChowdhuryA, KunduS et al.: Increased risk of antituberculosis drug-induced hepatotoxicity in individuals with glutathione S-transferase M1 null mutation.J. Gastroenterol. Hepatol.16(9) , 1033–1037 (2001).
   PubMed Web of Science ®Google Scholar
• Huang YS , SuWJ, HuangYH 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.J. Hepatol.47(1) , 128–134 (2007).
   PubMed Web of Science ®Google Scholar
• Lucena MI , AndradeRJ, MartínezC et al.: Glutathione-S-transferase M1 and T1 null genotypes as susceptibility factor for idiosyncratic drug-induced liver injury.Hepatology48(2) , 588–596 (2008).
   PubMed Web of Science ®Google Scholar
• Sutton A , KhouryH, Prip-BuusC, CepanecC, PessayreD, DegoulF: The Ala16Val genetic dimorphism modulates the import of human manganese superoxide dismutase into rat liver mitochondria.Pharmacogenetics13(3) , 145–157 (2003).
   PubMedGoogle Scholar
• Dansette PM , BonierbaleE, MinolettiC et al.: Drug-induced immunotoxicity.Eur. J. Drug. Metab. Pharmacokinet.23(4) , 443–451 (1998).
   PubMed Web of Science ®Google Scholar
• Mizutani T , ShinodaM, TanakaY et al.: Autoantibodies against CYP2D6 and other drug-metabolizing enzymes in autoimmune hepatitis type 2.Drug Metab. Rev.37(1) , 235–252 (2005).
   PubMed Web of Science ®Google Scholar
• Gut J , ChristenU, FreyN et al.: Molecular mimicry in halothane hepatitis: biochemical and structural characterization of lipoylated autoantigens.Toxicology97(1–3) , 199–224 (1995).
   PubMed Web of Science ®Google Scholar
• Bourdi M , TinelM, BeaunePH, PessayreD: Interactions of dihydralazine with cytochromes P4501A: a possible explanation for the appearance of anti-cytochrome P4501A2 autoantibodies.Mol. Pharmacol.45(6) , 1287–1295 (1994).
   PubMed Web of Science ®Google Scholar
• Masubuchi Y , HorieT: Mechanism-based inactivation of cytochrome P450s 1A2 and 3A4 by dihydralazine in human liver microsomes.Chem. Res. Toxicol.12(10) , 1028–1032 (1999).
   PubMed Web of Science ®Google Scholar
• Siegmund W , FrankeG, BieblerKE et al.: The influence of the acetylator phenotype for the clinical use of dihydralazine.Int. J. Clin. Pharmacol. Ther. Toxicol.23(Suppl. 1) , S74–S78 (1985).
   PubMedGoogle Scholar
• Oude Elferink RP , MeijerDK, KuipersF, JansenPL, GroenAK, GroothuisGM: Hepatobiliary secretion of organic compounds; molecular mechanisms of membrane transport.Biochim. Biophys. Acta.1241(2) , 215–268 (1995).
   PubMed Web of Science ®Google Scholar
• Smith AJ , van Helvoort A, van Meer G et al.: MDR3 P-glycoprotein, a phosphatidylcholine translocase, transports several cytotoxic drugs and directly interacts with drugs as judged by interference with nucleotide trapping. J. Biol. Chem.275(31) , 23530–23539 (2000).
   PubMed Web of Science ®Google Scholar
• Konig J , NiesAT, CuiY, LeierI, KepplerD: Conjugate export pumps of the multidrug resistance protein (MRP) family: localization, substrate specificity, and MRP2-mediated drug resistance.Biochim. Biophys. Acta.1461(2) , 377–394 (1999).
   PubMed Web of Science ®Google Scholar
• Cole SP , BhardwajG, GerlachJH et al.: Overexpression of a transporter gene in a multidrug-resistant human lung cancer cell line.Science258(5088) , 1650–1654 (1992).
   PubMed Web of Science ®Google Scholar
• Grant CE , KurzEU, ColeSP, DeeleyRG: Analysis of the intron–exon organization of the human multidrug-resistance protein gene (MRP) and alternative splicing of its mRNA.Genomics45(2) , 368–378 (1997).
