Site-specific hydroxylation at polyguanosine in double-stranded DNA by nickel(II) in the presence of SH compounds: comparison with singlet oxygen-induced DNA damage.
We examined the mechanism of DNA damage induced by carcinogenic Ni(II) in the presence of SH compounds. In the presence of model endogenous SH compounds, dithiothreitol (DTT), 1,4-dithio-L-threitol, and dithioerythritol, Ni(II) induced damage to (32)P-5'-end-labeled DNA fragments obtained from the human c-Ha-ras-1 protooncogene and the p53 tumor suppressor gene. The intensity of Ni(II)-mediated DNA damage induced by DTT was stronger than that by other model endogenous SH compounds, 1,4-dithio-L-threitol and dithioerythritol. DNA damage induced by Ni(II) plus DTT was observed only when the DNA was treated with piperidine, suggesting that Ni(II) plus DTT caused only base damage. Formamidopyrimidine-DNA glycosylase, which is known to recognize 8-oxodG as well as Fapy residues, treatment induced cleavage sites, mainly guanine residues, particularly at the 5'-GG-3', 5'-GGG-3', and 5'-GGGG-3' sequences, in DNA incubated with Ni(II) in the presence of DTT. SOD and catalase inhibited the DNA damage, suggesting that DNA damage involved superoxide anion and hydrogen peroxide. Sodium azide, a potent and relatively specific scavenger of (1)O(2), inhibited DNA damage by Ni(II) in the presence of DTT, whereas the sequence specificity of DNA damage was different from that obtained by (1)O(2) generating agent. The formation of 8-oxodG in calf thymus DNA by Ni(II) was observed with the physiological thiols, dihydrolipoic acid and mercaptopyruvate, as well as with DTT. These results suggest that Ni(II) and DTT form a reactive species, which may be responsible for causing guanine-specific DNA damage. Endogenous SH compounds, which have similar chemical structures to DTT, would participate in nickel carcinogenesis through causing oxidative DNA damage.
Oikawa
Shinji
S
Department of Hygiene, Mie University School of Medicine, Tsu, Mie 514-8507, Japan.
Hiraku
Yusuke
Y
Fujiwara
Tatsuhiko
T
Saito
Isao
I
Kawanishi
Shosuke
S
D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D002417:Cattle; D004249:DNA Damage; D004347:Drug Interactions; D016166:Free Radical Scavengers / Q000494:pharmacology; D006801:Humans; D009532:Nickel / Q000633:toxicity*; D010084:Oxidation-Reduction; D011068:Poly G / Q000737:chemistry*; D026082:Singlet Oxygen / Q000633:toxicity*; D013439:Sulfhydryl Reagents / Q000737:chemistry*
D002273:Carcinogens; D016166:Free Radical Scavengers; D013439:Sulfhydryl Reagents; D026082:Singlet Oxygen; D011068:Poly G; D009532:Nickel