title: DNA adducts of the tobacco carcinogens 2-amino-9H-pyrido[2,3-b]indole and 4-aminobiphenyl are formed at environmental exposure levels and persist in human hepatocytes.
abstract: Aromatic amines and structurally related heterocyclic aromatic amines (HAAs) are produced during the combustion of tobacco or during the high-temperature cooking of meat. Exposure to some of these chemicals may contribute to the etiology of several common types of human cancers. 2-Amino-9H-pyrido[2,3-b]indole (AαC) is the most abundant HAA formed in mainstream tobacco smoke: it arises in amounts that are 25-100 times greater than the levels of the arylamine, 4-aminobiphenyl (4-ABP), a human carcinogen. 2-Amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) is a prevalent HAA formed in cooked meats. AαC and MeIQx are rodent carcinogens; however, their carcinogenic potency in humans is unknown. A preliminary assessment of the carcinogenic potential of these HAAs in humans was conducted by examining the capacity of primary human hepatocytes to form DNA adducts of AαC and MeIQx, in comparison to 4-ABP, followed by the kinetics of DNA adduct removal by cellular enzyme repair systems. The principal DNA adducts formed were N-(deoxyguanosin-8-yl) (dG-C8) adducts. Comparable levels of DNA adducts were formed with AαC and 4-ABP, whereas adduct formation was ∼5-fold lower for MeIQx. dG-C8-AαC and dG-C8-4-ABP were formed at comparable levels in a concentration-dependent manner in human hepatocytes treated with procarcinogens over a 10,000-fold concentration range (1 nM-10 μM). Pretreatment of hepatocytes with furafylline, a selective inhibitor of cytochrome P450 1A2, resulted in a strong diminution of DNA adducts signifying that P450 1A2 is a major P450 isoform involved in bioactivation of these procarcinogens. The kinetics of adduct removal varied for each hepatocyte donor. Approximately half of the DNA adducts were removed within 24 h of treatment; however, the remaining lesions persisted over 5 days. The high levels of AαC present in tobacco smoke and its propensity to form persistent DNA adducts in human hepatocytes suggest that AαC can contribute to DNA damage and the risk of hepatocellular cancer in smokers.
authors.affiliation: UMR Inserm 1085 IRSET, Rennes1 University , UMS 3480 Biosit, F-35043 Rennes, France.
authors.forename: Gwendoline
authors.initials: G
authors.lastname: Nauwelaërs
authors.forename: Medjda
authors.initials: M
authors.lastname: Bellamri
authors.forename: Valérie
authors.initials: V
authors.lastname: Fessard
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Turesky
authors.forename: Sophie
authors.initials: S
authors.lastname: Langouët
mesh_terms: D000611:Aminobiphenyl Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002243:Carbolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002273:Carcinogens / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002478:Cells, Cultured; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D018736:DNA Adducts / Q000138:chemical synthesis / Q000737:chemistry / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004781:Environmental Exposure / Q000009:adverse effects*; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D013329:Structure-Activity Relationship
chemical_list: D000611:Aminobiphenyl Compounds; D002243:Carbolines; D002273:Carcinogens; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D018736:DNA Adducts; C006757:4-biphenylamine; D019388:Cytochrome P-450 CYP1A2; C017822:2-amino-9H-pyrido(2,3-b)indole