   PubMed Web of Science ®Google Scholar
• Tsujii H , KonigJ, RostD, StockelB, LeuschnerU, KepplerD: Exon–intron organization of the human multidrug-resistance protein 2 (MRP2) gene mutated in Dubin–Johnson syndrome.Gastroenterology117(3) , 653–660 (1999).
   PubMed Web of Science ®Google Scholar
• Mayer R , KartenbeckJ, BuchlerM, JedlitschkyG, LeierI, KepplerD: Expression of the MRP gene-encoded conjugate export pump in liver and its selective absence from the canalicular membrane in transport-deficient mutant hepatocytes.J. Cell. Biol.131(1) , 137–150 (1995).
   PubMed Web of Science ®Google Scholar
• Meier PJ , StiegerB: Molecular mechanisms in bile formation.News Physiol. Sci.15 , 89–93 (2000).
   PubMedGoogle Scholar
• Meier PJ , StiegerB: Bile salt transporters.Annu. Rev. Physiol.64 , 635–661 (2002).
   PubMed Web of Science ®Google Scholar
• Kullak-Ublick GA , StiegerB, MeierPJ: Enterohepatic bile salt transporters in normal physiology and liver disease.Gastroenterology126(1) , 322–342 (2004).
   PubMed Web of Science ®Google Scholar
• Awasthi CW , AwasthiS, ZimniakP: Multiple transport protein involved in the detoxification of endo- and xenobiotics.Front Biosci.15 , 427–437 (1997).
   Google Scholar
• Cantz T , NiesAT, BromM, HofmannAF, KepplerD: MRP2, a human conjugate export pump, is present and transports fluo 3 into apical vacuoles of Hep G2 cells.Am. J. Physiol. Gastrointest. Liver Physiol.278(4) , G522–G531 (2000).
   PubMed Web of Science ®Google Scholar
• Bolder U , TrangNV, HageyLR et al.: Sulindac is excreted into bile by a canalicular bile salt pump and undergoes a cholehepatic circulation in rats.Gastroenterology117(4) , 962–971 (1999).
   PubMed Web of Science ®Google Scholar
• Iverson SL , UetrechtJP: Identification of a reactive metabolite of terbinafine: insights into terbinafine-induced hepatotoxicity.Chem. Res. Toxicol.14(2) , 175–181 (2001).
   PubMed Web of Science ®Google Scholar
• Dietrich CG , de Waart DR, Ottenhoff R, Bootsma AH, van Gennip AH, Elferink RP: Mrp2-deficiency in the rat impairs biliary and intestinal excretion and influences metabolism and disposition of the food-derived carcinogen 2-amino-1-methyl-6-phenylimidazo. Carcinogenesis22(5) , 805–811 (2001).
   PubMed Web of Science ®Google Scholar
• Choi JH , AhnBM, YiJ et al.: MRP2 haplotypes confer differential susceptibility to toxic liver injury.Pharmacogenet. Genomics17(6) , 403–415 (2007).
   PubMed Web of Science ®Google Scholar
• Trauner M , MeierPJ, BoyerJL: Molecular pathogenesis of cholestasis.N. Engl. J. Med.339(17) , 1217–1227 (1998).
   PubMed Web of Science ®Google Scholar
• Dixon PH , WeerasekeraN, LintonKJ et al.: Heterozygous MDR3 missense mutation associated with intrahepatic cholestasis of pregnancy: evidence for a defect in protein trafficking.Hum. Mol. Genet.9(8) , 1209–1217 (2000).
   PubMed Web of Science ®Google Scholar
• Jacquemin E , CresteilD, ManouvrierS, BouteO, HadchouelM: Heterozygous non-sense mutation of the MDR3 gene in familial intrahepatic cholestasis of pregnancy.Lancet353(9148) , 210–211 (1999).
   PubMed Web of Science ®Google Scholar
• De Vree JM , JacqueminE, SturmE et al.: Mutations in the MDR3 gene cause progressive familial intrahepatic cholestasis.Proc. Natl Acad. Sci. USA95(1) , 282–287 (1998).
