Oxygen radical formation and DNA damage induced by metal compounds in relation to carcinogenicity

致癌的铬酸盐（VI）、次氮基三乙酸铁（III）、钴（II）和镍（II）与过氧化氢（H2 O2）相互作用产生羟基自由基（OH）、单线态氧和金属-氧络合物，引起DNA损伤。为了阐明活性氧在镍诱导的细胞DNA损伤中的作用，测定了镍化合物处理的培养细胞中8-羟基-2 ′-脱氧鸟苷（8-OH-dG）的产率。用Ni_3S_2或NiS处理细胞24小时，产生的8-OH-dG是未处理细胞的1.5倍。另一方面，由于铅离子不能与超氧阴离子（O2^-）或H2 O2形成高活性的OH和金属氧络合物，因此铅化合物不可能通过催化高活性氧的形成直接参与DNA损伤。因此，铅化合物诱导DNA损伤的间接机制应予以考虑。δ-氨基乙酰丙酸（ALA）是在铅中毒中积累的血红素前体。ALA对c-Ha-ras原癌基因的DNA片段在Cu（II）存在下造成损伤，但在Fe（II）存在下仅轻微损伤。结果表明，Cu（II）催化ALA自氧化过程中产生O2-和H2 O2，H2 O2与Cu（I）反应形成Cu（I）-过氧化氢复合物等隐OH自由基，导致DNA损伤。基于这些发现，我们提出氧自由基可能参与金属致癌作用。

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.