1995 Fiscal Year Final Research Report Summary
Oxygen radical formation and DNA damage induced by metal compounds in relation to carcinogenicity
| Project/Area Number |
06454227
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| Research Category |
Grant-in-Aid for General Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Research Field |
Hygiene
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| Research Institution | KYOTO UNIVERSITY |
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Principal Investigator |
KAWANISHI Shosuke Kyoto Univ., Fac.of Med.lecturer, 医学研究科, 講師 (10025637)
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| Project Period (FY) |
1994 – 1995
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| Keywords | carcinogenicity / metal compounds / DNA damage / 8-OH-dG / cultured cell / nickel compounds / inflammation / peroxynitrite |
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| Research Abstract |
Carcinogenic chromate(VI), iron (III) -nitrilotriacetate, cobalt (II) and nickel (II) interact with hydrogen peroxide (H2O2) to generate hydroxyl free radical (OH), singlet oxygen and metal-oxygen complex causing DNA damage. The yields of 8-hydroxyl-2'-deoxyguanosine (8-OH-dG) in the cultured cells treated with nickel compounds were measured in order to clarify the participation of reactive oxygen species in nickel-induced cellular DNA damage. Treatment of cells with Ni_3S_2 or NiS for 24 hrs produced about 1.5 fold 8-OH-dG compared with untreated cells. On the other hands, since lead ions have no abilities to generate highly reactive OH and metal-oxygen complex from superoxide anion (O2^-) or H2O2, there is no possiblity that lead compounds directly participate in DNA damage through catalyzing the formation of highly reactive oxygen species. Therefore, an indirect mechanism of DNA damage induced by lead compounds should be considered. delta-Aminolevulinic acid (ALA) is a heme precursor accumulated in lead poisoning. ALA caused damage to DNA fragments obtained from c-Ha-ras protooncogene in the presence of Cu (II), but only slightly in the presence of Fe (II). Our results indicate that O2^- and H2O2 are generated during the Cu(II)-catalyzed ALA autoxidation and that H2O2 reacts with Cu (I) to form crypto-OH radical, such as Cu (I) -peroxide complex, causing DNA damage. On the basis of these findings, we have proposed that oxygen radicals may participate in metal carcinogenesis.
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