Official reprint from UpToDate®
www.uptodate.com ©2016 UpToDate®

Drugs and the liver: Metabolism and mechanisms of injury

Section Editor
Keith D Lindor, MD
Deputy Editor
Anne C Travis, MD, MSc, FACG, AGAF


Many drugs, both prescription and over-the-counter, herbal products, or toxins can cause hepatotoxicity through a variety of mechanisms [1,2]. A high index of suspicion is often necessary to expeditiously establish the diagnosis.

The hepatic metabolism of drugs and the mechanisms by which drugs might injure the liver will be reviewed here. The different clinical patterns of drug-induced hepatotoxicity and the use of medications in patients with liver disease are discussed separately. (See "Drug-induced liver injury" and "Overview of the management of chronic hepatitis C virus infection", section on 'Dose adjustments of medications' and "Cirrhosis in adults: Overview of complications, general management, and prognosis", section on 'General management'.)


Drug-induced liver injury (DILI) is a well-recognized problem and symptomatically can mimic acute and chronic liver diseases. Over 1000 medications and herbal products have been implicated in the development of DILI [3,4]. DILI has an estimated annual incidence of between 10 and 19 per 100,000 persons exposed to prescription medications [5-12]. It accounts for up to 30 percent of cases of acute hepatitis, up to 10 percent of consultations by hepatologists, and is the most common cause of acute liver failure in the United States [13-20]. It is also the cause of acute jaundice in up to 50 percent of patients who present with new onset jaundice [8,9,13,21-26]. Finally, DILI is the most frequently cited reason for the withdrawal of medications from the marketplace and the list continues to grow [14,15,27-29].

Database of drugs, herbs, and supplements associated with hepatotoxicity — The National Institutes of Health (NIH) maintains a searchable database of drugs, herbal medications, and dietary supplements that have been associated with DILI [30]. In addition, in 2004 the DILI Network initiated a prospective, observational, longitudinal study of individuals two years of age or older with suspected DILI [31].


The liver is responsible for the selective uptake, concentration, metabolism, and excretion of the majority of drugs and toxins that are introduced into the body. While some parent drugs can directly cause hepatotoxicity, it is generally the metabolites of these compounds that lead to drug-induced liver injury (DILI). These compounds are processed by a variety of soluble and membrane-bound enzymes, especially those related to the hepatocyte endoplasmic reticulum. Each drug has its specific enzyme disposal pathway(s) of biotransformation involving one or more of these enzyme systems. Genetic variation in drug metabolism is increasingly being recognized as a factor in the development of DILI. Although less clear, environmental factors (eg, alcohol use) may also alter the processing of drugs and toxins.


Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Sep 2016. | This topic last updated: May 17, 2016.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2016 UpToDate, Inc.
  1. Lee WM. Drug-induced hepatotoxicity. N Engl J Med 1995; 333:1118.
  2. Chang CY, Schiano TD. Review article: drug hepatotoxicity. Aliment Pharmacol Ther 2007; 25:1135.
  3. Suzuki A, Andrade RJ, Bjornsson E, et al. Drugs associated with hepatotoxicity and their reporting frequency of liver adverse events in VigiBase: unified list based on international collaborative work. Drug Saf 2010; 33:503.
  4. Stirnimann G, Kessebohm K, Lauterburg B. Liver injury caused by drugs: an update. Swiss Med Wkly 2010; 140:w13080.
  5. Shapiro MA, Lewis JH. Causality assessment of drug-induced hepatotoxicity: promises and pitfalls. Clin Liver Dis 2007; 11:477.
  6. Friis H, Andreasen PB. Drug-induced hepatic injury: an analysis of 1100 cases reported to the Danish Committee on Adverse Drug Reactions between 1978 and 1987. J Intern Med 1992; 232:133.
  7. Pillans PI. Drug associated hepatic reactions in New Zealand: 21 years experience. N Z Med J 1996; 109:315.
  8. Sgro C, Clinard F, Ouazir K, et al. Incidence of drug-induced hepatic injuries: a French population-based study. Hepatology 2002; 36:451.
  9. Larrey D. Epidemiology and individual susceptibility to adverse drug reactions affecting the liver. Semin Liver Dis 2002; 22:145.
