AccScience Publishing / JCTR / Volume 3 / Issue 1 / DOI: 10.18053/jctres.03.2017S1.006
REVIEW

Role of nonalcoholic fatty liver disease as risk factor for drug-induced  hepatotoxicity

Julie Massart1 Karima Begriche2 Caroline Moreau2,3 Bernard Fromenty3*
Show Less
1 Department of Molecular Medicine and Surgery, Karolinska University Hospital, Karolinska Institute, Stockholm, Sweden
2 INSERM, U1241, Université de Rennes 1, Rennes, France
3 Service de Biochimie et Toxicologie, CHU Pontchaillou, Rennes, France
Received: 5 September 2016 | Revised: 26 October 2016 | Accepted: 1 November 2016 | Published online: 12 February 2017
© 2017 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution -Noncommercial 4.0 International License (CC-by the license) ( https://creativecommons.org/licenses/by-nc/4.0/ )
Abstract

Background: Obesity is often associated with nonalcoholic fatty liver disease (NAFLD), which refers to a large spectrum of hepatic lesions including fatty liver, nonalcoholic steatohepatitis (NASH) and cirrhosis. Different investigations showed or suggested that obesity and NAFLD are able to increase the risk of hepatotoxicity of different drugs. Some of these drugs could induce more frequently an acute hepatitis in obese individuals whereas others could worsen pre-existing NAFLD. 

 Aim: The main objective of the present review was to collect the available information regarding the role of NAFLD as risk factor for drug-induced hepatotoxicity. For this purpose, we performed a data-mining analysis using different queries including drug-induced liver injury (or DILI), drug-induced hepatotoxicity, fatty liver, nonalcoholic fatty liver disease (or NAFLD), steatosis and obesity. The main data from the collected articles are reported in this review and when available, some pathophysiological hypotheses are put forward.  

Relevance for patients: Drugs that could pose a potential risk in obese patients include compounds belonging to different pharmacological classes such as acetaminophen, halothane, methotrexate, rosiglitazone, stavudine and tamoxifen. For some of these drugs, experimental investigations in obese rodents confirmed the clinical observations and unveiled different pathophysiological mechanisms which could explain why these pharmaceuticals are particularly hepatotoxic in obesity and NAFLD. Other drugs such as pentoxifylline, phenobarbital and omeprazole might also pose a risk but more investigations are required to determine whether this risk is significant or not. Because obese people often take several drugs for the treatment of different obesity-related diseases such as type 2 diabetes, hyperlipidemia and coronary heart disease, it is urgent to identify the main pharmaceuticals that can cause acute hepatitis on a fatty liver background or induce NAFLD worsening.

Keywords
obesity
nonalcoholic fatty liver disease
drug
liver
toxicity
drug-induced liver injury
hepatotoxicity
cytochrome P450
mitochondria
acetaminophen
halothane
isoflurane
methotrexate
tamoxifen
pentoxifylline
rosiglitazone
stavudine
Conflict of interest
The authors declare they have no competing interests.
References

[1] Weng Z, Wang K, Li H, Shi Q. A comprehensive study of the  association between drug hepatotoxicity and daily dose, liver  metabolism, and lipophilicity using 975 oral medications. Oncotarget 2015; 6: 17031-17038.

[2] Björnsson ES, Hoofnagle JH. Categorization of drugs implicated in causing liver injury: Critical assessment based on  published case reports. Hepatology 2016; 63: 590-603.

[3] Robles-Diaz M, Lucena MI, Kaplowitz N, Stephens C, Medina-Caliz I, Gonzalez-Jimenez A, Ulzurrun E, Gonzalez AF,  Fernandez MC, Romero-Gomez M, Jimenez-Perez M, Bruguera M, Prieto M, Bessone F, Hernandez N, Arrese M, Andrade  RJ. Use of Hy's law and a new composite algorithm to predict  acute liver failure in patients with drug-induced liver injury.  Gastroenterology 2014; 147: 109-118.

[4] 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: 335-353.

[5] Webb GJ, Adams DH. Modeling idiosyncrasy: a novel animal  model of drug-induced liver injury. Hepatology 2015; 61:  1124-1126.

[6] Begriche K, Massart J, Robin MA, Borgne-Sanchez A, Fromenty B. Drug-induced toxicity on mitochondria and lipid  metabolism: mechanistic diversity and deleterious consequences for the liver. J Hepatol 2011; 54: 773-794. 

[7] Fromenty B. Drug-induced liver injury in obesity. J Hepatol  2013; 58: 824-826.

[8] Michaut A, Moreau C, Robin MA, Fromenty B. Acetaminophen-induced liver injury in obesity and nonalcoholic fatty  liver disease. Liver Int 2014; 34: e171- e179.

[9] Begriche K, Massart J, Robin MA, Bonnet F, Fromenty B.  Mitochondrial adaptations and dysfunctions in nonalcoholic  fatty liver disease. Hepatology 2013; 58: 1497-1507

[10] Xu R, Tao A, Zhang S, Deng Y, Chen G. Association between  patatin-like phospholipase domain containing 3 gene  (PNPLA3) polymorphisms and nonalcoholic fatty liver disease:  a HuGE review and meta-analysis. Sci Rep 2015; 5: 9284.

[11] Hardy T, Oakley F, Anstee QM, Day CP. Nonalcoholic fatty  liver disease: pathogenesis and disease spectrum. Annu Rev  Pathol 2016; 11: 451-496. 

[12] Poupeau A, Postic C. Cross-regulation of hepatic glucose metabolism via ChREBP and nuclear receptors. Biochim Biophys  Acta 2011; 1812: 995-1006. 

[13] Hirsova P, Ibrahim SH, Gores GJ, Malhi H. Lipotoxic lethal and  sublethal stress signaling in hepatocytes: relevance to NASH  pathogenesis. J Lipid Res 2016; 57: 1758-1770.

[14] Satapati S, Kucejova B, Duarte JA, Fletcher JA, Reynolds L,  Sunny NE, He T, Nair LA, Livingston K, Fu X, Merritt ME,Sherry AD, Malloy CR, Shelton JM, Lambert J, Parks EJ,  Corbin I, Magnuson MA, Browning JD, Burgess SC. Mitochondrial metabolism mediates oxidative stress and inflammation in fatty liver. J Clin Invest 2015; 125: 4447-4462.

[15] Kakimoto PA, Tamaki FK, Cardoso AR, Marana SR,  Kowaltowski AJ. H2O2 release from the very long chain  acyl-CoA dehydrogenase. Redox Biol 2015; 4: 375-380.

[16] Knockaert L, Fromenty B, Robin MA. Mechanisms of mitochondrial targeting of cytochrome P450 2E1: physiopathological role in liver injury and obesity. FEBS J 2011; 278:  4252-4260.

[17] Hartman JH, Martin HC, Caro AA, Pearce AR, Miller GP.  Subcellular localization of rat CYP2E1 impacts metabolic efficiency toward common substrates. Toxicology 2015; 338:  47-58.

[18] Aubert J, Begriche K, Knockaert L, Robin MA, Fromenty B.  Increased expression of cytochrome P450 2E1 in nonalcoholic  fatty liver disease: mechanisms and pathophysiological role.  Clin Res Hepatol Gastroenterol 2011; 35: 630-637.

[19] Weltman MD, Farrell GC, Hall P, Ingelman-Sundberg M, Liddle C. Hepatic cytochrome P450 2E1 is increased in patients  with nonalcoholic steatohepatitis. Hepatology 1998; 27:  128-133.

[20] Chalasani N, Gorski JC, Asghar MS, Asghar A, Foresman B,  Hall SD, Crabb DW. Hepatic cytochrome P450 2E1 activity in  nondiabetic patients with nonalcoholic steatohepatitis. Hepatology 2003; 37: 544-550.

[21] van Rongen A, Välitalo PA, Peeters MY, Boerma D, Huisman  FW, van Ramshorst B, van Dongen EP, van den Anker JN,  Knibbe CA. Morbidly obese patients exhibit increased  CYP2E1-mediated oxidation of acetaminophen. Clin Pharmacokinet 2016; 55: 833-847. 

[22] Schattenberg JM, Wang Y, Singh R, Rigoli RM, Czaja MJ.  Hepatocyte CYP2E1 overexpression and steatohepatitis lead  to impaired hepatic insulin signaling. J Biol Chem 2005; 280:  9887-9894.

[23] Kathirvel E, Morgan K, French SW, Morgan TR. Overexpression of liver-specific cytochrome P4502E1 impairs hepatic  insulin signaling in a transgenic mouse model of nonalcoholic  fatty liver disease. Eur J Gastroenterol Hepatol 2009; 21:  973-83.

[24] Michaut A, Le Guillou D, Moreau C, Bucher S, McGill MR,  Martinais S, Gicquel T, Morel I, Robin MA, Jaeschke H, Fromenty B. A cellular model to study drug-induced liver injury in  nonalcoholic fatty liver disease: Application to acetaminophen.  Toxicol Appl Pharmacol 2016; 292: 40-55.