references.citation: Int J Epidemiol. 2009 Dec;38(6):1497-511
references.pmid: 19720726
references.citation: Cancer Res. 1995 Dec 1;55(23):5574-9
references.pmid: 7585637
references.citation: Chem Res Toxicol. 2003 Sep;16(9):1162-73
references.pmid: 12971805
references.citation: Carcinogenesis. 2002 Jan;23(1):115-22
references.pmid: 11756232
references.citation: Carcinogenesis. 2007 Feb;28(2):342-9
references.pmid: 16926175
references.citation: Cancer Epidemiol Biomarkers Prev. 2007 Aug;16(8):1554-60
references.pmid: 17684128
references.citation: Cancer Epidemiol Biomarkers Prev. 2001 Jul;10(7):725-31
references.pmid: 11440957
references.citation: Mutat Res. 2002 Sep 30;506-507:187-95
references.pmid: 12351158
references.citation: Cancer Epidemiol Biomarkers Prev. 2007 Jul;16(7):1503-9
references.pmid: 17627018
references.citation: Cancer Res. 2010 Mar 15;70(6):2406-14
references.pmid: 20215514
references.citation: Mutat Res. 1999 Mar 8;424(1-2):237-47
references.pmid: 10064864
references.citation: J Natl Cancer Inst. 2004 Jan 21;96(2):99-106
references.pmid: 14734699
references.citation: Chem Res Toxicol. 2011 Jun 20;24(6):913-25
references.pmid: 21456541
references.citation: Environ Health Perspect. 1983 Mar;49:125-34
references.pmid: 6339219
references.citation: Am J Epidemiol. 1998 Feb 1;147(3):315-23
references.pmid: 9482507
references.citation: Chem Res Toxicol. 1991 Jul-Aug;4(4):391-407
references.pmid: 1912325
references.citation: Biochem Pharmacol. 1985 Sep 15;34(18):3337-45
references.pmid: 3929792
references.citation: Chem Res Toxicol. 2007 Feb;20(2):263-76
references.pmid: 17305409
references.citation: Chem Res Toxicol. 2009 Apr;22(4):726-33
references.pmid: 19243127
references.citation: Carcinogenesis. 1981;2(2):97-102
references.pmid: 6168407
references.citation: Anal Biochem. 1976 May 7;72:248-54
references.pmid: 942051
references.citation: Cancer Lett. 1997 Jan 1;111(1-2):105-9
references.pmid: 9022134
references.citation: Mutagenesis. 2011 Sep;26(5):605-18
references.pmid: 21642616
references.citation: IARC Monogr Eval Carcinog Risks Hum. 2012;100(Pt E):1-538
references.pmid: 23193840
references.citation: Chem Res Toxicol. 1998 Aug;11(8):925-36
references.pmid: 9705755
references.citation: Cancer Res. 1978 Jun;38(6):1479-96
references.pmid: 348302
references.citation: Mutat Res. 2002 Sep 30;506-507:205-14
references.pmid: 12351160
references.citation: Chem Res Toxicol. 1998 May;11(5):391-407
references.pmid: 9585469
references.citation: Cancer Epidemiol Biomarkers Prev. 2000 Jan;9(1):29-42
references.pmid: 10667461
references.citation: Carcinogenesis. 1996 Oct;17(10):2259-65
references.pmid: 8895498
references.citation: Proc Natl Acad Sci U S A. 1989 Oct;86(20):7696-700
references.pmid: 2813353
references.citation: J Cancer Res Clin Oncol. 1992;118(7):481-9
references.pmid: 1624539
references.citation: Cancer Epidemiol Biomarkers Prev. 2009 Jul;18(7):2098-106
references.pmid: 19549810
references.citation: Biochem Pharmacol. 2002 Feb 15;63(4):745-9
references.pmid: 11992643
references.citation: Cancer Res. 2008 Sep 1;68(17):6863-72
references.pmid: 18757397
references.citation: Chem Res Toxicol. 2010 Jul 19;23(7):1234-44
references.pmid: 20443584
references.citation: IARC Monogr Eval Carcinog Risks Hum. 2004;83:1-1438
references.pmid: 15285078
references.citation: Anal Chem. 2011 Feb 1;83(3):1093-101
references.pmid: 21194225
references.citation: Cancer Sci. 2004 Apr;95(4):290-9
references.pmid: 15072585
references.citation: Cancer Lett. 1980 Aug;10(2):141-9
