title: Nitric oxide and redox regulation in the liver: Part I. General considerations and redox biology in hepatitis.
abstract: Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are created in normal hepatocytes and are critical for normal physiologic processes, including oxidative respiration, growth, regeneration, apoptosis, and microsomal defense. When the levels of oxidation products exceed the capacity of normal antioxidant systems, oxidative stress occurs. This type of stress, in the form of ROS and RNS, can be damaging to all liver cells, including hepatocytes, Kupffer cells, stellate cells, and endothelial cells, through induction of inflammation, ischemia, fibrosis, necrosis, apoptosis, or through malignant transformation by damaging lipids, proteins, and/or DNA. In Part I of this review, we will discuss basic redox biology in the liver, including a review of ROS, RNS, and antioxidants, with a focus on nitric oxide as a common source of RNS. We will then review the evidence for oxidative stress as a mechanism of liver injury in hepatitis (alcoholic, viral, nonalcoholic). In Part II of this review, we will review oxidative stress in common pathophysiologic conditions, including ischemia/reperfusion injury, fibrosis, hepatocellular carcinoma, iron overload, Wilson's disease, sepsis, and acetaminophen overdose. Finally, biomarkers, proteomic, and antioxidant therapies will be discussed as areas for future therapeutic interventions.
authors.affiliation: Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Diana L
authors.initials: DL
authors.lastname: Diesen
authors.forename: Paul C
authors.initials: PC
authors.lastname: Kuo
mesh_terms: D000818:Animals; D006505:Hepatitis / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D026361:Reactive Nitrogen Species / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D009569:Nitric Oxide
references.citation: Eur J Biochem. 1995 Aug 15;232(1):188-91
references.pmid: 7556149
references.citation: Cancer Res. 2000 Oct 15;60(20):5862-9
references.pmid: 11059784
references.citation: Arch Biochem Biophys. 1993 Jan;300(1):115-23
references.pmid: 8424643
references.citation: Hepatology. 1997 Jul;26(1):135-42
references.pmid: 9214462
references.citation: J Nutr Health Aging. 2003;7(2):103-9
references.pmid: 12679830
references.citation: J Neurochem. 1999 Apr;72(4):1482-8
references.pmid: 10098852
references.citation: J Hepatol. 2004 Jan;40(1):60-8
references.pmid: 14672615
references.citation: Science. 1968 Nov 22;162(3856):917-8
references.pmid: 4386718
references.citation: Proc Natl Acad Sci U S A. 2002 Aug 20;99(17):11127-32
references.pmid: 12177414
references.citation: Alcohol. 1993 Nov-Dec;10(6):459-64
references.pmid: 8123200
references.citation: Proc Natl Acad Sci U S A. 2001 Feb 27;98(5):2652-7
references.pmid: 11226294
references.citation: J Gastroenterol Hepatol. 1997 Apr;12(4):305-13
references.pmid: 9195371
references.citation: FEBS Lett. 2003 Jan 30;535(1-3):106-12
references.pmid: 12560087
references.citation: J Biol Chem. 1999 Jun 11;274(24):17325-33
references.pmid: 10358093
references.citation: N Engl J Med. 1982 Sep 2;307(10):597-601
references.pmid: 7202119
references.citation: Adv Pharmacol. 1995;34:215-34
references.pmid: 8562436
references.citation: Mayo Clin Proc. 1980 Jul;55(7):434-8
references.pmid: 7382552
references.citation: J Biol Chem. 2000 Apr 14;275(15):10954-61
references.pmid: 10753895
references.citation: J Biol Chem. 1997 Nov 7;272(45):28191-3
references.pmid: 9353266
references.citation: Clin Cancer Res. 2001 May;7(5):1325-32
references.pmid: 11350902
references.citation: J Biol Chem. 2001 Jun 22;276(25):23077-83
references.pmid: 11304537
references.citation: Gastroenterology. 1996 Oct;111(4):1058-70
references.pmid: 8831602
references.citation: J Biol Chem. 2001 Sep 28;276(39):36664-72
references.pmid: 11477087
references.citation: Gut. 1994 Nov;35(11):1637-43
references.pmid: 7828989
references.citation: Gastroenterology. 2003 Mar;124(3):778-90
references.pmid: 12612915
