Chien Yuan-Hung, Bau Da-Tian, Jan Kun-Yan
Institute of Zoology, Academia Sinica, Taipei 11529, Taiwan, Republic of China.
Free Radic Biol Med. 2004 Apr 15;36(8):1011-7. doi: 10.1016/j.freeradbiomed.2004.01.011.
Sustained induction of nitric oxide (NO) in chronic inflammation may be mutagenic, through DNA damage induction and/or DNA repair inhibition. Although there is good evidence that NO can cause DNA damage, how NO is involved in DNA repair remains elusive. By using DNA synthesis inhibitors to accumulate DNA strand breaks in comet assay, we show that NO and peroxynitrite inhibit DNA-adduct excision in human fibroblasts damaged by UVC, 4-nitroquinoline 1-oxide, benzo[a]pyrene dihydrodiol epoxide, cisplatin, or mitomycin C, but not with methyl methane sulfonate. Treating cells with arsenite increased NO production and also inhibited the DNA-adduct excision induced by UVC, 4-nitroquinoline 1-oxide, benzo[a]pyrene dihydrodiol epoxide, cisplatin, and mitomycin C, but not by methyl methane sulfonate, H(2)O(2), sodium nitrosoprusside, or 3-morpholinosydnonimine. Arsenite inhibition of DNA-adduct excision was decreased by NO synthase inhibitors and NO scavengers. The nuclear extract prepared from fibroblasts pretreated with sodium nitrosoprusside, dipropylenetriamine NONOate, 3-morpholinosydnonimine, or arsenite also showed decreased activity in excising the DNA adducts induced by UVC and cisplatin but not by methyl methane sulfonate or H(2)O(2) plus Fe. These results are consistent with the notion that NO, peroxynitrite, and arsenite inhibit the DNA-adduct excision in nucleotide excision repair but not that in base excision repair.
在慢性炎症中持续诱导一氧化氮（NO）可能具有致突变性，其途径包括诱导DNA损伤和/或抑制DNA修复。尽管有充分证据表明NO可导致DNA损伤，但NO如何参与DNA修复仍不清楚。通过在彗星试验中使用DNA合成抑制剂来积累DNA链断裂，我们发现NO和过氧亚硝酸盐可抑制经紫外线C（UVC）、4-硝基喹啉1-氧化物、苯并[a]芘二氢二醇环氧化物、顺铂或丝裂霉素C损伤的人成纤维细胞中的DNA加合物切除，但对甲磺酸甲酯诱导的损伤无此作用。用亚砷酸盐处理细胞会增加NO的产生，并且也会抑制由UVC、4-硝基喹啉1-氧化物、苯并[a]芘二氢二醇环氧化物、顺铂和丝裂霉素C诱导的DNA加合物切除，但对甲磺酸甲酯、过氧化氢、硝普钠或3-吗啉代辛二酮诱导的损伤无此作用。一氧化氮合酶抑制剂和NO清除剂可降低亚砷酸盐对DNA加合物切除的抑制作用。用硝普钠、二亚丙基三胺NONOate、3-吗啉代辛二酮或亚砷酸盐预处理的成纤维细胞制备的核提取物在切除由UVC和顺铂诱导的DNA加合物时活性也降低，但对甲磺酸甲酯或过氧化氢加铁诱导的损伤无此作用。这些结果与以下观点一致，即NO、过氧亚硝酸盐和亚砷酸盐抑制核苷酸切除修复中的DNA加合物切除，但不抑制碱基切除修复中的该过程。
