Effects of NQO1 deficiency on levels of cyclopurines and other oxidative DNA lesions in liver and kidney of young mice.
I-compounds are bulky indigenous DNA adducts that can be detected by (32)P-postlabeling. A subgroup, termed type II I-compounds, represents DNA lesions induced by oxidative stress. Several major type II I-compounds have been identified as dinucleotides containing 3'-terminal 8,5'-cyclo-2'-deoxyadenosine (cA). Levels of type II I-compounds depend on the pro-oxidant status of the cell. For example, enhanced formation of such oxidative DNA lesions in newborn rodents appears to be a consequence of incomplete development of neonatal antioxidant defense systems. We tested the hypothesis that young mice deficient in NAD(P)H:quinone oxidoreductase 1 (NQO1), an antioxidant enzyme catalyzing the detoxification of quinones and their derivatives, show increased formation of these oxidative DNA lesions. Type II I-compound levels were determined by (32)P-postlabeling in liver and kidney DNA of untreated male wild-type or NQO1-null C57BL/6 mice of different ages. NQO1 catalytic activities and contents were measured by spectrophotometric and Western blotting techniques, respectively. Elevated oxidative adduct levels including those containing cA were detected in NQO1-null compared to wild-type mice at 10, 30 and 90 days in liver and at 30 and 90 days in kidney DNA. Furthermore, there were statistically significant inverse relationships between type II I-compound levels and NQO1 activities in wild-type mice up to 30 days of age. Taken together, the results suggest that NQO1 plays an important role in attenuating endogenous oxidative DNA damage in vivo. Our results show also that type II I-compounds represent useful and sensitive biomarkers with utility in studies of oxidative DNA damage and its consequences.
Zhou
Guo-Dong
GD
Department of Environmental and Occupational Health, School of Rural Public Health, Texas A&M University System, Bryan, TX, USA. gzhou@ibt.tamu.edu
Randerath
Kurt
K
Donnelly
Kirby C
KC
Jaiswal
Anil K
AK
D000818:Animals; D014408:Biomarkers, Tumor; D015153:Blotting, Western; D018736:DNA Adducts / Q000032:analysis*; D004249:DNA Damage; D007668:Kidney / Q000473:pathology; D008099:Liver / Q000473:pathology; D051379:Mice; D016660:NAD(P)H Dehydrogenase (Quinone); D009252:NADPH Dehydrogenase / Q000172:deficiency* / Q000494:pharmacology*; D018384:Oxidative Stress; D011687:Purines / Q000032:analysis; D017382:Reactive Oxygen Species; D013053:Spectrophotometry
D014408:Biomarkers, Tumor; D018736:DNA Adducts; D011687:Purines; D017382:Reactive Oxygen Species; D016660:NAD(P)H Dehydrogenase (Quinone); C491732:Nqo1 protein, mouse; D009252:NADPH Dehydrogenase