Fraga C G, Shigenaga M K, Park J W, Degan P, Ames B N
Department of Molecular and Cell Biology, University of California, Berkeley 94720.
Proc Natl Acad Sci U S A. 1990 Jun;87(12):4533-7. doi: 10.1073/pnas.87.12.4533.
Oxidative damage to DNA is shown to be extensive and could be a major cause of the physiological changes associated with aging and the degenerative diseases related to aging such as cancer. The oxidized nucleoside, 8-hydroxy-2'-deoxyguanosine (oh8dG), one of the approximately 20 known oxidative DNA damage products, has been measured in DNA isolated from various organs of Fischer 344 rats of different ages. oh8dG was present in the DNA isolated from all the organs studied: liver, brain, kidney, intestine, and testes. Steady-state levels of oh8dG ranged from 8 to 73 residues per 10(6) deoxyguanosine residues or 0.2-2.0 x 10(5) residues per cell. Levels of oh8dG in DNA increased with age in liver, kidney, and intestine but remained unchanged in brain and testes. The urinary excretion of oh8dG, which presumably reflects its repair from DNA by nuclease activity, decreased with age from 481 to 165 pmol per kg of body weight per day for urine obtained from 2-month- and 25-month-old rats, respectively. 8-Hydroxyguanine, the proposed repair product of a glycosylase activity, was also assayed in the urine. We estimate approximately 9 x 10(4) oxidative hits to DNA per cell per day in the rat. The results suggest that the age-dependent accumulation of oh8dG residues observed in DNA from liver, kidney, and intestine is principally due to the slow loss of DNA nuclease activity; however, an increase in the rate of oxidative DNA damage cannot be ruled out.
DNA的氧化损伤被证明是广泛存在的，可能是与衰老相关的生理变化以及与衰老相关的退行性疾病（如癌症）的主要原因。氧化核苷8-羟基-2'-脱氧鸟苷（oh8dG）是约20种已知的氧化性DNA损伤产物之一，已在从不同年龄的Fischer 344大鼠的各种器官中分离出的DNA中进行了测量。oh8dG存在于从所有研究的器官（肝脏、大脑、肾脏、肠道和睾丸）中分离出的DNA中。oh8dG的稳态水平范围为每10(6)个脱氧鸟苷残基中有8至73个残基，或每个细胞中有0.2 - 2.0×10(5)个残基。肝脏、肾脏和肠道中DNA的oh8dG水平随年龄增加而升高，但在大脑和睾丸中保持不变。oh8dG的尿排泄量（可能反映其通过核酸酶活性从DNA中修复的情况）随年龄下降，分别从2个月和25个月大的大鼠尿液中获得的每千克体重每天481至165皮摩尔。还对尿液中糖基化酶活性的推测修复产物8-羟基鸟嘌呤进行了测定。我们估计大鼠每个细胞每天约有9×10(4)次DNA氧化损伤。结果表明，在肝脏、肾脏和肠道的DNA中观察到的oh8dG残基随年龄的积累主要是由于DNA核酸酶活性的缓慢丧失；然而，不能排除氧化性DNA损伤速率的增加。