  10. Bell LN, Chalasani N. Epidemiology of idiosyncratic drug-induced liver injury. Semin Liver Dis 2009; 29:337.
  11. Björnsson ES, Bergmann OM, Björnsson HK, et al. Incidence, presentation, and outcomes in patients with drug-induced liver injury in the general population of Iceland. Gastroenterology 2013; 144:1419.
  12. Chalasani N, Bonkovsky HL, Fontana R, et al. Features and Outcomes of 899 Patients With Drug-Induced Liver Injury: The DILIN Prospective Study. Gastroenterology 2015; 148:1340.
  13. Larrey D. Drug-induced liver diseases. J Hepatol 2000; 32:77.
  14. Ostapowicz G, Fontana RJ, Schiødt FV, et al. Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States. Ann Intern Med 2002; 137:947.
  15. Larson AM, Polson J, Fontana RJ, et al. Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study. Hepatology 2005; 42:1364.
  16. Galan MV, Potts JA, Silverman AL, Gordon SC. The burden of acute nonfulminant drug-induced hepatitis in a United States tertiary referral center [corrected]. J Clin Gastroenterol 2005; 39:64.
  17. De Valle MB, Av Klinteberg V, Alem N, et al. Drug-induced liver injury in a Swedish University hospital out-patient hepatology clinic. Aliment Pharmacol Ther 2006; 24:1187.
  18. Meier Y, Cavallaro M, Roos M, et al. Incidence of drug-induced liver injury in medical inpatients. Eur J Clin Pharmacol 2005; 61:135.
  19. Lee WM. Drug-induced acute liver failure. Clin Liver Dis 2013; 17:575.
  20. Reuben A, Koch DG, Lee WM, Acute Liver Failure Study Group. Drug-induced acute liver failure: results of a U.S. multicenter, prospective study. Hepatology 2010; 52:2065.
  21. Norris W, Paredes AH, Lewis JH. Drug-induced liver injury in 2007. Curr Opin Gastroenterol 2008; 24:287.
  22. Vuppalanchi R, Liangpunsakul S, Chalasani N. Etiology of new-onset jaundice: how often is it caused by idiosyncratic drug-induced liver injury in the United States? Am J Gastroenterol 2007; 102:558.
  23. Akhtar AJ, Shaheen M. Jaundice in African-American and Hispanic patients with AIDS. J Natl Med Assoc 2007; 99:1381.
  24. Hussaini SH, O'Brien CS, Despott EJ, Dalton HR. Antibiotic therapy: a major cause of drug-induced jaundice in southwest England. Eur J Gastroenterol Hepatol 2007; 19:15.
  25. Jinjuvadia K, Kwan W, Fontana RJ. Searching for a needle in a haystack: use of ICD-9-CM codes in drug-induced liver injury. Am J Gastroenterol 2007; 102:2437.
  26. Wai CT, Tan BH, Chan CL, et al. Drug-induced liver injury at an Asian center: a prospective study. Liver Int 2007; 27:465.
  27. Regev A. How to avoid being surprised by hepatotoxicity at the final stages of drug development and approval. Clin Liver Dis 2013; 17:749.
  28. Watkins PB. Drug safety sciences and the bottleneck in drug development. Clin Pharmacol Ther 2011; 89:788.
  29. Chen M, Zhang J, Wang Y, et al. The liver toxicity knowledge base: a systems approach to a complex end point. Clin Pharmacol Ther 2013; 93:409.
  30. http://www.livertox.nih.gov/ (Accessed on January 05, 2016).
  31. Fontana RJ, Watkins PB, Bonkovsky HL, et al. Drug-Induced Liver Injury Network (DILIN) prospective study: rationale, design and conduct. Drug Saf 2009; 32:55.
  32. Park BK, Pirmohamed M, Kitteringham NR. The role of cytochrome P450 enzymes in hepatic and extrahepatic human drug toxicity. Pharmacol Ther 1995; 68:385.
  33. Gunawan BK, Kaplowitz N. Mechanisms of drug-induced liver disease. Clin Liver Dis 2007; 11:459.
  34. Nelson DR, Kamataki T, Waxman DJ, et al. The P450 superfamily: update on new sequences, gene mapping, accession numbers, early trivial names of enzymes, and nomenclature. DNA Cell Biol 1993; 12:1.
