title: Comparison of DNA adduct levels associated with oxidative stress in human pancreas.
abstract: DNA adducts associated with oxidative stress are believed to involve the formation of endogenous reactive species generated by oxidative damage and lipid peroxidation. Although these adducts have been reported in several human tissues by different laboratories, a comparison of the levels of these adducts in the same tissue samples has not been carried out. In this study, we isolated DNA from the pancreas of 15 smokers and 15 non-smokers, and measured the levels of 1,N6-etheno(2'-deoxy)guanosine (edA), 3, N4-etheno(2'-deoxy)cytidine (edC), 8-oxo-2'-deoxyguanosine (8-oxo-dG), and pyrimido[1,2-alpha]purin-10(3H)-one (m1G). Using the same DNA, the glutathione S-transferase (GST) M1, GSTT1, and NAD(P)H quinone reductase-1 (NQO1) genotypes were determined in order to assess the role of their gene products in modulating adduct levels through their involvement in detoxification of lipid peroxidation products and redox cycling, respectively. The highest adduct levels observed were for m1G, followed by 8-oxo-dG, edA, and edC, but there were no differences in adduct levels between smokers and non-smokers and no correlation with the age, sex or body mass index of the subject. Moreover, there was no correlation in adduct levels between edA and eC, or between edA or edC and m1G or 8-oxo-dG. However, there was a significant correlation (r=0.76; p<0.01) between the levels of 8-oxo-dG and m1G in human pancreas DNA. Neither GSTM1 nor NQO1 genotypes were associated with differences in any of the adduct levels. Although the sample set was limited, the data suggest that endogenous DNA adduct formation in human pancreas is not clearly derived from cigarette smoking or from (NQO1)-mediated redox cycling. Further, it appears that neither GSTM1 nor GSTT1 appreciably protects against endogenous adduct formation. Together with the lack of correlation between m1G and edA or edC, these data indicate that the malondialdehyde derived from lipid peroxidation may not contribute significantly to m1G adduct formation. On the other hand, the apparent correlation between m1G and 8-oxo-dG and their comparable high levels are consistent with the hypothesis that m1G is formed primarily by reaction of DNA with a base propenal, which, like 8-oxo-dG, is thought to be derived from hydroxyl radical attack on the DNA.
authors.affiliation: National Center for Toxicological Research (HFT-100), Jefferson, AR 72079, USA.
authors.forename: F F
authors.initials: FF
authors.lastname: Kadlubar
authors.forename: K E
authors.initials: KE
authors.lastname: Anderson
authors.forename: S
authors.initials: S
authors.lastname: Häussermann
authors.forename: N P
authors.initials: NP
authors.lastname: Lang
authors.forename: G W
authors.initials: GW
authors.lastname: Barone
authors.forename: P A
authors.initials: PA
authors.lastname: Thompson
authors.forename: S L
authors.initials: SL
authors.lastname: MacLeod
authors.forename: M W
authors.initials: MW
authors.lastname: Chou
authors.forename: M
authors.initials: M
authors.lastname: Mikhailova
authors.forename: J
authors.initials: J
authors.lastname: Plastaras
authors.forename: L J
authors.initials: LJ
authors.lastname: Marnett
authors.forename: J
authors.initials: J
authors.lastname: Nair
authors.forename: I
authors.initials: I
authors.lastname: Velic
authors.forename: H
authors.initials: H
authors.lastname: Bartsch
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000293:Adolescent; D000328:Adult; D002648:Child; D003562:Cytidine / Q000031:analogs & derivatives / Q000032:analysis; D018736:DNA Adducts / Q000032:analysis*; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000032:analysis; D005260:Female; D005982:Glutathione Transferase / Q000235:genetics; D006147:Guanine / Q000031:analogs & derivatives; D006801:Humans; D015227:Lipid Peroxidation; D008297:Male; D008875:Middle Aged; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics; D018384:Oxidative Stress; D010179:Pancreas / Q000737:chemistry* / Q000201:enzymology; D012150:Polymorphism, Restriction Fragment Length; D011687:Purines / Q000032:analysis; D011743:Pyrimidines / Q000032:analysis; D012907:Smoking
chemical_list: C012962:3,N(4)-ethenocytidine; D018736:DNA Adducts; D011687:Purines; D011743:Pyrimidines; C107643:pyrimido(1,2-a)purin-10(3H)-one; D003562:Cytidine; D006147:Guanine; D000080242:8-Hydroxy-2'-Deoxyguanosine; D016660:NAD(P)H Dehydrogenase (Quinone); C413545:glutathione S-transferase T1; D005982:Glutathione Transferase; D003849:Deoxyguanosine