references.citation: Gastroenterology. 1994 Apr;106(4):1085-105
references.pmid: 8143977
references.citation: J Immunol. 1995 Sep 15;155(6):2858-65
references.pmid: 7673702
references.citation: Free Radic Biol Med. 1997;22(1-2):287-305
references.pmid: 8958154
references.citation: J Clin Gastroenterol. 2005 Apr;39(4 Suppl 2):S162-6
references.pmid: 15758653
references.citation: Proc Natl Acad Sci U S A. 2001 Aug 14;98(17):9599-604
references.pmid: 11481452
references.citation: Ann Clin Biochem. 1986 Sep;23 ( Pt 5):514-20
references.pmid: 3767286
references.citation: Hepatology. 1997 May;25(5):1294-6
references.pmid: 9141458
references.citation: J Biol Chem. 2001 Aug 10;276(32):30085-91
references.pmid: 11404354
references.citation: Free Radic Biol Med. 1989;6(1):53-60
references.pmid: 2536343
references.citation: Hepatology. 1995 Mar;21(3):776-86
references.pmid: 7533126
references.citation: J Hepatol. 1998 Sep;29(3):495-501
references.pmid: 9765002
references.citation: Liver. 1994 Jun;14(3):138-40
references.pmid: 8078393
references.citation: J Pediatr. 2000 Jun;136(6):727-33
references.pmid: 10839867
references.citation: Mol Cell Biochem. 2002 May-Jun;234-235(1-2):39-48
references.pmid: 12162458
references.citation: Hepatology. 1992 Aug;16(2):448-53
references.pmid: 1639354
references.citation: Biochemistry (Mosc). 1998 Jul;63(7):766-81
references.pmid: 9721329
references.citation: Am J Physiol. 1999 May;276(5):G1069-73
references.pmid: 10329995
references.citation: Proc Natl Acad Sci U S A. 1991 Jan 15;88(2):365-9
references.pmid: 1703296
references.citation: Hepatology. 2003 Nov;38(5):1178-87
references.pmid: 14578856
references.citation: J Clin Invest. 2000 Oct;106(7):867-72
references.pmid: 11018074
references.citation: Liver Transpl. 2005 Sep;11(9):1031-47
references.pmid: 16123965
references.citation: Gut. 2000 Feb;46(2):255-9
references.pmid: 10644322
references.citation: Alcohol Clin Exp Res. 1989 Feb;13(1):15-9
references.pmid: 2646971
references.citation: Antioxid Redox Signal. 2004 Feb;6(1):19-24
references.pmid: 14713333
references.citation: J Pharmacol Exp Ther. 1991 Sep;258(3):1072-6
references.pmid: 1890612
references.citation: J Biol Chem. 2000 Jun 9;275(23):17237-40
references.pmid: 10770918
references.citation: Gastroenterology. 2003 Mar;124(3):708-24
references.pmid: 12612910
references.citation: Arch Biochem Biophys. 1993 Jul;304(1):209-18
references.pmid: 8323286
references.citation: Proc Natl Acad Sci U S A. 1998 Nov 10;95(23):13829-34
references.pmid: 9811886
references.citation: Free Radic Biol Med. 2002 Aug 1;33(3):350-5
references.pmid: 12126756
references.citation: Curr Gastroenterol Rep. 2005 Aug;7(4):308-16
references.pmid: 16042916
references.citation: Gut. 1990 Nov;31(11):1311-7
references.pmid: 2253918
references.citation: J Pathol. 1993 Sep;171(1):73-6
references.pmid: 8229461
references.citation: J Biol Chem. 1994 Mar 4;269(9):6765-72
references.pmid: 7509810
references.citation: J Biol Chem. 1996 Dec 27;271(52):33404-8
references.pmid: 8969202
references.citation: Mol Pharmacol. 1990 Jul;38(1):26-30
references.pmid: 2370854
references.citation: Nat Clin Pract Endocrinol Metab. 2007 Jun;3(6):458-69
references.pmid: 17515890
references.citation: Hepatology. 1994 Jan;19(1):217-28
references.pmid: 8276358
references.citation: J Viral Hepat. 2002 Nov;9(6):419-23
references.pmid: 12431203
references.citation: Proc Natl Acad Sci U S A. 1994 Apr 26;91(9):3559-63
references.pmid: 8170947
references.citation: Clin Biochem. 2007 Jul;40(11):776-80
references.pmid: 17477913
references.citation: Cancer Res. 2001 Jun 1;61(11):4365-70
references.pmid: 11389061
references.citation: Chem Res Toxicol. 1996 Jan-Feb;9(1):8-11
references.pmid: 8924620
references.citation: Hepatology. 2004 Jul;40(1):185-94
references.pmid: 15239102
references.citation: J Biomed Sci. 2001 Jan-Feb;8(1):59-70
references.pmid: 11173977
references.citation: Arch Biochem Biophys. 1990 Jul;280(1):1-8
references.pmid: 2191627
references.citation: Ann Hepatol. 2004 Jul-Sep;3(3):86-92