   PubMed Web of Science ®Google Scholar
• Rosmorduc O , HermelinB, PouponR: MDR3 gene defect in adults with symptomatic intrahepatic and gallbladder cholesterol cholelithiasis.Gastroenterology120(6) , 1459–1467 (2001).
   PubMed Web of Science ®Google Scholar
• Lang C , MeierY, StiegerB et al.: Mutations and polymorphisms in the bile salt export pump and the multidrug resistance protein 3 associated with drug-induced liver injury.Pharmacogenet. Genomics17(1) , 47–60 (2007).
   PubMed Web of Science ®Google Scholar
• Andrade RJ , CrespoE, UlzurrunE et al.: Polymorphic bile salt export pump transporter is a major determinant of hepatocellular drug-induced liver injury.Hepatology48 , 468A (2008) (Abstract).
   Web of Science ®Google Scholar
• Leemann T , TransonC, DayerP: Cytochrome P450TB (CYP2C): a major monooxygenase catalyzing diclofenac 4´-hydroxylation in human liver.Life Sci.52(1) , 29–34 (1993).
   PubMed Web of Science ®Google Scholar
• Transon C , LecoeurS, LeemannT, BeauneP, DayerP: Interindividual variability in catalytic activity and immunoreactivity of three major human liver cytochrome P450 isozymes.Eur. J. Clin. Pharmacol.51(1) , 79–85 (1996).
   PubMed Web of Science ®Google Scholar
• Tang W : The metabolism of diclofenac- enzymology and toxicology perspectives.Curr. Drug Metab.4(4) , 319–329 (2003).
   PubMed Web of Science ®Google Scholar
• Boelsterli UA : Diclofenac-induced liver injury: a paradigm of idiosyncratic drug toxicity.Toxicol. Appl. Pharmacol.192(3) , 307–322 (2003).
   PubMed Web of Science ®Google Scholar
• Aithal GP , RamsayL, DalyAK et al.: Hepatic adducts, circulating antibodies, and cytokine polymorphisms in patients with diclofenac hepatotoxicity.Hepatology39(5) , 1430–1440 (2004).
   PubMed Web of Science ®Google Scholar
• Njoku DB , GreenbergRS, BourdiM et al.: Autoantibodies associated with volatile anesthetic hepatitis found in the sera of a large cohort of pediatric anesthesiologists.Anesth. Analg.94(2) , 243–249 (2002).
   PubMed Web of Science ®Google Scholar
• Aithal GP : Diclofenac-induced liver injury: a paradigm of idiosyncratic drug toxicity.Expert. Opin. Drug Saf.3(6) , 519–523 (2004).
   PubMedGoogle Scholar
• Kaplowitz N : Drug-induced liver injury.Clin. Infect. Dis.38(Suppl. 2) , S44–S48 (2004).
   PubMed Web of Science ®Google Scholar
• Bourdi M , MasubuchiY, ReillyTP et al.: Protection against acetaminophen-induced liver injury and lethality by interleukin 10: role of inducible nitric oxide synthase.Hepatology35(2) , 289–298 (2002).
   PubMed Web of Science ®Google Scholar
• Masubuchi Y , BourdiM, ReillyTP, GrafML, GeorgeJW, PohlLR: Role of interleukin-6 in hepatic heat shock protein expression and protection against acetaminophen-induced liver disease.Biochem. Biophys. Res. Commun.304(1) , 207–212 (2003).
   PubMed Web of Science ®Google Scholar
• Bourdi M , EirasDP, HoltMP et al.: Role of IL-6 in an IL-10 and IL-4 double knockout mouse model uniquely susceptible to acetaminophen-induced liver injury.Chem. Res. Toxicol.20(2) , 208–216 (2007).
   PubMed Web of Science ®Google Scholar
• Pachkoria K , LucenaMI, CrespoE et al.: Analysis of IL-10, IL-4 and TNF-α polymorphisms in drug-induced liver injury (DILI) and its outcome.J. Hepatol.49(1) , 107–114 (2008).