[25] Brill MJ, Diepstraten J, van Rongen A, van Kralingen S, van  den Anker JN, Knibbe CA. Impact of obesity on drug metabolism and elimination in adults and children. Clin Pharmacokinet 2012; 51: 277-304. 

[26] Woolsey SJ, Mansell SE, Kim RB, Tirona RG, Beaton MD.  CYP3A activity and expression in nonalcoholic fatty liver  disease. Drug Metab Dispos 2015; 43: 1484-1490.

[27] Guengerich FP. Cytochrome P-450 3A4: regulation and role in  drug metabolism. Annu Rev Pharmacol Toxicol 1999; 39: 1-17.

[28] Finkelstein EA, Trogdon JG, Cohen JW, Dietz W. Annual medical spending attributable to obesity: payer-and service-specific estimates. Health Aff 2009; 28: w822-w831.

[29] ter Hofstede HJ, de Marie S, Foudraine NA, Danner SA,  Brinkman K. Clinical features and risk factors of lactic acidosis  following long-term antiretroviral therapy: 4 fatal cases. Int J  STD AIDS 2000; 11: 611-616.

[30] Wehling M. Non-steroidal anti-inflammatory drug use in  chronic pain conditions with special emphasis on the elderly  and patients with relevant comorbidities: management and  mitigation of risks and adverse effects. Eur J Clin Pharmacol  2014; 70: 1159-1172.

[31] Biour M, Ben Salem C, Chazouillères O, Grangé JD, Serfaty  L, Poupon R. Drug-induced liver injury: fourteenth updated  edition of the bibliographic database of liver injuries and related drugs. Gastroenterol Clin Biol 2004; 28: 720-759.

[32] Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A,  Talwalkar J, Reddy KR, Watkins PB, Navarro V, Barnhart H,  Gu J, Serrano J. Features and outcomes of 899 patients with  drug-induced liver injury: The DILIN prospective study. Gastroenterology 2015; 148: 1340-1352.

[33] Reuben A, Koch DG, Lee WM. Drug-induced acute liver failure: results of a U.S. multicenter, prospective study. Hepatology 2010; 52: 2065-2076.

[34] Aithal GP, Watkins PB, Andrade RJ, Larrey D, Molokhia M,  Takikawa H, Hunt CM, Wilke RA, Avigan M, Kaplowitz N,  Bjornsson E, Daly AK. Case definition and phenotype standardization in drug-induced liver injury. Clin Pharmacol Ther  2011; 89: 806-815.

[35] Cortez-Pinto H, Chatham J, Chacko VP, Arnold C, Rashid A,  Diehl AM. Alterations in liver ATP homeostasis in human  nonalcoholic steatohepatitis: a pilot study. JAMA 1999; 282:  1659-1664.

[36] Koliaki C, Roden M. Hepatic energy metabolism in human  diabetes mellitus, obesity and non-alcoholic fatty liver disease.  Mol Cell Endocrinol 2013; 379: 35-42.

[37] Serviddio G, Bellanti F, Vendemiale G. Free radical biology  for medicine: learning from nonalcoholic fatty liver disease.  Free Radic Biol Med 2013; 65: 952-968.

[38] Shaw PJ, Hopfensperger MJ, Ganey PE, Roth RA. Lipopolysaccharide and trovafloxacin coexposure in mice causes idiosyncrasy-like liver injury dependent on tumor necrosis factor-alpha. Toxicol Sci 2007; 100: 259-266.

[39] Ramm S, Mally A. Role of drug-independent stress factors in  liver injury associated with diclofenac intake. Toxicology  2013; 312: 83-96.

[40] Song BJ, Akbar M, Jo I, Hardwick JP, Abdelmegeed MA.  Translational implications of the alcohol-metabolizing enzymes, including cytochrome P450-2E1, in alcoholic and nonalcoholic liver disease. Adv Pharmacol 2015; 74: 303-372.

[41] Maes M, Vinken M, Jaeschke H. Experimental models of  hepatotoxicity related to acute liver failure. Toxicol Appl  Pharmacol 2016; 290: 86-97.

[42] Du K, Xie Y, McGill MR, Jaeschke H. Pathophysiological  significance of c-jun N-terminal kinase in acetaminophenhepatotoxicity. Expert Opin Drug Metab Toxicol 2015;  11:1769-1779.

[43] Watkins PB, Kaplowitz N, Slattery JT, Colonese CR, Colucci  SV, Stewart PW, Harris SC. Aminotransferase elevations in  healthy adults receiving 4 grams of acetaminophen daily: a  randomized controlled trial. JAMA 2006; 296: 87-93.

[44] Forget P, Wittebole X, Laterre PF. Therapeutic dose of acetaminophen may induce fulminant hepatitis in the presence of  risk factors: a report of two cases. Br J Anaesth 2009; 103:  899-900.

[45] Savino F, Lupica MM, Tarasco V, Locatelli E, Garazzino S,  Tovo PA. Fulminant hepatitis after 10 days of acetaminophen  treatment at recommended dosage in an infant. Pediatrics 2011;  127: e494-e497. 

[46] Claridge LC, Eksteen B, Smith A, Shah T, Holt AP. Acute liver  failure after administration of paracetamol at the maximum  recommended daily dose in adults. BMJ 2010; 341: c6764.

[47] Neuman MG, French SW, French BA, Seitz HK, Cohen LB,  Mueller S, Osna NA, Kharbanda KK, Seth D, Bautista A,  Thompson KJ, McKillop IH, Kirpich IA, McClain CJ, Bataller  R, Nanau RM, Voiculescu M, Opris M, Shen H, Tillman B, Li  J, Liu H, Thomes PG, Ganesan M, Malnick S. Alcoholic and  non-alcoholic steatohepatitis. Exp Mol Pathol 2014; 97: 492-510.

[48] Shi EC, Fisher R, McEvoy M, Vantol R, Rose M, Ham JM.  Factors influencing hepatic glutathione concentrations: a study  in surgical patients. Clin Sci 1982; 62: 279-283.

[49] Nguyen GC, Sam J, Thuluvath PJ. Hepatitis C is a predictor of  acute liver injury among hospitalizations for acetaminophen  overdose in the United States: a nationwide analysis. Hepatology 2008; 48: 1336-1341.

[50] Myers RP, Shaheen AA. Hepatitis C, alcohol abuse, and unintentional overdoses are risk factors for acetaminophen-related  hepatotoxicity. Hepatology 2009; 49: 1399-1400. 

[51] Rutherford A, Davern T, Hay JE, Murray NG, Hassanein T,  Lee WM, Chung RT. Influence of high body mass index on  outcome in acute liver failure. Clin Gastroenterol Hepatol  2006; 4: 1544-1549.

[52] Radosevich JJ, Patanwala AE, Erstad BL. Hepatotoxicity in  obese versus nonobese patients with acetaminophen poisoning  who are treated with intravenous N-acetylcysteine. Am J Ther  2016 2016; 23: e714-e719. 

[53] Blouin RA, Dickson P, McNamara PJ, Cibull M, McClain C.  Phenobarbital induction and acetaminophen hepatotoxicity:  resistance in the obese Zucker rodent. J Pharmacol Exp Ther  1987; 243: 565-570.

[54] Aubert J, Begriche K, Delannoy M, Morel I, Pajaud J, Ribault  C, Lepage S, McGill MR, Lucas-Clerc C, Turlin B, Robin MA,  Jaeschke H, Fromenty B. Differences in early acetaminophen  hepatotoxicity between obese ob/ob and db/db mice. J Pharmacol Exp Ther 2012; 342: 676-687.

[55] O'Shea D, Davis SN, Kim RB, Wilkinson GR. Effect of fasting and obesity in humans on the 6-hydroxylation of chlorzoxazone: a putative probe of CYP2E1 activity. Clin Pharmacol Ther 1994; 56: 359-367.

[56] Lucas D, Farez C, Bardou LG, Vaisse J, Attali JR, Valensi PCytochrome P450 2E1 activity in diabetic and obese patients  as assessed by chlorzoxazone hydroxylation. Fundam Clin  Pharmacol 1998; 12: 553-558.

[57] Emery MG, Fisher JM, Chien JY, Kharasch ED, Dellinger EP,  Kowdley KV, Thummel KE. CYP2E1 activity before and after  weight loss in morbidly obese subjects with nonalcoholic fatty  liver disease. Hepatology 2003; 38: 428-435.

[58] Wang Z, Hall SD, Maya JF, Li L, Asghar A, Gorski JC. Diabetes mellitus increases the in vivo activity of cytochrome  P450 2E1 in humans. Br J Clin Pharmacol 2003; 55: 77-85.

[59] Qizilbash AH. Halothane hepatitis. Can Med Assoc J 1973;  108: 171-177.

[60] Moult PJ, Sherlock S. Halothane-related hepatitis. A clinical  study of twenty-six cases. Q J Med 1975; 44: 99-114.

