title: Drug metabolism alterations in nonalcoholic fatty liver disease.
abstract: Drug-metabolizing enzymes play a vital role in the elimination of the majority of therapeutic drugs. The major organ involved in drug metabolism is the liver. Chronic liver diseases have been identified as a potential source of significant interindividual variation in metabolism. Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the United States, affecting between 60 and 90 million Americans, yet the vast majority of NAFLD patients are undiagnosed. NAFLD encompasses a spectrum of pathologies, ranging from steatosis to nonalcoholic steatohepatitis and fibrosis. Numerous animal studies have investigated the effects of NAFLD on hepatic gene expression, observing significant alterations in mRNA, protein, and activity levels. Information on the effects of NAFLD in human patients is limited, though several significant investigations have recently been published. Significant alterations in the activity of drug-metabolizing enzymes may affect the clearance of therapeutic drugs, with the potential to result in adverse drug reactions. With the enormous prevalence of NAFLD, it is conceivable that every drug currently on the market is being given to patients with NAFLD. The current review is intended to present the results from both animal models and human patients, summarizing the observed alterations in the expression and activity of the phase I and II drug-metabolizing enzymes.
authors: Department of Pharmacology and Toxicology, University of Arizona, Tucson, USA.
authors: Matthew D
authors: MD
authors: Merrell
authors: Nathan J
authors: NJ
authors: Cherrington
references: Int J Mol Med. 2005 Oct;16(4):631-5
references: 16142397
references: N Engl J Med. 2001 Feb 15;344(7):495-500
references: 11172192
references: Gene. 2004 Sep 29;340(1):99-109
references: 15556298
references: J Hepatol. 2007 Apr;46(4):708-18
references: 17275126
references: J Nutr Biochem. 2011 Jan;22(1):38-45
references: 20303728
references: Am J Clin Nutr. 1997 Dec;66(6):1323-31
references: 9394682
references: Annu Rev Pathol. 2010;5:145-71
references: 20078219
references: Drug Metab Dispos. 1999 Jun;27(6):695-700
references: 10348799
references: Free Radic Biol Med. 2010 Jan 15;48(2):357-71
references: 19914374
references: Am J Gastroenterol. 1983 Jun;78(6):374-7
references: 6859017
references: Drug Metab Dispos. 2011 Apr;39(4):571-9
references: 21245286
references: Hepatology. 2005 Sep;42(3):665-74
references: 16116632
references: JAMA. 2010 Jan 20;303(3):235-41
references: 20071471
references: J Med Assoc Thai. 2008 May;91(5):733-8
references: 18672640
references: Annu Rev Pharmacol Toxicol. 2005;45:51-88
references: 15822171
references: AAPS J. 2006 Mar 10;8(1):E101-11
references: 16584116
references: Hepatol Res. 2007 Jun;37(6):410-5
references: 17539815
references: Drug Metab Dispos. 2006 Sep;34(9):1556-62
references: 16763015
references: Drug Metab Dispos. 2010 Dec;38(12):2293-301
references: 20805291
references: Pharmacogenet Genomics. 2008 Apr;18(4):325-37
references: 18334917
references: Contraception. 2010 Oct;82(4):314-23
references: 20851224
references: Mayo Clin Proc. 1980 Jul;55(7):434-8
references: 7382552
references: Liver Int. 2006 Feb;26(1):32-8
references: 16420508
references: Semin Liver Dis. 2008 Nov;28(4):339-50
references: 18956290
references: MedGenMed. 2003 Apr 16;5(2):14
references: 14603113
references: Proc Natl Acad Sci U S A. 2009 Nov 3;106(44):18831-6
references: 19850873
references: J Proteomics. 2010 Jun 16;73(8):1612-31
references: 20399915
references: Hepatology. 1998 Jan;27(1):128-33
references: 9425928