  35. Peterson JA, Graham SE. A close family resemblance: the importance of structure in understanding cytochromes P450. Structure 1998; 6:1079.
  36. Smith G, Stubbins MJ, Harries LW, Wolf CR. Molecular genetics of the human cytochrome P450 monooxygenase superfamily. Xenobiotica 1998; 28:1129.
  37. Werck-Reichhart D, Feyereisen R. Cytochromes P450: a success story. Genome Biol 2000; 1:REVIEWS3003.
  38. Danielson PB. The cytochrome P450 superfamily: biochemistry, evolution and drug metabolism in humans. Curr Drug Metab 2002; 3:561.
  39. Ehrenpreis ED, Ehrenpreis S. Cytochrome P450: Role in drug-induced hepatotoxicity. Clin Liver Dis 1998; 2:457.
  40. Watkins PB. Drug metabolism by cytochromes P450 in the liver and small bowel. Gastroenterol Clin North Am 1992; 21:511.
  41. Wrighton SA, VandenBranden M, Ring BJ. The human drug metabolizing cytochromes P450. J Pharmacokinet Biopharm 1996; 24:461.
  42. Wilkinson GR. Cytochrome P4503A (CYP3A) metabolism: prediction of in vivo activity in humans. J Pharmacokinet Biopharm 1996; 24:475.
  43. Ketter TA, Flockhart DA, Post RM, et al. The emerging role of cytochrome P450 3A in psychopharmacology. J Clin Psychopharmacol 1995; 15:387.
  44. Murray M. Mechanisms and significance of inhibitory drug interactions involving cytochrome P450 enzymes (review). Int J Mol Med 1999; 3:227.
  45. Gu L, Gonzalez FJ, Kalow W, Tang BK. Biotransformation of caffeine, paraxanthine, theobromine and theophylline by cDNA-expressed human CYP1A2 and CYP2E1. Pharmacogenetics 1992; 2:73.
  46. Lehmann DE. Enzymatic shunting: resolving the acetaminophen-warfarin controversy. Pharmacotherapy 2000; 20:1464.
  47. DeLeve LD, Kaplowitz N. Mechanisms of drug-induced liver disease. Gastroenterol Clin North Am 1995; 24:787.
  48. Waxman DJ. P450 gene induction by structurally diverse xenochemicals: central role of nuclear receptors CAR, PXR, and PPAR. Arch Biochem Biophys 1999; 369:11.
  49. Stachulski AV, Baillie TA, Park BK, et al. The generation, detection, and effects of reactive drug metabolites. Med Res Rev 2013; 33:985.
  50. Leone A, Nie A, Brandon Parker J, et al. Oxidative stress/reactive metabolite gene expression signature in rat liver detects idiosyncratic hepatotoxicants. Toxicol Appl Pharmacol 2014; 275:189.
  51. Sugatani J. Function, genetic polymorphism, and transcriptional regulation of human UDP-glucuronosyltransferase (UGT) 1A1. Drug Metab Pharmacokinet 2013; 28:83.
  52. Nelson SD. Mechanisms of acetaminophen-induced liver disease. In: Drug-Induced Liver Disease, Kaplowitz N, DeLeve LD (Eds), Marcel Dekker, New York 2003. p.287.
  53. Zhou SF. Structure, function and regulation of P-glycoprotein and its clinical relevance in drug disposition. Xenobiotica 2008; 38:802.
  54. Dean M. The human ATP-binding cassette (ABC) transporter superfamily. National Center for Biotechnology Information (NCBI), National Library of Medicine, Bethesda, MD, 2002.
  55. Pauli-Magnus C, Meier PJ. Hepatobiliary transporters and drug-induced cholestasis. Hepatology 2006; 44:778.
  56. Daly AK, Aithal GP, Leathart JB, et al. Genetic susceptibility to diclofenac-induced hepatotoxicity: contribution of UGT2B7, CYP2C8, and ABCC2 genotypes. Gastroenterology 2007; 132:272.
  57. Choi JH, Ahn BM, Yi J, et al. MRP2 haplotypes confer differential susceptibility to toxic liver injury. Pharmacogenet Genomics 2007; 17:403.