[61] Brunt EM, White H, Marsh JW, Holtmann B, Peters MG.  Fulminant hepatic failure after repeated exposure to isoflurane  anesthesia: a case report. Hepatology 1991; 13: 1017-1021.

[62] Gunaratnam NT, Benson J, Gandolfi AJ, Chen M. Suspected  isoflurane hepatitis in an obese patient with a history of halothane hepatitis. Anesthesiology 1995; 83: 1361-1364. 

[63] Eghtesadi-Araghi P, Sohrabpour A, Vahedi H, Saberi-Firoozi  M. Halothane hepatitis in Iran: a review of 59 cases. World J  Gastroenterol. 2008; 14: 5322-5326.

[64] Böttiger LE, Dalén E, Hallén B. Halothane-induced liver  damage: an analysis of the material reported to the Swedish  Adverse Drug Reaction Committee, 1966-1973. Acta Anaesthesiol Scand 1976; 20: 40-46.

[65] Kharasch ED, Hankins DC, Cox K. Clinical isoflurane metabolism by cytochrome P450 2E1. Anesthesiology 1999; 90:  766-771

[66] Park BK, Kitteringham NR, O'Neill PM. Metabolism of fluorine-containing drugs. Annu Rev Pharmacol Toxicol 2001; 41:  443-470.

[67] Becker GL. Fatty acid lessens halothane's inhibition of energy  metabolism in isolated hepatocytes. Anesth Analg 1990; 70:  22-28.

[68] Gut J, Christen U, Huwyler J. Mechanisms of halothane toxicity: novel insights. Pharmacol Ther 1993; 58: 133-155.

[69] Kinugawa H, Kawahara M, Amakata Y, Maeda T. Halothane-induced cytotoxicity in isolated rat hepatocytes: an electron microscopic study. In Vivo 1993; 7: 497-501.

[70] Dansette PM, Bonierbale E, Minoletti C, Beaune PH, Pessayre  D, Mansuy D. Drug-induced immunotoxicity. Eur J Drug  Metab Pharmacokinet 1998; 23: 443-451.

[71] Brasil LJ, San-Miguel B, Kretzmann NA, Amaral JL, Zettler  CG, Marroni N, Gonzalez-Gallego J, Tunon MJ. Halothane  induces oxidative stress and NF-kappaB activation in rat liver:  protective effect of propofol. Toxicology 2006; 227: 53-61.

[72] Kim H, Oh E, Im H, Mun J, Yang M, Khim JY, Lee E, Lim  SH, Kong MH, Lee M, Sul D. Oxidative damages in the DNA,  lipids, and proteins of rats exposed to isofluranes and alcohols.  Toxicology 2006; 220: 169-178.

[73] Bentley JB, Vaughan RW, Gandolfi AJ, Cork RC. Halothane  biotransformation in obese and nonobese patients. Anesthesiology 1982; 57: 94-97.

[74] Young SR, Stoelting RK, Peterson C, Madura JA. Anesthetic  biotransformation and renal function in obese patients during  and after methoxyflurane or halothane anesthesia. Anesthesiology 1975; 42: 451-457.

[75] Prey S, Paul C. Effect of folic or folinic acid supplementation  on methotrexate-associated safety and efficacy in inflammatory disease: a systematic review. Br J Dermatol 2009; 160:  622-628.

[76] Romao VC, Lima A, Bernardes M, Canhao H, Fonseca JE.  Three decades of low-dose methotrexate in rheumatoid arthritis: can we predict toxicity? Immunol Res 2014; 60: 289-310.

[77] West SG. Methotrexate hepatotoxicity. Rheum Dis Clin North  Am 1997; 23: 883-915.

[78] Rabinowich L, Shibolet O. Drug induced steatohepatitis: an  uncommon culprit of a common disease. Biomed Res Int  2015; 2015: 168905.

[79] Banerjee AK, Lakhani S, Vincent M, Selby P. Dose-dependent  acute hepatitis associated with administration of high dose  methotrexate. Hum Toxicol 1988; 7: 561-562.

[80] Stine JG, Chalasani N. Chronic liver injury induced by drugs:  a systematic review. Liver Int 2015; 35: 2343-2353.

[81] Langman G, Hall PM, Todd G. Role of non-alcoholic steatohepatitis in methotrexate-induced liver injury. J Gastroenterol  Hepatol 2001; 16: 1395-1401.

[82] Ramachandran R, Kakar S. Histological patterns in  drug-induced liver disease. J Clin Pathol 2009; 62: 481-492

[83] Wang Y, Lin Z, Liu Z, Harris S, Kelly R, Zhang J, Ge W, Chen  M, Borlak J, Tong W. A unifying ontology to integrate histological and clinical observations for drug-induced liver injury.  Am J Pathol 2013; 182: 1180-1187.

[84] Ahern MJ, Smith MD, Roberts-Thomson PJ. Methotrexate  hepatotoxicity: what is the evidence? Inflamm Res 1998; 47:  148-151.

[85] Rosenberg P, Urwitz H, Johannesson A, Ros AM, Lindholm J,  Kinnman N, Hultcrantz R. Psoriasis patients with diabetes type  2 are at high risk of developing liver fibrosis during methotrexate treatment. J Hepatol 2007; 46: 1111-1118.

[86] Malatjalian DA, Ross JB, Williams CN, Colwell SJ, Eastwood  BJ. Methotrexate hepatotoxicity in psoriatics: report of 104  patients from Nova Scotia, with analysis of risks from obesity,  diabetes and alcohol consumption during long term follow-up.  Can J Gastroenterol 1996; 10: 369-375.

[87] Kent PD, Luthra HS, Michet C. Risk factors for methotrexate-induced abnormal laboratory monitoring results in patients  with rheumatoid arthritis. J Rheumatol 2004; 31: 1727-1731.

[88] Montaudié H, Sbidian E, Paul C, Maza A, Gallini A, Aractingi  S, Aubin F, Bachelez H, Cribier B, Joly P, Jullien D, Le Maître  M, Misery L, Richard MA, Ortonne JP. Methotrexate in psoriasis: a systematic review of treatment modalities, incidence,  risk factors and monitoring of liver toxicity. J Eur Acad Dermatol Venereol 2011; 25 (Suppl 2): 12-18.

[89] Yeo CM, Chong VH, Earnest A, Yang WL. Prevalence and risk  factors of methotrexate hepatotoxicity in Asian patients with  psoriasis. World J Hepatol 2013; 5: 275-280.

[90] Schmajuk G, Miao Y, Yazdany J, Boscardin WJ, Daikh DI,Steinman MA. Identification of risk factors for elevated  transaminases in methotrexate users through an electronic  health record. Arthritis Care Res 2014; 66: 1159-1166.

[91] Zachariae H, Kragballe K, Søgaard H. Methotrexate induced  liver cirrhosis. Studies including serial liver biopsies during  continued treatment. Br J Dermatol 1980; 102: 407-412.

[92] Whiting-O'Keefe QE, Fye KH, Sack KD. Methotrexate and  histologic hepatic abnormalities: a meta-analysis. Am J Med.  1991; 90: 711-716.

[93] Davila-Fajardo CL, Swen JJ, Cabeza Barrera J, Guchelaar HJ.  Genetic risk factors for drug-induced liver injury in rheumatoid  arthritis patients using low-dose methotrexate. Pharmacogenomics 2013; 14: 63-73.

[94] Tarantino G, Conca P, Basile V, Gentile A, Capone D, Polichetti G, Leo E. A prospective study of acute drug-induced  liver injury in patients suffering from non-alcoholic fatty liver  disease. Hepatol Res 2007; 37: 410-415.

[95] Chalasani N, Aljadhey H, Kesterson J, Murray MD, Hall SD.  Patients with elevated liver enzymes are not at higher risk for  statin hepatotoxicity. Gastroenterology 2004; 126: 1287-1292.

[96] Bays H, Cohen DE, Chalasani N, Harrison SA. An assessment  by the Statin Liver Safety Task Force: 2014 update. J Clin  Lipidol 2014; 8: S47-S57.

[97] Mattar W, Juliar B, Gradus-Pizlo I, Kwo PY. Amiodarone  hepatotoxicity in the context of the metabolic syndrome and  right-sided heart failure. J Gastrointestin Liver Dis 2009; 18:  419-423.

[98] Tsukamoto H, Towner SJ, Ciofalo LM, French SW. Ethanol-induced liver fibrosis in rats fed high fat diet. Hepatology  1986; 6: 814-822.

[99] Naveau S, Giraud V, Borotto E, Aubert A, Capron F, Chaput JC.  Excess weight risk factor for alcoholic liver disease. Hepatology 1997; 25: 108-111.

[100] Hart CL, Morrison DS, Batty GD, Mitchell RJ, Davey Smith G.  Effect of body mass index and alcohol consumption on liver  disease: analysis of data from two prospective cohort studies.  BMJ 2010; 340: c1240.