references.pmid: 7006799
references.citation: Chem Res Toxicol. 2003 Oct;16(10):1251-63
references.pmid: 14565767
references.citation: Biochem J. 2007 Jun 1;404(2):207-15
references.pmid: 17335415
references.citation: Chem Res Toxicol. 2008 Jan;21(1):45-52
references.pmid: 18052109
references.citation: Crit Rev Toxicol. 2009;39(8):659-78
references.pmid: 19743944
references.citation: Chem Res Toxicol. 1992 Jul-Aug;5(4):479-90
references.pmid: 1391614
references.citation: Nutr Cancer. 2009;61(4):437-46
references.pmid: 19838915
references.citation: Nicotine Tob Res. 2011 Feb;13(2):120-6
references.pmid: 21173043
references.citation: Environ Health Perspect. 1993 Mar;99:273-5
references.pmid: 8319642
references.citation: Arch Biochem Biophys. 2001 May 1;389(1):130-4
references.pmid: 11370663
references.citation: J Biol Chem. 2006 Sep 1;281(35):25297-306
references.pmid: 16835218
references.citation: Chem Res Toxicol. 1992 Nov-Dec;5(6):749-55
references.pmid: 1489923
references.citation: Biochemistry. 2007 Jul 24;46(29):8498-516
references.pmid: 17602664
references.citation: Nucleic Acids Res. 2011 Nov 1;39(20):8752-64
references.pmid: 21764772
references.citation: J Biol Chem. 2012 Apr 27;287(18):14960-72
references.pmid: 22393056
references.citation: Mutat Res. 2009 Dec 1;671(1-2):13-9
references.pmid: 19682468
references.citation: Carcinogenesis. 1999 Apr;20(4):545-51
references.pmid: 10223180
references.citation: Chem Res Toxicol. 2011 Aug 15;24(8):1169-214
references.pmid: 21688801
references.citation: Chem Res Toxicol. 1993 Sep-Oct;6(5):649-56
references.pmid: 8292742
references.citation: Proc Natl Acad Sci U S A. 1991 Jun 15;88(12):5350-4
references.pmid: 2052611
references.citation: Cancer Epidemiol Biomarkers Prev. 2004 Jun;13(6):1071-8
references.pmid: 15184267
references.citation: Nucleic Acids Res. 2012 Oct;40(19):9675-90
references.pmid: 22904073
references.citation: Food Chem Toxicol. 1997 Jun;35(6):555-65
references.pmid: 9225013
references.citation: Proc Natl Acad Sci U S A. 2001 Jul 17;98(15):8507-12
references.pmid: 11438709
references.citation: Carcinogenesis. 2000 Jul;21(7):1347-54
references.pmid: 10874013
references.citation: Drug Metab Dispos. 1996 Apr;24(4):395-400
references.pmid: 8801053
references.citation: Carcinogenesis. 1999 Sep;20(9):1825-30
references.pmid: 10469630
references.citation: J Pharmacol Exp Ther. 1991 Mar;256(3):1189-94
references.pmid: 2005581
references.citation: Cancer Epidemiol Biomarkers Prev. 2007 Jul;16(7):1341-7
references.pmid: 17626999
references.citation: J Chromatogr B Analyt Technol Biomed Life Sci. 2004 Mar 25;802(1):167-73
references.pmid: 15036008
references.citation: Cancer Res. 2006 Nov 1;66(21):10541-7
references.pmid: 17079477
references.citation: Mutat Res. 1997 May 12;376(1-2):235-41
references.pmid: 9202760
references.citation: Carcinogenesis. 2012 Nov;33(11):2108-18
references.pmid: 22822096
references.citation: Environ Pollut. 1991;70(3):255-65
references.pmid: 15092136
references.citation: Chem Rev. 2006 Feb;106(2):253-76
references.pmid: 16464005
references.citation: Biochem Biophys Res Commun. 1978 Aug 14;83(3):915-20
references.pmid: 361041
references.citation: Drug Metab Dispos. 1993 Jan-Feb;21(1):43-9
references.pmid: 8095225
references.citation: Chem Res Toxicol. 1997 Oct;10(10):1192-7
references.pmid: 9348443
references.citation: Chem Res Toxicol. 2001 Feb;14(2):211-21
references.pmid: 11258970
references.citation: J Hepatol. 1997;26 Suppl 2:73-80
references.pmid: 9204412