references: J Hepatol. 2007 Jun;46(6):1133-42
references: 17445934
references: Chem Res Toxicol. 2010 May 17;23(5):977-85
references: 20402460
references: J Hepatol. 2006 Oct;45(4):600-6
references: 16899321
references: Int J Mol Med. 2007 Sep;20(3):351-8
references: 17671740
references: Mol Cell Biol. 2004 Sep;24(18):7931-40
references: 15340055
references: Semin Liver Dis. 2008 Nov;28(4):386-95
references: 18956295
references: Biol Pharm Bull. 2006 Aug;29(8):1634-8
references: 16880618
references: JAMA. 2002 Oct 9;288(14):1723-7
references: 12365955
references: Int J Mol Med. 2010 Jun;25(6):837-44
references: 20428786
references: Mol Pharmacol. 2006 Dec;70(6):1925-34
references: 16988011
references: Int J Obes Relat Metab Disord. 1998 Jan;22(1):39-47
references: 9481598
references: Mol Pharm. 2008 Jan-Feb;5(1):77-91
references: 18189363
references: Drug Metab Dispos. 2004 Sep;32(9):909-14
references: 15319330
references: Liver Int. 2005 Aug;25(4):760-71
references: 15998427
references: Gut. 2007 Apr;56(4):565-74
references: 16950832
references: J Hepatol. 1998 Mar;28(3):410-6
references: 9551678
references: Int J Exp Pathol. 2006 Feb;87(1):1-16
references: 16436109
references: Drug Metab Rev. 2006;38(4):769-89
references: 17145701
references: Clin Sci (Lond). 2008 Sep;115(5):141-50
references: 18662168
references: Curr Drug Metab. 2009 Jun;10(5):508-19
references: 19689247
references: Hepatology. 2008 Sep;48(3):792-8
references: 18752331
references: Am J Med. 1979 Nov;67(5):811-6
references: 507094
references: Microcirculation. 2006 Jan;13(1):19-27
references: 16393943
references: J Clin Psychopharmacol. 2001 Oct;21(5):500-15
references: 11593076
references: Curr Drug Metab. 2008 May;9(4):310-22
references: 18473749
references: JAMA. 2002 Jan 16;287(3):356-9
references: 11790215
references: J Pharmacol Exp Ther. 1987 Jun;241(3):921-7
references: 3598908
references: Curr Drug Metab. 2009 Sep;10(7):754-80
references: 19702528
references: Toxicol In Vitro. 2007 Mar;21(2):271-6
references: 16950596
references: Hepatology. 2009 Oct;50(4):1282-93
references: 19637286
references: Drug Metab Rev. 2009;41(4):573-643
references: 19645588
references: Gastroenterology. 1998 Apr;114(4):842-5
references: 9547102
references: Eur J Gastroenterol Hepatol. 2006 Apr;18(4):411-2
references: 16538113
references: Hepatology. 2005 Sep;42(3):650-6
references: 16037946
references: Drug Metab Dispos. 2008 Feb;36(2):294-302
references: 17967931
references: Free Radic Biol Med. 2008 Mar 1;44(5):723-38
references: 18078827
references: J Clin Invest. 2000 Apr;105(8):1067-75
references: 10772651
references: Gastroenterology. 1996 Dec;111(6):1645-53
references: 8942745
references: Eur J Intern Med. 2008 Mar;19(2):75-82
references: 18249301
references: Clin Chim Acta. 2003 Jul 1;333(1):19-39
references: 12809732
references: World J Gastroenterol. 2009 Apr 21;15(15):1863-8
references: 19370784
references: Am J Physiol Gastrointest Liver Physiol. 2008 May;294(5):G1281-7
references: 18388185
references: Obes Surg. 2009 May;19(5):617-24
references: 19280268
references: Popul Health Metr. 2010 Oct 22;8:29
references: 20969750
references: J Ethnopharmacol. 2011 Jan 7;133(1):37-45
references: 20832461
references: J Biol Chem. 2010 Mar 19;285(12):9292-300
references: 20089859
references: J Clin Invest. 2004 Jul;114(2):147-52
references: 15254578
references: Toxicol Appl Pharmacol. 2010 Jun 15;245(3):326-34
references: 20350562
references: Drug Metab Dispos. 2007 Jan;35(1):1-8
references: 17020953
references: Hepatol Res. 2008 Dec;38(12):1204-12
references: 18637145
references: Curr Drug Metab. 2008 Sep;9(7):614-21