references.pmid: 15505592
references.citation: J Leukoc Biol. 1994 Dec;56(6):751-8
references.pmid: 7527831
references.citation: Hepatology. 1995 Jun;21(6):1610-7
references.pmid: 7768506
references.citation: Biochem Biophys Res Commun. 1997 Nov 17;240(2):419-24
references.pmid: 9388494
references.citation: J Biol Chem. 2002 Aug 9;277(32):28411-7
references.pmid: 12032149
references.citation: Biochem J. 1997 Sep 15;326 ( Pt 3):791-7
references.pmid: 9307029
references.citation: Free Radic Biol Med. 1994 Feb;16(2):229-39
references.pmid: 8005519
references.citation: Br J Cancer. 1993 Mar;67(3):531-6
references.pmid: 8439503
references.citation: Dig Dis Sci. 1985 Sep;30(9):838-44
references.pmid: 4028913
references.citation: Proc Natl Acad Sci U S A. 1993 Dec 1;90(23):11147-51
references.pmid: 7504296
references.citation: Hepatology. 2001 Dec;34(6):1158-63
references.pmid: 11732005
references.citation: Anal Biochem. 1997 Jun 15;249(1):1-9
references.pmid: 9193701
references.citation: Hepatology. 1989 Mar;9(3):349-51
references.pmid: 2920991
references.citation: Alcohol. 2002 Jul;27(3):173-7
references.pmid: 12163146
references.citation: Dig Dis Sci. 2001 May;46(5):1072-6
references.pmid: 11341651
references.citation: Shock. 2000 Jun;13(6):413-24
references.pmid: 10847627
references.citation: J Biol Chem. 2002 Sep 13;277(37):34223-8
references.pmid: 12091382
references.citation: Alcohol. 1987 Mar-Apr;4(2):81-5
references.pmid: 3580137
references.citation: J Exp Med. 1989 Nov 1;170(5):1769-74
references.pmid: 2509627
references.citation: Alcohol Clin Exp Res. 1991 Aug;15(4):573-92
references.pmid: 1928631
references.citation: Adv Pharmacol. 1997;38:601-28
references.pmid: 8895826
references.citation: Hepatology. 2004 Jan;39(1):197-203
references.pmid: 14752838
references.citation: FASEB J. 1997 Feb;11(2):118-24
references.pmid: 9039953
references.citation: J Hepatol. 2000 Oct;33(4):616-22
references.pmid: 11059866
references.citation: Am J Physiol. 1992 Oct;263(4 Pt 1):G579-85
references.pmid: 1415718
references.citation: J Virol. 2004 Aug;78(16):8835-43
references.pmid: 15280491
references.citation: Nat Rev Mol Cell Biol. 2005 Feb;6(2):150-66
references.pmid: 15688001
references.citation: J Hepatol. 2000 Feb;32(2):331-8
references.pmid: 10707875
references.citation: Hepatology. 2003 Nov;38(5):1188-98
references.pmid: 14578857
references.citation: Science. 1996 Nov 22;274(5291):1379-83
references.pmid: 8910279
references.citation: Gastroenterology. 1998 Dec;115(6):1541-51
references.pmid: 9834283
references.citation: Ann Surg. 1990 Oct;212(4):462-9; discussion 470-1
references.pmid: 2121110
references.citation: Biochem Pharmacol. 2005 Feb 15;69(4):569-77
references.pmid: 15670576
references.citation: Gastroenterology. 2003 Dec;125(6):1834-44
references.pmid: 14724835
references.citation: Transplant Proc. 2002 Nov;34(7):2659-61
references.pmid: 12431565
references.citation: Biofactors. 1998;8(1-2):93-6
references.pmid: 9699015
references.citation: Alcohol Clin Exp Res. 1996 Sep;20(6):1065-70
references.pmid: 8892528
references.citation: Free Radic Biol Med. 2003 Jan 1;34(1):1-10
references.pmid: 12498974
references.citation: Chem Biol Interact. 1988;65(3):223-34
references.pmid: 2837334
references.citation: Hepatology. 1999 Dec;30(6):1473-80
references.pmid: 10573527
references.citation: Bioessays. 1990 Sep;12(9):429-35
references.pmid: 2256907
references.citation: Science. 1999 Apr 23;284(5414):651-4
references.pmid: 10213689
references.citation: Proc Natl Acad Sci U S A. 1993 Jan 15;90(2):522-6
references.pmid: 7678458
references.citation: Proc Natl Acad Sci U S A. 1997 Feb 18;94(4):1441-6
references.pmid: 9037072
references.citation: Toxicol Lett. 1992 Dec;63(3):231-41
references.pmid: 1488774
references.citation: Proc Natl Acad Sci U S A. 2001 May 8;98(10):5560-5
references.pmid: 11320206
references.citation: J Clin Invest. 1997 Feb 1;99(3):403-13
references.pmid: 9022073
references.citation: J Hepatol. 2001 Apr;34(4):587-92
references.pmid: 11394660
