Studies focused on testing the hypothesis that nickel and other transition metal carcinogens initiate tumors through generation of DNA- damaging free radicals have been continued in chemical and animal models. The following results were obtained: (1) Histidine, a physiological carrier of transition metals, was found to enhance greatly iron(III)-, chromium(III)-, copper(II)-, and cobalt(II)-mediated oxidation by hydrogen peroxide of free 2'-deoxyguanosine (dG) to promutagenic 8-oxo- 2'-deoxyguanosine (8-oxo-dG). In calf thymus DNA, histidine enhanced oxidation of dG residues only with copper(II). (2) Metal chelation drugs, desferoxamine and EDTA, either inhibited or enhanced metal/histidine-mediated dG oxidation in a complex metal chelate- and substrate-specific way, indicating that chelation therapy may sometimes increase the danger of DNA damage. (3) Nickel(II) complex with tetraglycine (NiG4) appeared to be much more active than nickel(II)- histidyl complexes toward in vitro oxidation by H2O2 of guanine residues in free dG, DNA, and nucleohistone. 8-Oxo-dG was only a transient product of that oxidation. 2,6-Diamino-4-hydroxy-5-formamido-pyrimidine (FapyGua) was also identified among the products. The results indicate generation of hydroxyl radical or nickel-oxo species in the reaction of H2O2 with NiG4 at physiological pH. (4) Parenterally administered cobalt(II) acetate was found to produce oxidative DNA base damage in rats; the damage was organ-specific. Eight DNA base products in renal chromatin (mostly 5-hydroxycytosine), five in hepatic chromatin (mostly FapyGua), and two in pulmonary chromatin (5-hydroxymethyluracil and 4,6- diamino-5-formamidopyrimidine), were increased from 30% to more than 200% over control levels with increasing Co(II) dose. The bases determined were typical products of hydroxyl radical attack on DNA, suggesting a role for this radical in the mechanism(s) of DNA damage caused by Co(II) in vivo. Some of these bases, especially 5-hydroxycytosine, are known to be promutagenic and may thus be involved in the mechanisms of cobalt(II)-induced carcinogenesis.