[101] Xu J, Lai KK, Verlinsky A, Lugea A, French SW, Cooper MP,  Ji C, Tsukamoto H. Synergistic steatohepatitis by moderate  obesity and alcohol in mice despite increased adiponectin and  p-AMPK. J Hepatol 2011; 55: 673-682.

[102] Everitt H, Hu M, Ajmo JM, Rogers CQ, Liang X, Zhang R,  Yin H, Choi A, Bennett ES, You M. Ethanol administration  exacerbates the abnormalities in hepatic lipid oxidation in genetically obese mice. Am J Physiol Gastrointest Liver Physiol  2013; 304: G38-G47.

[103] Tan TC, Crawford DH, Jaskowski LA, Subramaniam VN,  Clouston AD, Crane DI, Bridle KR, Anderson GJ, Fletcher  LM. Excess iron modulates endoplasmic reticulum stress-associated pathways in a mouse model of alcohol and high-fat  diet-induced liver injury. Lab Invest 2013; 93: 1295-1312.

[104] Massart J, Begriche K, Buron N, Porceddu M, Borgne-Sanchez A, Fromenty B. Drug-induced inhibition of mitochondrial fatty acid oxidation and steatosis. Curr Pathobiol Rep  2013; 1: 147-157.

[105] Mitchell C, Robin MA, Mayeuf A, Mahrouf-Yorgov M,  Mansouri A, Hamard M, Couton D, Fromenty B, Gilgenkrantz  H. Protection against hepatocyte mitochondrial dysfunction  delays fibrosis progression in mice. Am J Pathol 2009; 175:  1929-1937.

[106] Rehman H, Liu Q, Krishnasamy Y, Shi Z, Ramshesh VK,  Haque K, Schnellmann RG, Murphy MP, Lemasters JJ, Rockey  DC, Zhong Z. The mitochondria-targeted antioxidant MitoQ  attenuates liver fibrosis in mice. Int J Physiol Pathophysiol  Pharmacol 2016; 8: 14-27.

[107] Winnike JH, Li Z, Wright FA, Macdonald JM, O'Connell TM,  Watkins PB. Use of pharmaco-metabonomics for early prediction of acetaminophen-induced hepatotoxicity in humans. Clin  Pharmacol Ther 2010; 88: 45-51.

[108] Watelet J, Laurent V, Bressenot A, Bronowicki JP, Larrey D,  Peyrin-Biroulet L. Toxicity of chronic paracetamol ingestion.  Aliment Pharmacol Ther 2007; 26: 1543-1544.

[109] Trenti T, Bertolotti M, Castellana CN, Ferrari A, Pini LA,  Sternieri E. Plasma glutathione level in paracetamol daily  abuser patients. Changes in plasma cysteine and thiol groups  after reduced glutathione administration. Toxicol Lett 1992;  64-65: 757-761

[110] Emmett M. Acetaminophen toxicity and 5-oxoproline (pyroglutamic acid): a tale of two cycles, one an ATP-depleting  futile cycle and the other a useful cycle. Clin J Am Soc Nephrol  2014; 9: 191-200.

[111] Kato H, Fujigaki Y, Inoue R, Asakawa S, Shin S, Shima T,  Furunishi J, Higaki M, Tanemoto M, Yamaguchi Y, Hoshimoto  K, Uozaki H, Uchida S. Therapeutic dose of acetaminophen as  a possible risk factor for acute kidney injury: learning from two  healthy young adult cases. Intern Med 2014; 53: 1531-1534.

[112] Sudano I, Flammer AJ, Périat D, Enseleit F, Hermann M,  Wolfrum M, Hirt A, Kaiser P, Hurlimann D, Neidhart M, Gay S,  Holzmeister J, Nussberger J, Mocharla P, Landmesser U, Haile  SR, Corti R, Vanhoutte PM, Lüscher TF, Noll G, Ruschitzka F.  Acetaminophen increases blood pressure in patients with coronary artery disease. Circulation 2010; 122: 1789-1796.

[113] Savransky V, Reinke C, Jun J, Bevans-Fonti S, Nanayakkara A,  Li J, Myers AC, Torbenson MS, Polotsky VY. Chronic intermittent hypoxia and acetaminophen induce synergistic liver  injury in mice. Exp Physiol 2009; 94: 228-239.

[114] Mast C, Joly C, Savary-Auzeloux I, Remond D, Dardevet D,  Papet I. Skeletal muscle wasting occurs in adult rats under  chronic treatment with paracetamol when glutathione-dependent detoxification is highly activated. J Physiol Pharmacol  2014; 65: 623-631.

[115] Mobasher MA, de Toro-Martín J, Gonzalez-Rodríguez A,  Ramos S, Letzig LG, James LP, Muntané J, Alvarez C, Valverde AM. Essential role of protein-tyrosine phosphatase 1B in  the modulation of insulin signaling by acetaminophen in  hepatocytes. J Biol Chem 2014; 289: 29406-294019.

[116] Hu J, Ramshesh VK, McGill MR, Jaeschke H, Lemasters JJ.  Low dose acetaminophen induces reversible mitochondrial  dysfunction associated with transient c-Jun N-terminal kinase  activation in mouse liver. Toxicol Sci 2016; 150: 204-215.

[117] Kendig EL, Schneider SN, Clegg DJ, Genter MB, Shertzer HG.  Over-the-counter analgesics normalize blood glucose and body  composition in mice fed a high fat diet. Biochem Pharmacol  2008; 76: 216-224. 

[118] Shertzer HG, Schneider SN, Kendig EL, Clegg DJ, D'Alessio  DA, Genter M B. Acetaminophen normalizes glucose homeostasis in mouse models for diabetes. Biochem Pharmacol 2008;  75: 1402-1410.

[119] Larrain S, Rinella ME. A myriad of pathways to NASH. Clin  Liver Dis 2012; 16: 525-548.

[120] Rafacho A, Ortsäter H, Nadal A, Quesada I. Glucocorticoid  treatment and endocrine pancreas function: implications for  glucose homeostasis, insulin resistance and diabetes. J Endocrinol 2014; 223: R49-R62.

[121] D'souza AM, Beaudry JL, Szigiato AA, Trumble SJ, Snook LA,  Bonen A, Giacca A, Riddell MC. Consumption of a high-fat  diet rapidly exacerbates the development of fatty liver disease  that occurs with chronically elevated glucocorticoids. Am J  Physiol Gastrointest Liver Physiol 2012; 302: G850-G863.

[122] Poggioli R, Ueta CB, Drigo RA, Castillo M, Fonseca TL,  Bianco AC. Dexamethasone reduces energy expenditure and  increases susceptibility to diet-induced obesity in mice. Obesity  2013; 21: E415-E420.

[123] Kimberg DV, Loud AV, Wiener J. Cortisone-induced alterations  in mitochondrial function and structure. J Cell Biol 1968; 37:  63-79.

[124] Lettéron P, Brahimi-Bourouina N, Robin MA, Moreau A,  Feldmann G, Pessayre D. Glucocorticoids inhibit mitochondrial matrix acyl-CoA dehydrogenases and fatty acid beta-oxidation. Am J Physiol 1997; 272: G1141-G1150.

[125] Roussel D, Dumas JF, Simard G, Malthièry Y, Ritz P. Kinetics  and control of oxidative phosphorylation in rat liver mitochondria after dexamethasone treatment. Biochem J 2004; 382:  491-499.

[126] Fernandez FG, Ritter J, Goodwin JW, Linehan DC, Hawkins  WG, Strasberg SM. Effect of steatohepatitis associated with  irinotecan or oxaliplatin pretreatment on resectability of hepatic  colorectal metastases. J Am Coll Surg 2005; 200: 845-853.

[127] Vauthey JN, Pawlik TM, Ribero D, Wu TT, Zorzi D, Hoff PM,  Xiong HQ, Eng C, Lauwers GY, Mino-Kenudson M, Risio M,  Muratore A, Capussotti L, Curley SA, Abdalla EK. Chemotherapy regimen predicts steatohepatitis and an increase in  90-day mortality after surgery for hepatic colorectal metastases.  J Clin Oncol 2006; 24: 2065-2072.

[128] Mallick P, Shah P, Gandhi A, Ghose R. Impact of obesity on  accumulation of the toxic irinotecan metabolite, SN-38, in  mice. Life Sci 2015; 139: 132-138.

[129] Laharie D, Seneschal J, Schaeverbeke T, Doutre MS,  Longy-Boursier M, Pellegrin JL, Chabrun E, Villars S, Zerbib  F, de Lédinghen V. Assessment of liver fibrosis with transient  elastography and FibroTest in patients treated with methotrexate for chronic inflammatory diseases: a case-control study. J  Hepatol 2010; 53: 1035-1040.

