Glaab W E, Hill R B, Skopek T R
Department of Genetic and Cellular Toxicology, Merck Research Laboratories, WP45-320, West Point, PA 19486, USA.
Carcinogenesis. 2001 Oct;22(10):1709-13. doi: 10.1093/carcin/22.10.1709.
Genomic instability associated with deficiencies in mismatch repair (MMR) plays a critical role in tumorigenesis. Here we have investigated the contribution of oxidative damage to this instability in MMR-defective cells. Treatment with H(2)O(2) produced less cytotoxicity in MMR-deficient cells than in those proficient in MMR, supporting a role for MMR in the recognition and/or processing of oxidative damage. Additionally, growth of MMR-defective cells in the presence of the antioxidant ascorbate (500 microM) reduced the spontaneous mutation rate at the hypoxanthine-guanine phosphoribosyl transferase (HPRT) locus by up to 50% and reduced microsatellite instability by 30%. Induction of HPRT mutants by exogenously added H(2)O(2) was also significantly suppressed by ascorbate. Collectively, these results suggest that (i) oxidative damage contributes significantly to the spontaneous mutator phenotype in MMR-defective cells, (ii) this damage may select for MMR-deficient cells due to their increased resistance to cell killing and (iii) dietary antioxidants may help to suppress the mutator phenotype and resulting carcinogenesis in individuals with compromised MMR.
与错配修复（MMR）缺陷相关的基因组不稳定性在肿瘤发生中起关键作用。在此，我们研究了氧化损伤对MMR缺陷细胞中这种不稳定性的影响。与MMR功能正常的细胞相比，用H₂O₂处理MMR缺陷细胞产生的细胞毒性更小，这支持了MMR在氧化损伤的识别和/或处理中发挥作用。此外，在抗氧化剂抗坏血酸（500微摩尔）存在的情况下，MMR缺陷细胞的生长使次黄嘌呤 - 鸟嘌呤磷酸核糖转移酶（HPRT）位点的自发突变率降低了高达50%，微卫星不稳定性降低了30%。抗坏血酸也显著抑制了外源性添加H₂O₂诱导的HPRT突变体。总体而言，这些结果表明：（i）氧化损伤对MMR缺陷细胞中的自发突变表型有显著贡献；（ii）由于MMR缺陷细胞对细胞杀伤的抗性增加，这种损伤可能会选择MMR缺陷细胞；（iii）饮食中的抗氧化剂可能有助于抑制MMR功能受损个体的突变表型及由此导致的癌症发生。