  58. Ulzurrun E, Stephens C, Crespo E, et al. Role of chemical structures and the 1331T>C bile salt export pump polymorphism in idiosyncratic drug-induced liver injury. Liver Int 2013; 33:1378.
  59. Chalasani N, Björnsson E. Risk factors for idiosyncratic drug-induced liver injury. Gastroenterology 2010; 138:2246.
  60. Tanaka E. Update: genetic polymorphism of drug metabolizing enzymes in humans. J Clin Pharm Ther 1999; 24:323.
  61. Hasler JA. Pharmacogenetics of cytochromes P450. Mol Aspects Med 1999; 20:12.
  62. Dorne JL, Walton K, Renwick AG. Human variability in xenobiotic metabolism and pathway-related uncertainty factors for chemical risk assessment: a review. Food Chem Toxicol 2005; 43:203.
  63. Pachkoria K, Lucena MI, Molokhia M, et al. Genetic and molecular factors in drug-induced liver injury: a review. Curr Drug Saf 2007; 2:97.
  64. Daly AK, Day CP. Genetic association studies in drug-induced liver injury. Semin Liver Dis 2009; 29:400.
  65. Vuilleumier N, Rossier MF, Chiappe A, et al. CYP2E1 genotype and isoniazid-induced hepatotoxicity in patients treated for latent tuberculosis. Eur J Clin Pharmacol 2006; 62:423.
  66. Huang YS, Su WJ, Huang YH, 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 2007; 47:128.
  67. Aithal GP, Ramsay L, Daly AK, et al. Hepatic adducts, circulating antibodies, and cytokine polymorphisms in patients with diclofenac hepatotoxicity. Hepatology 2004; 39:1430.
  68. Ueshima Y, Tsutsumi M, Takase S, et al. Acetaminophen metabolism in patients with different cytochrome P-4502E1 genotypes. Alcohol Clin Exp Res 1996; 20:25A.
  69. Marez D, Legrand M, Sabbagh N, et al. Polymorphism of the cytochrome P450 CYP2D6 gene in a European population: characterization of 48 mutations and 53 alleles, their frequencies and evolution. Pharmacogenetics 1997; 7:193.
  70. Ohno M, Yamaguchi I, Yamamoto I, et al. Slow N-acetyltransferase 2 genotype affects the incidence of isoniazid and rifampicin-induced hepatotoxicity. Int J Tuberc Lung Dis 2000; 4:256.
  71. Cho HJ, Koh WJ, Ryu YJ, et al. Genetic polymorphisms of NAT2 and CYP2E1 associated with antituberculosis drug-induced hepatotoxicity in Korean patients with pulmonary tuberculosis. Tuberculosis (Edinb) 2007; 87:551.
  72. Possuelo LG, Castelan JA, de Brito TC, et al. Association of slow N-acetyltransferase 2 profile and anti-TB drug-induced hepatotoxicity in patients from Southern Brazil. Eur J Clin Pharmacol 2008; 64:673.
  73. Roy B, Chowdhury A, Kundu S, et al. Increased risk of antituberculosis drug-induced hepatotoxicity in individuals with glutathione S-transferase M1 'null' mutation. J Gastroenterol Hepatol 2001; 16:1033.
  74. Leiro V, Fernández-Villar A, Valverde D, et al. Influence of glutathione S-transferase M1 and T1 homozygous null mutations on the risk of antituberculosis drug-induced hepatotoxicity in a Caucasian population. Liver Int 2008; 28:835.
  75. Lucena MI, Andrade RJ, Martínez C, et al. Glutathione S-transferase m1 and t1 null genotypes increase susceptibility to idiosyncratic drug-induced liver injury. Hepatology 2008; 48:588.
  76. Du H, Chen X, Fang Y, et al. Slow N-acetyltransferase 2 genotype contributes to anti-tuberculosis drug-induced hepatotoxicity: a meta-analysis. Mol Biol Rep 2013; 40:3591.
  77. Lang C, Meier Y, Stieger B, et al. Mutations and polymorphisms in the bile salt export pump and the multidrug resistance protein 3 associated with drug-induced liver injury. Pharmacogenet Genomics 2007; 17:47.