references: 18781913
references: Hepatology. 2006 Aug;44(2):458-65
references: 16871574
references: JAMA. 2003 Jun 11;289(22):3000-4
references: 12799409
references: Obes Surg. 2004 May;14(5):635-7
references: 15186630
references: Biochem J. 2009 Jan 1;417(1):183-93
references: 18752470
references: Endocr Res. 1987;13(2):101-21
references: 3622404
references: J Biol Chem. 2005 Feb 11;280(6):4367-73
references: 15572372
references: Semin Liver Dis. 2008 Nov;28(4):370-9
references: 18956293
references: Curr Drug Metab. 2009 Jul;10(6):567-78
references: 19702536
references: Carcinogenesis. 2008 May;29(5):1022-32
references: 18321868
references: Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2010 Jun;154(2):103-16
references: 20668491
references: PLoS One. 2010 Aug 16;5(8):e12147
references: 20808936
references: Curr Drug Metab. 2009 Sep;10(7):730-53
references: 19702527
references: Biochem Biophys Res Commun. 1999 Feb 16;255(2):300-6
references: 10049703
references: World J Gastroenterol. 2009 Jun 21;15(23):2817-33
references: 19533803
references: J Clin Invest. 1994 Dec;94(6):2209-14
references: 7989576
references: Biochem J. 2009 Jan 1;417(1):43-54
references: 18778245
references: Diabetes Metab Res Rev. 2002 Mar-Apr;18(2):149-55
references: 11994907
references: Clin Pharmacol Ther. 2009 Apr;85(4):434-8
references: 19212314
references: Drug Metab Dispos. 2010 Dec;38(12):2091-5
references: 20736325
references: J Pharmacol Exp Ther. 1993 Jun;265(3):1333-8
references: 8510012
references: Biochim Biophys Acta. 2009 Nov;1792(11):1080-6
references: 19733654
references: Arch Toxicol. 2008 Dec;82(12):959-64
references: 18488193
references: Curr Drug Metab. 2009 Sep;10(7):713-29
references: 19702529
references: Drug Metab Dispos. 2001 Mar;29(3):207-12
references: 11181485
references: Pediatrics. 2005 May;115(5):e561-5
references: 15867021
references: J Biochem Mol Toxicol. 2007;21(4):216-20
references: 17721935
references: Oncogene. 2006 Mar 13;25(11):1673-8
references: 16550167
references: Clin Gastroenterol Hepatol. 2008 Jul;6(7):799-802
references: 18486560
references: J Gastroenterol Hepatol. 2008 Nov;23(11):1635-48
references: 18752564
references: Toxicol Mech Methods. 2005;15(2):121-4
references: 20021072
references: Biochem Pharmacol. 2007 Jan 1;73(1):155-62
references: 17049493
references: Surg Obes Relat Dis. 2009 May-Jun;5(3):323-8
references: 19356994
references: Am J Clin Nutr. 2004 Mar;79(3):502-9
references: 14985228
references: World J Gastroenterol. 2006 Apr 7;12(13):2080-5
references: 16610061
references: Contemp Clin Trials. 2010 Jan;31(1):62-70
references: 19761871
references: Drug Metab Dispos. 2004 Nov;32(11):1201-8
references: 15304429
references: Pediatrics. 2006 Oct;118(4):1388-93
references: 17015527
references: Hepatology. 2003 Mar;37(3):544-50
references: 12601351
references: Leg Med (Tokyo). 2008 Jul;10(4):177-84
references: 18280196
references: Lancet. 2002 Oct 12;360(9340):1155-62
references: 12387968
references: Biopharm Drug Dispos. 2009 Oct;30(7):345-55
references: 19725016
references: Hepatol Res. 2006 Jan;34(1):57-63
references: 16321567
references: Mol Aspects Med. 2009 Feb-Apr;30(1-2):42-59
references: 18601945
references: Liver Int. 2007 Aug;27(6):764-71
references: 17617119
references: J Pediatr Gastroenterol Nutr. 2011 Feb;52(2):198-202
references: 21240014
references: Ann Surg. 2010 Jun;251(6):1041-8
references: 20485142
references: Toxicol Appl Pharmacol. 2008 Aug 1;230(3):327-37
references: 18501395
references: J Mol Endocrinol. 2005 Apr;34(2):299-315
references: 15821098
references: Obesity (Silver Spring). 2008 Oct;16(10):2323-30
references: 18719634