[130] Kim TY, Kim JY, Sohn JH, Lee HS, Bang SY, Kim Y, Kim MY,  Jeong WK. Assessment of substantial liver fibrosis by real-timeshear wave elastography in methotrexate-treated patients with  rheumatoid arthritis. J Ultrasound Med 2015; 34: 1621-1630.

[131] Hardwick RN, Clarke JD, Lake AD, Canet MJ, Anumol T,  Street SM, Merrell MD, Goedken MJ, Snyder SA, Cherrington  NJ. Increased susceptibility to methotrexate-induced toxicity in  nonalcoholic steatohepatitis. Toxicol Sci 2014; 142: 45-55.

[132] Kyriakides M, Hardwick RN, Jin Z, Goedken MJ, Holmes E,  Cherrington NJ, Coen M. Systems level metabolic phenotype  of methotrexate administration in the context of non-alcoholic  steatohepatitis in the rat. Toxicol Sci 2014; 142: 105-116. 

[133] Jha P, Knopf A, Koefeler H, Mueller M, Lackner C, Hoefler G,  Claudel T, Trauner M. Role of adipose tissue in methionine-choline-deficient model of non-alcoholic steatohepatitis  (NASH). Biochim Biophys Acta 2014; 1842: 959-970.

[134] Yamamoto N, Lopes LC, Campello AP, Klüppel ML. Methotrexate: studies on cellular metabolism. II-Effects on mitochondrial oxidative metabolism and ion transport. Cell Biochem Funct 1989; 7: 129-134.

[135] Schumacher JD, Guo GL. Mechanistic review of drug-induced  steatohepatitis. Toxicol Appl Pharmacol 2015; 289: 40-47.

[136] Belinsky GS, Parke AL, Huang Q, Blanchard K, Jayadev S,  Stoll R, Rothe M, Achenie LE, Gupta RR, Wu GY, Rosenberg  DW. The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci  2007; 97: 582-594

[137] Sreekumar R, Rosado B, Rasmussen D, Charlton M. Hepatic  gene expression in histologically progressive nonalcoholic  steatohepatitis. Hepatology 2003; 38: 244-251.

[138] Rensen SS, Slaats Y, Driessen A, Peutz-Kootstra CJ, Nijhuis J,  Steffensen R, Greve JW, Buurman WA. Activation of the  complement system in human nonalcoholic fatty liver disease.  Hepatology 2009; 50: 1809-1817.

[139] Hillebrandt S, Wasmuth HE, Weiskirchen R, Hellerbrand C,  Keppeler H, Werth A, Schirin-Sokhan R, Wilkens G, Geier A,  Lorenzen J, Köhl J, Gressner AM, Matern S, Lammert F.  Complement factor 5 is a quantitative trait gene that modifies  liver fibrogenesis in mice and humans. Nat Genet 2005; 37:  835-843.

[140] Schmitt J, Roderfeld M, Sabrane K, Zhang P, Tian Y, Mertens  JC, Frei P, Stieger B, Weber A, Müllhaupt B, Roeb E, Geier A.  Complement factor C5 deficiency significantly delays the  progression of biliary fibrosis in bile duct-ligated mice. Biochem Biophys Res Commun 2012; 418: 445-450. 

[141] Igoudjil A, Begriche K, Pessayre D, Fromenty B. Mitochondrial, metabolic and genotoxic effects of antiretroviral nucleoside reverse-transcriptase inhibitors. Anti-Infect Agents Med  Chem 2006; 5: 273-292.

[142] Nunez M. Clinical syndromes and consequences of antiretroviral-related hepatotoxicity. Hepatology 2010; 52: 1143-1155.

[143] Schon E, Fromenty B. Alterations of mitochondrial DNA in  liver diseases. In: Mitochondria in Liver Disease. Kaplowitz N,  Han D, eds. Taylor & Francis, New-York, 2016: pp 279-309.

[144] Tien PC, Barrón Y, Justman JE, Hyman C, Cohen MH, Young  M, Kovacs A, Cole SR. Antiretroviral therapies associated with  lipoatrophy in HIV-infected women. AIDS Patient Care STDS  2007; 21: 297-305.

[145] de Waal R, Cohen K, Maartens G. Systematic review of antiretroviral-associated lipodystrophy: lipoatrophy, but not cen-tral fat gain, is an antiretroviral adverse drug reaction. PLoS  One 2013; 8: e63623.

[146] Gougeon ML, Pénicaud L, Fromenty B, Leclercq P, Viard JP,  Capeau J. Adipocytes targets and actors in the pathogenesis of  HIV-associated lipodystrophy and metabolic alterations. Antivir Ther 2004; 9: 161-177

[147] Tien PC, Schneider MF, Cole SR, Levine AM, Cohen M,  DeHovitz J, Young M, Justman JE. Antiretroviral therapy exposure and insulin resistance in the Women's Interagency HIV  study. J Acquir Immune Defic Syndr 2008; 49: 369-376.

[148] Walker UA, Venhoff N, Koch EC, Olschewski M, Schneider J,  Setzer B. Uridine abrogates mitochondrial toxicity related to  nucleoside analogue reverse transcriptase inhibitors in HepG2  cells. Antivir Ther 2003; 8: 463-470.

[149] Lebrecht D, Vargas-Infante YA, Setzer B, Kirschner J, Walker  UA. Uridine supplementation antagonizes zalcitabine-induced  microvesicular steatohepatitis in mice. Hepatology 2007; 45:  72-79.

[150] Gardner K, Hall PA, Chinnery PF, Payne BA. HIV treatment  and associated mitochondrial pathology: review of 25 years of  in vitro, animal, and human studies. Toxicol Pathol 2014; 42:  811-822.

[151] Igoudjil A, Abbey-Toby A, Begriche K, Grodet A, Chataigner  K, Peytavin G, Maachi M, Colin M, Robin MA, Lettéron P,  Feldmann G, Pessayre D, Fromenty B. High doses of stavudine  induce fat wasting and mild liver damage without impairing  mitochondrial respiration in mice. Antivir Ther 2007; 12:  389-400.

[152] Igoudjil A, Massart J, Begriche K, Descatoire V, Robin MA,  Fromenty B. High concentrations of stavudine impair fatty acid  oxidation without depleting mitochondrial DNA in cultured rat  hepatocytes. Toxicol In Vitro 2008; 22: 887-898. 

[153] Nagiah S, Phulukdaree A, Chuturgoon A. Mitochondrial and  oxidative stress response in HepG2 cells following acute and  prolonged exposure to antiretroviral drugs. J Cell Biochem  2015; 116: 1939-1946. 

[154] Guaraldi G, Squillace N, Stentarelli C, Orlando G, D'Amico R,  Ligabue G, Fiocchi F, Zona S, Loria P, Esposito R, Palella F.  Nonalcoholic fatty liver disease in HIV-infected patients referred to a metabolic clinic: prevalence, characteristics, and  predictors. Clin Infect Dis 2008; 47: 250-257.

[155] Ingiliz P, Valantin MA, Duvivier C, Medja F, Dominguez S,  Charlotte F, Tubiana R, Poynard T, Katlama C, Lombès A,  Benhamou Y. Liver damage underlying unexplained transaminase elevation in human immunodeficiency virus-1 monoinfected patients on antiretroviral therapy. Hepatology 2009;  49: 436-442.

[156] Lemoine M, Serfaty L, Capeau J. From nonalcoholic fatty liver  to nonalcoholic steatohepatitis and cirrhosis in HIV-infected  patients: diagnosis and management. Curr Opin Infect Dis  2012; 25: 10-16.

[157] Foufelle F, Fromenty B. Role of endoplasmic reticulum stress  in drug-induced toxicity. Pharmacol Res Perspect 2016; 4:  e00211.

[158] Stankov MV, Panayotova-Dimitrova D, Leverkus M, VondranFW, Bauerfeind R, Binz A, Behrens GM. Autophagy inhibition  due to thymidine analogues as novel mechanism leading to hepatocyte dysfunction and lipid accumulation. AIDS 2012;  26: 1995-2006.

[159] Geddes R, Knight S, Moosa MY, Reddi A, Uebel K, Sunpath H.  A high incidence of nucleoside reverse transcriptase inhibitor  (NRTI)-induced lactic acidosis in HIV-infected patients in a South African context. S Afr Med J 2006; 96: 722-724.

[160] Bolhaar MG, Karstaedt AS. A high incidence of lactic acidosis  and symptomatic hyperlactatemia in women receiving highly  active antiretroviral therapy in Soweto, South Africa. Clin Infect Dis 2007; 45: 254-260.

[161] Wester CW, Okezie OA, Thomas AM, Bussmann H, Moyo S,  Muzenda T, Makhema J, van Widenfelt E, Musonda R, Novitsky V, Gaolathe T, Ndwapi N, Essex M, Kuritzkes DR,  DeGruttola V, Marlink RG. Higher-than-expected rates of lactic  acidosis among highly active antiretroviral therapy-treated  women in Botswana: preliminary results from a large randomized clinical trial. J Acquir Immune Defic Syndr 2007; 46:  318-322.