  78. Kindmark A, Jawaid A, Harbron CG, et al. Genome-wide pharmacogenetic investigation of a hepatic adverse event without clinical signs of immunopathology suggests an underlying immune pathogenesis. Pharmacogenomics J 2008; 8:186.
  79. Daly AK, Donaldson PT, Bhatnagar P, et al. HLA-B*5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin. Nat Genet 2009; 41:816.
  80. Larrey D, Pageaux GP. Genetic predisposition to drug-induced hepatotoxicity. J Hepatol 1997; 26 Suppl 2:12.
  81. O'Donohue J, Oien KA, Donaldson P, et al. Co-amoxiclav jaundice: clinical and histological features and HLA class II association. Gut 2000; 47:717.
  82. Andrade RJ, Lucena MI, Alonso A, et al. HLA class II genotype influences the type of liver injury in drug-induced idiosyncratic liver disease. Hepatology 2004; 39:1603.
  83. Berson A, Fréneaux E, Larrey D, et al. Possible role of HLA in hepatotoxicity. An exploratory study in 71 patients with drug-induced idiosyncratic hepatitis. J Hepatol 1994; 20:336.
  84. Stephens C, López-Nevot MÁ, Ruiz-Cabello F, et al. HLA alleles influence the clinical signature of amoxicillin-clavulanate hepatotoxicity. PLoS One 2013; 8:e68111.
  85. Lucena MI, Andrade RJ, Kaplowitz N, et al. Phenotypic characterization of idiosyncratic drug-induced liver injury: the influence of age and sex. Hepatology 2009; 49:2001.
  86. Hautekeete ML, Horsmans Y, Van Waeyenberge C, et al. HLA association of amoxicillin-clavulanate--induced hepatitis. Gastroenterology 1999; 117:1181.
  87. Uetrecht JP. New concepts in immunology relevant to idiosyncratic drug reactions: the "danger hypothesis" and innate immune system. Chem Res Toxicol 1999; 12:387.
  88. Uetrecht J. Immune-mediated adverse drug reactions. Chem Res Toxicol 2009; 22:24.
  89. Uetrecht J. Immunoallergic drug-induced liver injury in humans. Semin Liver Dis 2009; 29:383.
  90. Strnad P, Zhou Q, Hanada S, et al. Keratin variants predispose to acute liver failure and adverse outcome: race and ethnic associations. Gastroenterology 2010; 139:828.
  91. Prescott LF. Paracetamol, alcohol and the liver. Br J Clin Pharmacol 2000; 49:291.
  92. Rumack BH. Acetaminophen hepatotoxicity: the first 35 years. J Toxicol Clin Toxicol 2002; 40:3.
  93. Schiødt FV, Lee WM, Bondesen S, et al. Influence of acute and chronic alcohol intake on the clinical course and outcome in acetaminophen overdose. Aliment Pharmacol Ther 2002; 16:707.
  94. Zimmerman HJ, Maddrey WC. Acetaminophen (paracetamol) hepatotoxicity with regular intake of alcohol: analysis of instances of therapeutic misadventure. Hepatology 1995; 22:767.
  95. Black M, Raucy J. Acetaminophen, alcohol, and cytochrome P-450. Ann Intern Med 1986; 104:427.
  96. Perrot N, Nalpas B, Yang CS, Beaune PH. Modulation of cytochrome P450 isozymes in human liver, by ethanol and drug intake. Eur J Clin Invest 1989; 19:549.
  97. Lucas D, Ménez C, Girre C, et al. Decrease in cytochrome P4502E1 as assessed by the rate of chlorzoxazone hydroxylation in alcoholics during the withdrawal phase. Alcohol Clin Exp Res 1995; 19:362.
  98. Lauterburg BH, Velez ME. Glutathione deficiency in alcoholics: risk factor for paracetamol hepatotoxicity. Gut 1988; 29:1153.
  99. Lewis JH. Medication-related and other forms of toxic liver injury. In: Clin Prac Gastroenterol, Brandt LJ (Ed), Churchill Livingstone, Philadelphia 1998. p.855.
  100. Alvares AP, Pantuck EJ, Anderson KE, et al. Regulation of drug metabolism in man by environmental factors. Drug Metab Rev 1979; 9:185.
