Kadlubar F F, Anderson K E, Häussermann S, Lang N P, Barone G W, Thompson P A, MacLeod S L, Chou M W, Mikhailova M, Plastaras J, Marnett L J, Nair J, Velic I, Bartsch H
National Center for Toxicological Research (HFT-100), Jefferson, AR 72079, USA.
Mutat Res. 1998 Sep 20;405(2):125-33. doi: 10.1016/s0027-5107(98)00129-8.
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.
与氧化应激相关的DNA加合物被认为涉及由氧化损伤和脂质过氧化产生的内源性活性物质的形成。尽管不同实验室已在多种人体组织中报道了这些加合物，但尚未对同一组织样本中这些加合物的水平进行比较。在本研究中，我们从15名吸烟者和15名非吸烟者的胰腺中分离出DNA，并测量了1,N6-乙烯基（2'-脱氧）鸟苷（edA）、3,N4-乙烯基（2'-脱氧）胞苷（edC）、8-氧代-2'-脱氧鸟苷（8-氧代-dG）和嘧啶并[1,2-α]嘌呤-10（3H）-酮（m1G）的水平。使用相同的DNA，确定了谷胱甘肽S-转移酶（GST）M1、GSTT1和NAD（P）H醌还原酶-1（NQO1）的基因型，以分别评估其基因产物通过参与脂质过氧化产物的解毒和氧化还原循环在调节加合物水平中的作用。观察到的最高加合物水平是m1G，其次是8-氧代-dG、edA和edC，但吸烟者和非吸烟者之间的加合物水平没有差异，且与受试者年龄、性别或体重指数无关。此外，edA和eC之间、edA或edC与m1G或8-氧代-dG之间的加合物水平没有相关性。然而，人胰腺DNA中8-氧代-dG和m1G的水平之间存在显著相关性（r = 0.76；p < 0.01）。GSTM1和NQO1基因型均与任何加合物水平的差异无关。尽管样本量有限，但数据表明人胰腺中内源性DNA加合物的形成并非明显源于吸烟或（NQO1）介导的氧化还原循环。此外，似乎GSTM1和GSTT1均未明显预防内源性加合物的形成。连同m1G与edA或edC之间缺乏相关性，这些数据表明脂质过氧化产生的丙二醛可能对m1G加合物的形成贡献不大。另一方面，m1G与8-氧代-dG之间明显的相关性及其相当高的水平与以下假设一致，即m1G主要由DNA与碱基丙烯醛反应形成，而碱基丙烯醛与8-氧代-dG一样，被认为是由羟基自由基攻击DNA产生的。