[162] Wester CW, Eden SK, Shepherd BE, Bussmann H, Novitsky V,  Samuels DC, Hendrickson SL, Winkler CA, O'Brien SJ, Essex  M, D'Aquila RT, DeGruttola V, Marlink RG. Risk factors for  symptomatic hyperlactatemia and lactic acidosis among combination antiretroviral therapy-treated adults in Botswana: results from a clinical trial. AIDS Res Hum Retroviruses 2012;  28: 759-765.

[163] Coghlan ME, Sommadossi JP, Jhala NC, Many WJ, Saag MS,  Johnson VA. Symptomatic lactic acidosis in hospitalized antiretroviral-treated patients with human immunodeficiency virus infection: a report of 12 cases. Clin Infect Dis 2001; 33:  1914-1921.

[164] Thursz MR, Richardson P, Allison M, Austin A, Bowers M,  Day CP, Downs N, Gleeson D, MacGilchrist A, Grant A, Hood  S, Masson S, McCune A, Mellor J, O'Grady J, Patch D,  Ratcliffe I, Roderick P, Stanton L, Vergis N, Wright M, Ryder S,  Forrest EH. Prednisolone or pentoxifylline for alcoholic hepatitis. N Engl J Med 2015; 372: 1619-1628.

[165] Nguyen TA, DeShazo JP, Thacker LR, Puri P, Sanyal AJ. The  worsening profile of alcoholic hepatitis in the United States.  Alcohol Clin Exp Res 2016; 40: 1295-1303.

[166] Adams LA, Zein CO, Angulo P, Lindor KD. A pilot trial of  pentoxifylline in nonalcoholic steatohepatitis. Am J Gastroenterol 2004; 99: 2365-2368.

[167] Satapathy SK, Sakhuja P, Malhotra V, Sharma BC, Sarin SK.  Beneficial effects of pentoxifylline on hepatic steatosis, fibrosis  and necroinflammation in patients with non-alcoholic steatohepatitis. J Gastroenterol Hepatol 2007; 22: 634-638.

[168] Du J, Ma YY, Yu CH, Li YM. Effects of pentoxifylline on  nonalcoholic fatty liver disease: a meta-analysis. World J Gastroenterol 2014; 20: 569-577.

[169] Van Wagner LB, Koppe SW, Brunt EM, Gottstein J,  Gardikiotes K, Green RM, Rinella ME. Pentoxifylline for the  treatment of non-alcoholic steatohepatitis: a randomized controlled trial. Ann Hepatol 2011; 10: 277-286

[170] Baniasadi N, Salajegheh F, Pardakhty A, Seyedmirzaee SM,  Hayatbakhsh MM, Nikpoor AR, Mohammadi M. Effects of  pentoxifylline on non-alcoholic steatohepatitis: a randomized,  double-blind, placebo-controlled trial in iran. Hepat Mon 2015;  15: e32418.

[171] Massart J, Robin MA, Noury F, Fautrel A, Lettéron P, Bado A,  Eliat PA, Fromenty B. Pentoxifylline aggravates fatty liver in  obese and diabetic ob/ob mice by increasing intestinal glucose  absorption and activating hepatic lipogenesis. Br J Pharmacol  2012; 165: 1361-1374.

[172] Koppe SW, Sahai A, Malladi P, Whitington PF, Green RM.  Pentoxifylline attenuates steatohepatitis induced by the methionine choline deficient diet. J Hepatol 2004; 41: 592-598.

[173] Lane JD, Feinglos MN, Surwit RS. Caffeine increases ambulatory glucose and postprandial responses in coffee drinkers  with type 2 diabetes. Diabetes Care 2008; 31: 221-222.

[174] Lane JD, Lane AJ, Surwit RS, Kuhn CM, Feinglos MN. Pilot  study of caffeine abstinence for control of chronic glucose in  type 2 diabetes. J Caffeine Res 2012; 2: 45-47.

[175] Wei P, Zhang J, Egan-Hafley M, Liang S, Moore DD. The  nuclear receptor CAR mediates specific xenobiotic induction of  drug metabolism. Nature 2000; 407: 920-923.

[176] Elcombe CR, Peffer RC, Wolf DC, Bailey J, Bars R, Bell D,  Cattley RC, Ferguson SS, Geter D, Goetz A, Goodman JI,  Hester S, Jacobs A, Omiecinski CJ, Schoeny R, Xie W, Lake  BG. Mode of action and human relevance analysis for nuclear  receptor-mediated liver toxicity: A case study with phenobarbital as a model constitutive androstane receptor (CAR) activator. Crit Rev Toxicol 2014; 44: 64-82.

[177] Morel G, Cossec B, Lambert AM, Binet S. Evaluation of rat  hepatic 2E1 activity in function of age, sex and inducers: choice  of an experimental model capable of testing the hepatotoxicity  of low molecular weight compounds. Toxicol Lett 1999; 106:  171-180.

[178] Madan A, Graham RA, Carroll KM, Mudra DR, Burton LA,  Krueger LA, Downey AD, Czerwinski M, Forster J,  Ribadeneira MD, Gan LS, LeCluyse EL, Zech K, Robertson P  Jr, Koch P, Antonian L, Wagner G, Yu L, Parkinson A. Effects  of prototypical microsomal enzyme inducers on cytochrome  P450 expression in cultured human hepatocytes. Drug Metab  Dispos 2003; 31: 421-431.

[179] Zhao X, Zhang JJ, Wang X, Bu XY, Lou YQ, Zhang GL. Effect  of berberine on hepatocyte proliferation, inducible nitric oxide  synthase expression, cytochrome P450 2E1 and 1A2 activities  in diethylnitrosamine- and phenobarbital-treated rats. Biomed  Pharmacother 2008; 62: 567-572.

[180] Zannikos PN, Bandyopadhyay AM, Robertson LW, Blouin RA.  Effect of nutritional obesity on the induction of CYP2B enzymes following phenobarbital treatment. Drug Metab Dispos  1993; 21: 782-787.

[181] Zong H, Armoni M, Harel C, Karnieli E, Pessin JE. Cytochrome P-450 CYP2E1 knockout mice are protected against  high-fat diet-induced obesity and insulin resistance. Am J  Physiol Endocrinol Metab 2012; 302: E532-E539.

[182] Abdelmegeed MA, Banerjee A, Yoo SH, Jang S, Gonzalez FJ,Song BJ. Critical role of cytochrome P450 2E1 (CYP2E1) in  the development of high fat-induced non-alcoholic steatohepatitis. J Hepatol 2012; 57: 860-866.

[183] Chen YY, Zhang CL, Zhao XL, Xie KQ, Zeng T. Inhibition of  cytochrome P4502E1 by chlormethiazole attenuated acute  ethanol-induced fatty liver. Chem Biol Interact 2014; 222:  18-26.

[184] Abdelmegeed MA, Choi Y, Ha SK, Song BJ. Cytochrome  P450-2E1 promotes aging-related hepatic steatosis, apoptosis  and fibrosis through increased nitroxidative stress. Free Radic  Biol Med 2016; 91: 188-202.

[185] Begriche K, Igoudjil A, Pessayre D, Fromenty B. Mitochondrial dysfunction in NASH: causes, consequences and possible  means to prevent it. Mitochondrion 2006; 6: 1-28. 

[186] Soccio RE, Chen ER, Lazar MA. Thiazolidinediones and the  promise of insulin sensitization in type 2 diabetes. Cell Metab.  2014; 20: 573-591.

[187] Kohlroser J, Mathai J, Reichheld J, Banner BF, Bonkovsky HL.  Hepatotoxicity due to troglitazone: report of two cases and review of adverse events reported to the United States Food and  Drug Administration. Am J Gastroenterol 2000; 95: 272-276. 

[188] Ikeda T. Drug-induced idiosyncratic hepatotoxicity: prevention  strategy developed after the troglitazone case. Drug Metab  Pharmacokinet 2011; 26: 60-70.

[189] Yokoi T. Troglitazone. Handb Exp Pharmacol 2010; 196:  419-435

[190] Hu D, Wu CQ, Li ZJ, Liu Y, Fan X, Wang QJ, Ding RG.  Characterizing the mechanism of thiazolidinedione-induced  hepatotoxicity: An in vitro model in mitochondria. Toxicol  Appl Pharmacol 2015; 284: 134-141.

[191] Al-Salman J, Arjomand H, Kemp DG, Mittal M. Hepatocellular  injury in a patient receiving rosiglitazone. A case report. Ann  Intern Med 2000; 132: 121-124.

[192] Forman LM, Simmons DA, Diamond RH. Hepatic failure in a  patient taking rosiglitazone. Ann Intern Med 2000; 132:  118-121.

[193] Nadanaciva S, Dykens JA, Bernal A, Capaldi RA, Will Y.  Mitochondrial impairment by PPAR agonists and statins identified via immunocaptured OXPHOS complex activities and  respiration. Toxicol Appl Pharmacol 2007; 223: 277-287.