  101. Pantuck EJ, Pantuck CB, Garland WA, et al. Stimulatory effect of brussels sprouts and cabbage on human drug metabolism. Clin Pharmacol Ther 1979; 25:88.
  102. Hakooz N, Hamdan I. Effects of dietary broccoli on human in vivo caffeine metabolism: a pilot study on a group of Jordanian volunteers. Curr Drug Metab 2007; 8:9.
  103. Daković-Svajcer K, Samojlik I, Rasković A, et al. The activity of liver oxidative enzymes after single and multiple grapefruit juice ingestion. Exp Toxicol Pathol 1999; 51:304.
  104. Hukkanen J, Jacob P 3rd, Benowitz NL. Effect of grapefruit juice on cytochrome P450 2A6 and nicotine renal clearance. Clin Pharmacol Ther 2006; 80:522.
  105. Brill S, Zimmermann C, Berger K, et al. In vitro interactions with repeated grapefruit juice administration--to peel or not to peel? Planta Med 2009; 75:332.
  106. Zhang W, Parentau H, Greenly RL, et al. Effect of protein-calorie malnutrition on cytochromes P450 and glutathione S-transferase. Eur J Drug Metab Pharmacokinet 1999; 24:141.
  107. Whitcomb DC, Block GD. Association of acetaminophen hepatotoxicity with fasting and ethanol use. JAMA 1994; 272:1845.
  108. Price VF, Miller MG, Jollow DJ. Mechanisms of fasting-induced potentiation of acetaminophen hepatotoxicity in the rat. Biochem Pharmacol 1987; 36:427.
  109. Kurtovic J, Riordan SM. Paracetamol-induced hepatotoxicity at recommended dosage. J Intern Med 2003; 253:240.
  110. Flockhart DA, Oesterheld JR. Cytochrome P450-mediated drug interactions. Child Adolesc Psychiatr Clin N Am 2000; 9:43.
  111. Kalgutkar AS, Obach RS, Maurer TS. Mechanism-based inactivation of cytochrome P450 enzymes: chemical mechanisms, structure-activity relationships and relationship to clinical drug-drug interactions and idiosyncratic adverse drug reactions. Curr Drug Metab 2007; 8:407.
  112. Stepan AF, Walker DP, Bauman J, et al. Structural alert/reactive metabolite concept as applied in medicinal chemistry to mitigate the risk of idiosyncratic drug toxicity: a perspective based on the critical examination of trends in the top 200 drugs marketed in the United States. Chem Res Toxicol 2011; 24:1345.
  113. Poellinger L. Mechanistic aspects--the dioxin (aryl hydrocarbon) receptor. Food Addit Contam 2000; 17:261.
  114. Le Couteur DG, McLean AJ. The aging liver. Drug clearance and an oxygen diffusion barrier hypothesis. Clin Pharmacokinet 1998; 34:359.
  115. Hilmer SN, Shenfield GM, Le Couteur DG. Clinical implications of changes in hepatic drug metabolism in older people. Ther Clin Risk Manag 2005; 1:151.
  116. Wrighton SA, Stevens JC. The human hepatic cytochromes P450 involved in drug metabolism. Crit Rev Toxicol 1992; 22:1.
  117. Mitchell SJ, Hilmer SN Associate Professor. Drug-induced liver injury in older adults. Ther Adv Drug Saf 2010; 1:65.
  118. Hunt CM, Yuen NA, Stirnadel-Farrant HA, Suzuki A. Age-related differences in reporting of drug-associated liver injury: data-mining of WHO Safety Report Database. Regul Toxicol Pharmacol 2014; 70:519.
  119. Lucena MI, Andrade RJ, Fernández MC, et al. Determinants of the clinical expression of amoxicillin-clavulanate hepatotoxicity: a prospective series from Spain. Hepatology 2006; 44:850.
  120. Sharma SK, Balamurugan A, Saha PK, et al. Evaluation of clinical and immunogenetic risk factors for the development of hepatotoxicity during antituberculosis treatment. Am J Respir Crit Care Med 2002; 166:916.
  121. Benedetti MS, Whomsley R, Canning M. Drug metabolism in the paediatric population and in the elderly. Drug Discov Today 2007; 12:599.