references.citation: Acta Paediatr Scand Suppl. 1989;361:78-85
references.pmid: 2485589
references.citation: Hepatology. 2003 Aug;38(2):428-35
references.pmid: 12883487
references.citation: J Hepatol. 2000 May;32(5):798-804
references.pmid: 10845667
references.citation: Hepatology. 1996 Jan;23(1):155-63
references.pmid: 8550035
references.citation: Hepatology. 2002 Jul;36(1):122-34
references.pmid: 12085356
references.citation: Hepatology. 2006 Mar;43(3):506-14
references.pmid: 16496325
references.citation: J Med Virol. 2005 Aug;76(4):489-97
references.pmid: 15977232
references.citation: J Hepatol. 2003 Jan;38(1):32-8
references.pmid: 12480557
references.citation: J Gastroenterol Hepatol. 2000 Jul;15(7):718-24
references.pmid: 10937675
references.citation: Genes Cells. 1998 May;3(5):321-30
references.pmid: 9685183
references.citation: J Clin Invest. 1998 Apr 1;101(7):1343-52
references.pmid: 9525976
references.citation: Biochem Biophys Res Commun. 1994 Oct 14;204(1):169-75
references.pmid: 7945356
references.citation: Hepatology. 2004 Jan;39(1):81-9
references.pmid: 14752826
references.citation: J Hepatol. 1996 Oct;25(4):538-46
references.pmid: 8912154
references.citation: Hepatology. 1994 Oct;20(4 Pt 1):961-5
references.pmid: 7927238
references.citation: J Biol Chem. 2000 Jan 7;275(1):705-12
references.pmid: 10617670
references.citation: Biochem Biophys Res Commun. 1993 Aug 16;194(3):1044-50
references.pmid: 8352762
references.citation: J Biol Chem. 1997 Dec 5;272(49):31138-48
references.pmid: 9388267
references.citation: Gut. 2005 Jul;54(7):987-93
references.pmid: 15951547
references.citation: J Hepatol. 1988 Apr;6(2):137-43
references.pmid: 3411096
references.citation: J Biol Chem. 2005 Nov 11;280(45):37481-8
references.pmid: 16150732
references.citation: FASEB J. 1997 Sep;11(11):851-7
references.pmid: 9285483
references.citation: Cell. 1994 Sep 23;78(6):931-6
references.pmid: 7923362
references.citation: Annu Rev Pharmacol Toxicol. 2004;44:239-67
references.pmid: 14744246
references.citation: FASEB J. 1992 Jan 6;6(2):724-30
references.pmid: 1537462
references.citation: Biochem Pharmacol. 1989 Apr 15;38(8):1313-9
references.pmid: 2495801
references.citation: Hepatology. 1995 Jul;22(1):223-34
references.pmid: 7541386
references.citation: J Exp Med. 1989 Apr 1;169(4):1467-72
references.pmid: 2926330
references.citation: Life Sci. 1989;45(2):183-7
references.pmid: 2747425
references.citation: J Hepatol. 2001 Nov;35(5):613-8
references.pmid: 11690707
references.citation: Trends Microbiol. 2005 Apr;13(4):159-63
references.pmid: 15817385
references.citation: Gastroenterology. 2002 Feb;122(2):366-75
references.pmid: 11832451
references.citation: Metab Brain Dis. 2002 Dec;17(4):325-34
references.pmid: 12602509
references.citation: Gastroenterology. 2003 Aug;125(2):437-43
references.pmid: 12891546
references.citation: Hepatology. 2000 Oct;32(4 Pt 1):770-8
references.pmid: 11003621
references.citation: Am J Physiol Gastrointest Liver Physiol. 2006 May;290(5):G847-51
references.pmid: 16603728
references.citation: Alcohol. 2002 Jul;27(3):155-62
references.pmid: 12163143
references.citation: Redox Rep. 2003;8(3):135-41
references.pmid: 12935310
references.citation: Toxicol Sci. 2001 Aug;62(2):212-20
references.pmid: 11452133
references.citation: J Leukoc Biol. 2004 Dec;76(6):1180-6
references.pmid: 15371490
references.citation: Free Radic Biol Med. 1999 Dec;27(11-12):1284-91
references.pmid: 10641722
references.citation: J Clin Invest. 2004 Dec;114(12):1752-61
references.pmid: 15599400
references.citation: J Biochem Mol Toxicol. 2001;15(6):317-21
references.pmid: 11835631
references.citation: Gastroenterology. 1994 Nov;107(5):1430-5
references.pmid: 7926507
references.citation: Free Radic Res Commun. 1989;7(3-6):189-94
references.pmid: 2555274
references.citation: J Biol Chem. 1997 Jan 10;272(2):1402-11
references.pmid: 8995451
references.citation: Hepatology. 2003 Nov;38(5):1136-45
references.pmid: 14578852
references.citation: Surgery. 1998 Aug;124(2):278-83
references.pmid: 9706149