[194] Chang E, Park CY, Park SW. Role of thiazolidinediones, insulin  sensitizers, in non-alcoholic fatty liver disease. J Diabetes Investig 2013; 4: 517-524.

[195] Ratziu V, Charlotte F, Bernhardt C, Giral P, Halbron M, Lenaour G, Hartmann-Heurtier A, Bruckert E, Poynard T; LIDO  Study Group. Long-term efficacy of rosiglitazone in nonalcoholic steatohepatitis: results of the fatty liver improvement by  rosiglitazone therapy (FLIRT 2) extension trial. ology 2010; 51:  445-453. 

[196] Ratziu V. Pharmacological agents for NASH. Nat Rev Gastroenterol Hepatol 2013; 10: 676-685.

[197] Neuschwander-Tetri BA, Brunt EM, Wehmeier KR, Oliver D,  Bacon BR. Improved nonalcoholic steatohepatitis after 48  weeks of treatment with the PPAR- ligand rosiglitazone.  Hepatology. 2003; 38: 1008-1017.

[198] Neuschwander-Tetri BA, Brunt EM, Wehmeier KR, Sponseller  CA, Hampton K, Bacon BR. Interim results of a pilot study  demonstrating the early effects of the PPAR- ligand rosiglitazone on insulin sensitivity, aminotransferases, hepatic steatosis and body weight in patients with non-alcoholic steatohepatitis. J Hepatol 2003; 38: 434-440.

[199] Lemoine M, Serfaty L, Cervera P, Capeau J, Ratziu V. Hepatic  molecular effects of rosiglitazone in human non-alcoholic steatohepatitis suggest long-term pro-inflammatory damage.  Hepatol Res 2014; 44: 1241-1247.

[200] Watkins SM, Reifsnyder PR, Pan HJ, German JB, Leiter EH.  Lipid metabolome-wide effects of the PPAR agonist rosiglitazone. J Lipid Res 2002; 43: 1809-1817.

[201] Pan HJ, Reifsnyder P, Vance DE, Xiao Q, Leiter EH. Pharmacogenetic analysis of rosiglitazone-induced hepatosteatosis  in new mouse models of type 2 diabetes. Diabetes 2005; 54:  1854-1862.

[202] Garcia-Ruiz I, Rodríguez-Juan C, Díaz-Sanjuán T, Martínez  MA, Muñoz-Yagüe T, Solís-Herruzo JA. Effects of rosiglitazone on the liver histology and mitochondrial function in ob/ob  mice. Hepatology 2007; 46: 414-423.

[203] Zhou M, Xu A, Lam KS, Tam PK, Che CM, Chan L, Lee IK,  Wu D, Wang Y. Rosiglitazone promotes fatty acyl CoA accumulation and excessive glycogen storage in livers of mice  without adiponectin. J Hepatol 2010; 53: 1108-1116.

[204] Rull A, Geeraert B, Aragonès G, Beltrán-Debón R,  Rodríguez-Gallego E, García-Heredia A, Pedro-Botet J, Joven  J, Holvoet P, Camps J. Rosiglitazone and fenofibrate exacerbate  liver steatosis in a mouse model of obesity and hyperlipidemia.  A transcriptomic and metabolomic study. J Proteome Res 2014;  13: 1731-1743.

[205] Gao M, Ma Y, Alsaggar M, Liu D. Dual outcomes of rosiglitazone treatment on fatty liver. AAPS J 2016; 18: 1023-1031.

[206] Yang YJ, Kim KM, An JH, Lee DB, Shim JH, Lim YS, Lee HC,  Lee YS, Ahn JH, Jung KH, Kim SB. Clinical significance of  fatty liver disease induced by tamoxifen and toremifene in  breast cancer patients. Breast 2016; 28: 67-72.

[207] Ogawa Y, Murata Y, Nishioka A, Inomata T, Yoshida S. Tamoxifen-induced fatty liver in patients with breast cancer.  Lancet 1998; 351: 725.

[208] Nishino M, Hayakawa K, Nakamura Y, Morimoto T, Mukaihara S. Effects of tamoxifen on hepatic fat content and the development of hepatic steatosis in patients with breast cancer:  high frequency of involvement and rapid reversal after completion of tamoxifen therapy. AJR Am J Roentgenol 2003; 180:  129-134.

[209] Pratt DS, Knox TA, Erban J. Tamoxifen-induced steatohepatitis. Ann Intern Med 1995; 123: 236.

[210] Oien KA, Moffat D, Curry GW, Dickson J, Habeshaw T, Mills  PR, MacSween RN. Cirrhosis with steatohepatitis after adjuvant tamoxifen. Lancet 1999; 353: 36-37.

[211] Saphner T, Triest-Robertson S, Li H, Holzman P. The association of nonalcoholic steatohepatitis and tamoxifen in patients  with breast cancer. Cancer 2009; 115: 3189-3195.

[212] Elefsiniotis IS, Pantazis KD, Ilias A, Pallis L, Mariolis A,Glynou I, Kada H, Moulakakis A. Tamoxifen induced hepatotoxicity in breast cancer patients with pre-existing liver steatosis: the role of glucose intolerance. Eur J Gastroenterol Hepatol  2004; 16: 593-598.

[213] Bruno S, Maisonneuve P, Castellana P, Rotmensz N, Rossi S,  Maggioni M, Persico M, Colombo A, Monasterolo F,  Casadei-Giunchi D, Desiderio F, Stroffolini T, Sacchini V,  Decensi A, Veronesi U. Incidence and risk factors for  non-alcoholic steatohepatitis: prospective study of 5408  women enrolled in Italian tamoxifen chemoprevention trial.  BMJ 2005; 330: 932.

[214] Pinto HC, Baptista A, Camilo ME, de Costa EB, Valente A, de  Moura MC. Tamoxifen-associated steatohepatitis--report of  three cases. J Hepatol 1995; 23: 95-97.

[215] Takamura T, Shimizu A, Komura T, Ando H, Zen Y, Minato H,  Matsushita E, Kaneko S. Selective estrogen receptor modulator  raloxifene-associated aggravation of nonalcoholic steatohepatitis. Intern Med 2007; 46: 579-581.

[216] Larosche I, Lettéron P, Fromenty B, Vadrot N, Abbey-Toby A,  Feldmann G, Pessayre D, Mansouri A. Tamoxifen inhibits  topoisomerases, depletes mitochondrial DNA, and triggers  steatosis in mouse liver. J Pharmacol Exp Ther 2007; 321:  526-535

[217] Tuquet C, Dupont J, Mesneau A, Roussaux J. Effects of tamoxifen on the electron transport chain of isolated rat liver  mitochondria. Cell Biol Toxicol 2000; 16: 207-219.

[218] Cardoso CM, Custódio JB, Almeida LM, Moreno AJ. Mechanisms of the deleterious effects of tamoxifen on mitochondrial  respiration rate and phosphorylation efficiency. Toxicol Appl  Pharmacol 2001; 176: 145-152.

[219] Parvez S, Tabassum H, Rehman H, Banerjee BD, Athar M,  Raisuddin S. Catechin prevents tamoxifen-induced oxidative  stress and biochemical perturbations in mice. Toxicology 2006;  225: 109-118.

[220] Parvez S, Tabassum H, Banerjee BD, Raisuddin S. Taurine  prevents tamoxifen-induced mitochondrial oxidative damage in  mice. Basic Clin Pharmacol Toxicol 2008; 102: 382-387.

[221] Leone A, Nie A, Brandon Parker J, Sawant S, Piechta LA,  Kelley MF, Mark Kao L, Jim Proctor S, Verheyen G, Johnson  MD, Lord PG, McMillian MK. Oxidative stress/reactive metabolite gene expression signature in rat liver detects idiosyncratic hepatotoxicants. Toxicol Appl Pharmacol 2014; 275:  189-197.

[222] Kakimoto PA, Kowaltowski AJ. Effects of high fat diets on  rodent liver bioenergetics and oxidative imbalance. Redox Biol  2016; 8: 216-225.

[223] Farrell GC. Drug-induced hepatic injury. J Gastroenterol  Hepatol 1997; 12: S242-S250.

[224] Fréneaux E, Labbe G, Letteron P, The Le Dinh, Degott C,  Genève J, Larrey D, Pessayre D. Inhibition of the mitochondrial  oxidation of fatty acids by tetracycline in mice and in man:  possible role in microvesicular steatosis induced by this antibiotic. Hepatology 1988; 8: 1056-1062.

[225] Amacher DE, Martin BA. Tetracycline-induced steatosis in  primary canine hepatocyte cultures. Fundam Appl Toxicol1997; 40: 256-263.

[226] Yu HY, Wang BL, Zhao J, Yao XM, Gu Y, Li Y. Protective  effect of bicyclol on tetracycline-induced fatty liver in mice.  Toxicology 2009; 261: 112-118.