  122. Hunt CM, Westerkam WR, Stave GM. Effect of age and gender on the activity of human hepatic CYP3A. Biochem Pharmacol 1992; 44:275.
  123. Morgan ET. Regulation of cytochromes P450 during inflammation and infection. Drug Metab Rev 1997; 29:1129.
  124. Leise MD, Poterucha JJ, Talwalkar JA. Drug-induced liver injury. Mayo Clin Proc 2014; 89:95.
  125. Verbeeck RK. Pharmacokinetics and dosage adjustment in patients with hepatic dysfunction. Eur J Clin Pharmacol 2008; 64:1147.
  126. Debinski HS, Lee CS, Danks JA, et al. Localization of uridine 5'-diphosphate-glucuronosyltransferase in human liver injury. Gastroenterology 1995; 108:1464.
  127. Elbekai RH, Korashy HM, El-Kadi AO. The effect of liver cirrhosis on the regulation and expression of drug metabolizing enzymes. Curr Drug Metab 2004; 5:157.
  128. Chalasani N, Aljadhey H, Kesterson J, et al. Patients with elevated liver enzymes are not at higher risk for statin hepatotoxicity. Gastroenterology 2004; 126:1287.
  129. Vuppalanchi R, Teal E, Chalasani N. Patients with elevated baseline liver enzymes do not have higher frequency of hepatotoxicity from lovastatin than those with normal baseline liver enzymes. Am J Med Sci 2005; 329:62.
  130. Russo MW, Scobey M, Bonkovsky HL. Drug-induced liver injury associated with statins. Semin Liver Dis 2009; 29:412.
  131. Lewis JH, Mortensen ME, Zweig S, et al. Efficacy and safety of high-dose pravastatin in hypercholesterolemic patients with well-compensated chronic liver disease: Results of a prospective, randomized, double-blind, placebo-controlled, multicenter trial. Hepatology 2007; 46:1453.
  132. Chalasani N. Statins and hepatotoxicity: focus on patients with fatty liver. Hepatology 2005; 41:690.
  133. Cohen DE, Anania FA, Chalasani N, National Lipid Association Statin Safety Task Force Liver Expert Panel. An assessment of statin safety by hepatologists. Am J Cardiol 2006; 97:77C.
  134. Browning JD. Statins and hepatic steatosis: perspectives from the Dallas Heart Study. Hepatology 2006; 44:466.
  135. Chen M, Suzuki A, Borlak J, et al. Drug-induced liver injury: Interactions between drug properties and host factors. J Hepatol 2015; 63:503.
  136. Senior JR. What is idiosyncratic hepatotoxicity? What is it not? Hepatology 2008; 47:1813.
  137. Uetrecht J. Idiosyncratic drug reactions: current understanding. Annu Rev Pharmacol Toxicol 2007; 47:513.
  138. Lammert C, Einarsson S, Saha C, et al. Relationship between daily dose of oral medications and idiosyncratic drug-induced liver injury: search for signals. Hepatology 2008; 47:2003.
  139. Russmann S, Kullak-Ublick GA, Grattagliano I. Current concepts of mechanisms in drug-induced hepatotoxicity. Curr Med Chem 2009; 16:3041.
  140. Russo MW, Galanko JA, Shrestha R, et al. Liver transplantation for acute liver failure from drug induced liver injury in the United States. Liver Transpl 2004; 10:1018.
  141. Han D, Dara L, Win S, et al. Regulation of drug-induced liver injury by signal transduction pathways: critical role of mitochondria. Trends Pharmacol Sci 2013; 34:243.
  142. Chen M, Borlak J, Tong W. High lipophilicity and high daily dose of oral medications are associated with significant risk for drug-induced liver injury. Hepatology 2013; 58:388.
  143. Lammert C, Bjornsson E, Niklasson A, Chalasani N. Oral medications with significant hepatic metabolism at higher risk for hepatic adverse events. Hepatology 2010; 51:615.
  144. Holt MP, Ju C. Mechanisms of drug-induced liver injury. AAPS J 2006; 8:E48.
  145. Morgan RE, Trauner M, van Staden CJ, et al. Interference with bile salt export pump function is a susceptibility factor for human liver injury in drug development. Toxicol Sci 2010; 118:485.