references: Hepatology. 2003 Jun;37(6):1286-92
references: 12774006
references: Life Sci. 1999;65(26):2851-9
references: 10622274
references: PLoS One. 2010 Mar 08;5(3):e9570
references: 20221393
references: Hepatology. 2003 May;37(5):1202-19
references: 12717402
references: Cell Biochem Biophys. 2007;48(2-3):73-8
references: 17709876
references: Hepatology. 2003 Aug;38(2):428-35
references: 12883487
references: Int J Obes Relat Metab Disord. 1999 Jan;23(1):48-53
references: 10094576
references: J Pediatr Gastroenterol Nutr. 2006 Oct;43(4):413-27
references: 17033514
references: Biochem J. 2007 Feb 1;401(3):735-41
references: 17032173
references: Hepatology. 2002 Dec;36(6):1349-54
references: 12447858
references: J Clin Gastroenterol. 2003 Apr;36(4):371
references: 12642751
references: Gastroenterology. 2002 Jul;123(1):134-40
references: 12105842
references: Aliment Pharmacol Ther. 2008 Sep 1;28(5):503-22
references: 18532991
references: J Biol Chem. 2009 Sep 18;284(38):25984-92
references: 19617349
references: Am J Gastroenterol. 2008 Jun;103(6):1372-9
references: 18510618
references: Br J Nutr. 1999 Oct;82(4):257-62
references: 10655974
references: Annu Rev Pharmacol Toxicol. 2006;46:123-49
references: 16402901
references: Aliment Pharmacol Ther. 2005 Nov 15;22(10):897-905
references: 16268963
references: Curr Drug Metab. 2009 Sep;10(7):692-9
references: 19702532
references: Trop Gastroenterol. 2004 Jul-Sep;25(3):130-4
references: 15682660
references: Drug Metab Rev. 2007;39(1):159-234
references: 17364884
references: Mol Pharmacol. 2008 Apr;73(4):1282-9
references: 18187584
references: J Clin Gastroenterol. 2006 Sep;40(8):745-52
references: 16940890
references: J Pharmacol Exp Ther. 2007 Aug;322(2):770-7
references: 17522342
references: Obes Surg. 2010 May;20(5):640-50
references: 20119733
references: Drug Metab Dispos. 2006 Oct;34(10):1677-87
references: 16815962
references: Endocr Rev. 2010 Dec;31(6):817-44
references: 20592272
references: Biochem Pharmacol. 1992 Apr 15;43(8):1868-71
references: 1575780
references: World J Gastroenterol. 1999 Aug;5(4):301-304
references: 11819452
references: Free Radic Biol Med. 2004 May 15;36(10):1199-207
references: 15110384
references: Drug Metab Dispos. 2009 Oct;37(10):2087-94
references: 19651758
references: Eur J Pharmacol. 2009 Oct 12;620(1-3):138-44
references: 19698707
references: Mol Carcinog. 2009 Feb;48(2):91-104
references: 18618599
references: Hepatology. 2005 Oct;42(4):905-14
references: 16175602
references: Biochem Pharmacol. 2010 Sep 15;80(6):771-7
references: 20457141
references: J Clin Invest. 2005 May;115(5):1343-51
references: 15864352
references: Hepatol Res. 2007 Jan;37(1):50-7
references: 17300698
references: Am J Physiol Gastrointest Liver Physiol. 2008 Jan;294(1):G27-38
references: 17947452
references: Aliment Pharmacol Ther. 2008 Mar 1;27(5):412-21
references: 18081738
references: Ann Hepatol. 2006 Jan-Mar;5(1):30-3
references: 16531962
references: Am J Physiol Gastrointest Liver Physiol. 2010 Feb;298(2):G283-94
references: 19926817
references: Mol Pharmacol. 2010 Oct;78(4):666-74
references: 20592274
references: Drug Metab Pharmacokinet. 2007 Aug;22(4):287-98
references: 17827783
references: J Clin Pharm Ther. 2000 Jun;25(3):165-75
references: 10886461
references: Clin Pharmacokinet. 2009;48(10):635-51
references: 19743886
references: J Hepatol. 2004 Nov;41(5):751-7
references: 15519647
references: Clin Sci (Lond). 2004 Mar;106(3):261-8
references: 14556645
references: Ann N Y Acad Sci. 2010 Sep;1205:240-4
references: 20840279
references: Rev Gastroenterol Mex. 2006 Oct-Dec;71(4):453-9
references: 17542278