   PubMed Web of Science ®Google Scholar
• Carr DF , AlfirevicA, TugwoodJD et al.: Molecular and genetic association of interleukin-6 in tacrine-induced hepatotoxicity.Pharmacogenet. Genomics17(11) , 961–972 (2007).
   PubMed Web of Science ®Google Scholar
• Hautekeete ML , HorsmansY, van Waeyenberge C et al.: HLA association of amoxicillin-clavulanate – induced hepatitis. Gastroenterology117(5) , 1181–1186 (1999).
   PubMed Web of Science ®Google Scholar
• Daly AK , DonaldsonPT, BhatnagarP et al.: HLA-B*5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin.Nat. Genet.41(7) , 816–819 (2009).
   PubMed Web of Science ®Google Scholar
• Donaldson PT , BhatnagarP, GrahamJ et al.: Susceptibility to drug-induced liver injury is determined by HLA class-II genotype.Hepatology48 , 464A (2008) (Abstract).
   Web of Science ®Google Scholar
• Mallal S , NolanD, WittC et al.: Association between presence of HLA-B*5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir.Lancet359(9308) , 727–732 (2002).
   PubMed Web of Science ®Google Scholar
• Berson A , FreneauxE, LarreyD et al.: Possible role of HLA in hepatotoxicity. An exploratory study in 71 patients with drug-induced idiosyncratic hepatitis.J. Hepatol.20(3) , 336–342 (1994).
   PubMed Web of Science ®Google Scholar
• Andrade RJ , LucenaMI, AlonsoA et al.: HLA class II genotype influences the type of liver injury in drug-induced idiosyncratic liver disease.Hepatology39(6) , 1603–1612 (2004).
   PubMed Web of Science ®Google Scholar
• Johnson GC , EspositoL, BarrattBJ et al.: Haplotype tagging for the identification of common disease genes.Nat. Genet.29(2) , 233–237 (2001).
   PubMed Web of Science ®Google Scholar
• de Bakker PI , YelenskyR, Pe‘erI, GabrielSB, DalyMJ, AltshulerD: Efficiency and power in genetic association studies.Nat. Genet.37(11) , 1217–1223 (2005).
   PubMed Web of Science ®Google Scholar
• Davey SG , EbrahimS, LewisS, HansellAL, PalmerLJ, BurtonPR: Genetic epidemiology and public health: hope, hype, and future prospects.Lancet366(9495) , 1484–1498 (2005).
   PubMed Web of Science ®Google Scholar
• Hattersley AT , McCarthyMI: What makes a good genetic association study?Lancet366(9493) , 1315–1323 (2005).
   PubMed Web of Science ®Google Scholar
• Romeo S , KotzlitinaJ, XingC et al.: Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease.Nat. Genet.40(12) , 1461–1465 (2008).
   PubMed Web of Science ®Google Scholar
• Roses AD : Pharmacogenetics and drug development: the path to safer and more effective drugs.Nat. Rev. Genet.5(9) , 645–656 (2004).
   PubMed Web of Science ®Google Scholar
• Kindmark A , JawaidA, HarbronCG et al.: Genome-wide pharmacogenetic investigation of a hepatic adverse event without clinical signs of immunopathology suggests an underlying immune pathogenesis.Pharmacogenomics J.8(3) , 186–195 (2008).
   PubMed Web of Science ®Google Scholar
• Harrill AH , WatkinsPB, SuS et al.: Mouse population-guided resequencing reveals that variants in CD44 contribute to acetaminophen-induced liver injury in humans.Genome. Res. (2009) (Epub ahead of print).
   PubMed Web of Science ®Google Scholar
• Andrade RJ , LucenaMI, FernándezMC et al.: Drug-induced liver injury: an analysis of 461 incidences submitted to the Spanish Registry over a 10-year period.Gastroenterology129(2) , 512–521 (2005).
   PubMed Web of Science ®Google Scholar

▪ Website

• International HapMap Project http://www.hapmap.org/ (Accessed 18July, 2009)
   Google Scholar