  146. Aleo MD, Luo Y, Swiss R, et al. Human drug-induced liver injury severity is highly associated with dual inhibition of liver mitochondrial function and bile salt export pump. Hepatology 2014; 60:1015.
  147. McGill MR, Williams CD, Xie Y, et al. Acetaminophen-induced liver injury in rats and mice: comparison of protein adducts, mitochondrial dysfunction, and oxidative stress in the mechanism of toxicity. Toxicol Appl Pharmacol 2012; 264:387.
  148. Gunawan B, Kaplowitz N. Clinical perspectives on xenobiotic-induced hepatotoxicity. Drug Metab Rev 2004; 36:301.
  149. Kaplowitz N. Biochemical and cellular mechanisms of toxic liver injury. Semin Liver Dis 2002; 22:137.
  150. Kaplowitz N. Idiosyncratic drug hepatotoxicity. Nat Rev Drug Discov 2005; 4:489.
  151. Kaplowitz N. Causality assessment versus guilt-by-association in drug hepatotoxicity. Hepatology 2001; 33:308.
  152. Knowles SR, Uetrecht J, Shear NH. Idiosyncratic drug reactions: the reactive metabolite syndromes. Lancet 2000; 356:1587.
  153. Spielberg SP, Gordon GB, Blake DA, et al. Predisposition to phenytoin hepatotoxicity assessed in vitro. N Engl J Med 1981; 305:722.
  154. Liu ZX, Kaplowitz N. Immune-mediated drug-induced liver disease. Clin Liver Dis 2002; 6:755.
  155. Jaeschke H, McGill MR, Ramachandran A. Oxidant stress, mitochondria, and cell death mechanisms in drug-induced liver injury: lessons learned from acetaminophen hepatotoxicity. Drug Metab Rev 2012; 44:88.
  156. Labbe G, Pessayre D, Fromenty B. Drug-induced liver injury through mitochondrial dysfunction: mechanisms and detection during preclinical safety studies. Fundam Clin Pharmacol 2008; 22:335.
  157. Li J, Uetrecht JP. The danger hypothesis applied to idiosyncratic drug reactions. Handb Exp Pharmacol 2010; :493.
  158. Wong WM, Wu PC, Yuen MF, et al. Antituberculosis drug-related liver dysfunction in chronic hepatitis B infection. Hepatology 2000; 31:201.
  159. Levy M. Role of viral infections in the induction of adverse drug reactions. Drug Saf 1997; 16:1.
  160. Robin MA, Le Roy M, Descatoire V, Pessayre D. Plasma membrane cytochromes P450 as neoantigens and autoimmune targets in drug-induced hepatitis. J Hepatol 1997; 26 Suppl 1:23.
  161. Liu ZX, Kaplowitz N. Role of innate immunity in acetaminophen-induced hepatotoxicity. Expert Opin Drug Metab Toxicol 2006; 2:493.
  162. Shear NH, Spielberg SP. Anticonvulsant hypersensitivity syndrome. In vitro assessment of risk. J Clin Invest 1988; 82:1826.
  163. Larrey D, Vial T, Micaleff A, et al. Hepatitis associated with amoxycillin-clavulanic acid combination report of 15 cases. Gut 1992; 33:368.
  164. Kleckner HB, Yakulis V, Heller P. Letter: Severe hypersensitivity to diphenylhydantoin with circulating antibodies to the drug. Ann Intern Med 1975; 83:522.
  165. Pohl LR. Drug-induced allergic hepatitis. Semin Liver Dis 1990; 10:305.
  166. Czaja AJ. Drug-induced autoimmune-like hepatitis. Dig Dis Sci 2011; 56:958.
  167. Orman ES, Conjeevaram HS, Vuppalanchi R, et al. Clinical and histopathologic features of fluoroquinolone-induced liver injury. Clin Gastroenterol Hepatol 2011; 9:517.
  168. Ghabril M, Bonkovsky HL, Kum C, et al. Liver injury from tumor necrosis factor-α antagonists: analysis of thirty-four cases. Clin Gastroenterol Hepatol 2013; 11:558.
  169. Björnsson E, Talwalkar J, Treeprasertsuk S, et al. Drug-induced autoimmune hepatitis: clinical characteristics and prognosis. Hepatology 2010; 51:2040.