COMPARISON OF DNA ADDUCT LEVELS ASSOCIATED WITH OXIDATIVE STRESS IN HUMAN PANCREAS

DNA adducts associated with oxidative stress are believed to involve t he formation of endogenous reactive species generated by oxidative dam age and lipid peroxidation. Although these adducts have been reported in several human tissues by different laboratories, a comparison of th e levels of these adducts in the same tissue samples has not been carr ied out. In this study, we isolated DNA from the pancreas of 15 smoker s and 15 non-smokers, and measured the levels of 1,N-6-etheno(2'-deoxy )guanosine (edA), 3,N-4-etheno(2'-deoxy)cytidine (edC), 8-oxo-2'-deoxy guanosine (8-oxo-dG), and pyrimido[1,2-alpha]purin-10(3H)-one (m(1)G). Using the same DNA, the glutathione S-transferase (GST) MI, GSTT1, an d NAD(P)H quinone reductase-l (NQO(1)) genotypes were determined in or der to assess the role of their gene products in modulating adduct lev els through their involvement in detoxification of lipid peroxidation products and redox cycling, respectively. The highest adduct levels ob served were for m(1)G, followed by 8-oxo-dG, edA, and edC, but there w ere no differences in adduct levels between smokers and non-smokers an d 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 m(1)G or 8-oxo-dG. However, there was a si gnificant correlation (r = 0.76; p < 0.01) between the levels of 8-oxo -dG and m(1)G in human pancreas DNA. Neither GSTM1 nor NQO(1) genotype s were associated with differences in any of the adduct levels. Althou gh the sample set was Limited, the data suggest that endogenous DNA ad duct formation in human pancreas is not clearly derived from cigarette smoking or from (NQO(1))-mediated redox cycling. Further, it appears that neither GSTM1 nor GSTT1 appreciably protects against endogenous a dduct formation. Together with the lack of correlation between m(1)G a nd edA or edC, these data indicate that the malondialdehyde derived fr om lipid peroxidation may not contribute significantly to m(1)G adduct formation. On the other hand, the apparent correlation between m(1)G and 8-oxo-dG and their comparable high levels are consistent with the hypothesis that m(1)G is formed primarily by reaction of DNA with a ba se propenal, which, like 8-oxo-dG, is thought to be derived from hydro xyl radical attack on the DNA. (C) 1998 Elsevier Science B.V. All righ ts reserved.