[227] Deng Z, Yan S, Hu H, Duan Z, Yin L, Liao S, Sun Y, Yin D, Li  G. Proteomic profile of carbonylated proteins in rat liver: discovering possible mechanisms for tetracycline-induced steatosis. Proteomics 2015; 15: 148-59.

[228] Zhang L, Ging NC, Komoda T, Hanada T, Suzuki T, Watanabe  K. Antibiotic susceptibility of mammalian mitochondrial translation. FEBS Lett 2005; 579: 6423-6427.

[229] McKee EE, Ferguson M, Bentley AT, Marks TA. Inhibition of  mammalian mitochondrial protein synthesis by oxazolidinones.  Antimicrob Agents Chemother 2006; 50: 2042-2049.

[230] Moullan N, Mouchiroud L, Wang X, Ryu D, Williams EG,  Mottis A, Jovaisaite V, Frochaux MV, Quiros PM, Deplancke  B, Houtkooper RH, Auwerx J. Tetracyclines disturb mitochondrial function across eukaryotic models: a call for caution  in biomedical research. Cell Rep 2017; in press.

[231] Ito M, Suzuki J, Sasaki M, Watanabe K, Tsujioka S, Takahashi  Y, Gomori A, Hirose H, Ishihara A, Iwaasa H, Kanatani A.  Development of nonalcoholic steatohepatitis model through  combination of high-fat diet and tetracycline with morbid obesity in mice. Hepatol Res 2006; 34: 92-98.

[232] Labbe G, Fromenty B, Freneaux E, Morzelle V, Letteron P,  Berson A, Pessayre D. Effects of various tetracycline derivatives on in vitro and in vivo beta-oxidation of fatty acids, egress  of triglycerides from the liver, accumulation of hepatic triglycerides, and mortality in mice. Biochem Pharmacol 1991;  41: 638-641

[233] Cuenca-Lopez MD, Karachitos A, Massarotto L, Oliveira PJ,  Aguirre N, Galindo MF, Kmita H, Jordán J. Minocycline exerts  uncoupling and inhibiting effects on mitochondrial respiration  through adenine nucleotide translocase inhibition. Pharmacol  Res 2012; 65: 120-128.

[234] Lettéron P, Sutton A, Mansouri A, Fromenty B, Pessayre D.  Inhibition of microsomal triglyceride transfer protein: another  mechanism for drug-induced steatosis in mice. Hepatology  2003; 38: 133-140.

[235] Anthérieu S, Rogue A, Fromenty B, Guillouzo A, Robin MA.  Induction of vesicular steatosis by amiodarone and tetracycline  is associated with up-regulation of lipogenic genes in HepaRG  cells. Hepatology 2011; 53: 1895-1905.

[236] Schoepfer AM, Engel A, Fattinger K, Marbet UA, Criblez D,  Reichen J, Zimmermann A, Oneta CM. Herbal does not mean  innocuous: ten cases of severe hepatotoxicity associated with  dietary supplements from Herbalife products. J Hepatol 2007;  47: 521-526.

[237] Chalasani N, Fontana RJ, Bonkovsky HL, Watkins PB, Davern  T, Serrano J, Yang H, Rochon J. Causes, clinical features, and  outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology 2008; 135:  1924-1934.

[238] Seeff LB, Bonkovsky HL, Navarro VJ, Wang G. Herbal prod-ucts and the liver: a review of adverse effects and mechanisms.  Gastroenterology 2015; 148: 517-532.

[239] Sorrentino P, Tarantino G, Conca P, Perrella A, Terracciano  ML, Vecchione R, Gargiulo G, Gennarelli N, Lobello R. Silent  non-alcoholic fatty liver disease-a clinical-histological study. J  Hepatol 2004; 41: 751-757.

[240] Marchesini G, Moscatiello S, Di Domizio S, Forlani G. Obesity-associated liver disease. J Clin Endocrinol Metab 2008; 93:  S74-S80.

[241] Palekar NA, Naus R, Larson SP, Ward J, Harrison SA. Clinical  model for distinguishing nonalcoholic steatohepatitis from  simple steatosis in patients with nonalcoholic fatty liver disease. Liver Int 2006; 26: 151-156.

[242] Fierbinteanu-Braticevici C, Dina I, Petrisor A, Tribus L, Negreanu L, Carstoiu C. Noninvasive investigations for non alcoholic fatty liver disease and liver fibrosis. World J Gastroenterol 2010; 16: 4784-4791.

[243] Sgro C, Clinard F, Ouazir K, Chanay H, Allard C, Guilleminet  C, Lenoir C, Lemoine A, Hillon P. Incidence of drug-induced  hepatic injuries: a French population-based study. Hepatology  2002; 36: 451-455.

[244] Donato MT, Jiménez N, Serralta A, Mir J, Castell JV, GómezLechón MJ. Effects of steatosis on drug-metabolizing capability of primary human hepatocytes. Toxicol In Vitro 2007; 21:  271-276

[245] Tirosh O, Ilan E, Anavi S, Ramadori G, Madar Z. Nutritional  lipid-induced oxidative stress leads to mitochondrial dysfunction followed by necrotic death in FaO hepatocytes. Nutrition  2009; 25: 200-208.

[246] Janorkar AV, King KR, Megeed Z, Yarmush ML. Development  of an in vitro cell culture model of hepatic steatosis using  hepatocyte-derived reporter cells. Biotechnol Bioeng 2009;  102: 1466-1474.

[247] Luo Y, Rana P, Will Y. Palmitate increases the susceptibility of  cells to drug-induced toxicity: an in vitro method to identify  drugs with potential contraindications in patients with metabolic disease. Toxicol Sci 2012; 129: 346-362.

[248] Kim MS, Lee KT, Iseli TJ, Hoy AJ, George J, Grewal T,  Roufogalis BD. Compound K modulates fatty acid-induced lipid droplet formation and expression of proteins involved in  lipid metabolism in hepatocytes. Liver Int 2013; 33:  1583-1593.

[249] Chang JJ, Hsu MJ, Huang HP, Chung DJ, Chang YC, Wang CJ.Mulberry anthocyanins inhibit oleic acid induced lipid accumulation by reduction of lipogenesis and promotion of hepatic  lipid clearance. J Agric Food Chem 2013; 61: 6069-6076.

[250] Park MJ, Kim DI, Choi JH, Heo YR, Park SH. New role of  irisin in hepatocytes: The protective effect of hepatic steatosis  in vitro. Cell Signal 2015; 27: 1831-1839.

[251] Garcia-Ruiz I, Solís-Muñoz P, Fernández-Moreira D,  Muñoz-Yagüe T, Solís-Herruzo JA. In vitro treatment of  HepG2 cells with saturated fatty acids reproduces mitochondrial dysfunction found in nonalcoholic steatohepatitis. Dis  Model Mech 2015; 8: 183-191.

[252] Siculella L, Tocci R, Rochira A, Testini M, Gnoni A, Damiano  F. Lipid accumulation stimulates the cap-independent translation of SREBP-1a mRNA by promoting hnRNP A1 binding to  its 5'-UTR in a cellular model of hepatic steatosis. Biochim  Biophys Acta 2016; 1861: 471-481.

[253] Porceddu M, Buron N, Roussel C, Labbe G, Fromenty B,  Borgne-Sanchez A. Prediction of liver injury induced by  chemicals in human with a multiparametric assay on isolated  mouse liver mitochondria. Toxicol Sci 2012; 129: 332-345. 

[254] Finsterer J, Segall L. Drugs interfering with mitochondrial  disorders. Drug Chem Toxicol 2010; 33: 138-151

[255] Hynes J, Nadanaciva S, Swiss R, Carey C, Kirwan S, Will Y. A  high-throughput dual parameter assay for assessing drug- induced mitochondrial dysfunction provides additional predictivity over two established mitochondrial toxicity assays. Toxicol In Vitro 2013; 27: 560-569.

[256] Neuschwander-Tetri BA. Hepatic lipotoxicity and the pathogenesis of nonalcoholic steatohepatitis: the central role of  nontriglyceride fatty acid metabolites. Hepatology 2010; 52:  774-788.

[257] Duwaerts CC, Maher JJ. Mechanisms of liver injury in  non-alcoholic steatohepatitis. Curr Hepatol Rep 2014; 13:  119-129.

[258] Lavallard VJ, Gual P. Autophagy and non-alcoholic fatty liver  disease. Biomed Res Int 2014; 2014: 120179.

[259] Anstee QM, Day CP. The genetics of nonalcoholic fatty liver  disease: spotlight on PNPLA3 and TM6SF2. Semin Liver Dis  2015; 35: 270-290.

[260] Trépo E, Romeo S, Zucman-Rossi J, Nahon P. PNPLA3 gene  in liver diseases. J Hepatol 2016; 65: 399-412.

Share
Back to top
Journal of Clinical and Translational Research, Electronic ISSN: 2424-810X Print ISSN: 2382-6533, Published by AccScience Publishing