Dimethylformamide (DMF) has been suspected to associate with
cancers in exposed workers, whereas there has been inadequate evidence for carcinogenicity in experimental animals. We demonstrated that H(2)O(2) was generated during the degradation of DMF under aerobic conditions, and that the amount of H(2)O(2) was enhanced by exposure to solar light or by the contamination of trace
metal. Experiments using (32)P-5'-end-labeled
DNA fragments revealed that the degraded DMF induced DNA damage in the presence of Cu(II). However, purified DMF did not induce DNA damage even in the presence of Cu(II). Addition of purified DMF enhanced DNA damage induced by H(2)O(2) in the presence of Cu(II). The degraded DMF caused Cu(II)-mediated DNA cleavage frequently at
thymine and
cytosine residues. The similar pattern of site-specific DNA damage was observed with purified DMF and H(2)O(2).
Bathocuproine and
catalase inhibited the DNA damage, indicating the involvement of Cu(I) and H(2)O(2). A typical free hydroxy radical scavenger showed no inhibitory effect on the DNA damage. Addition of purified DMF enhanced about 3-4-fold 8-oxo-7, 8-dihydro-2'-deoxyguanosine formation induced by H(2)O(2) and Cu(II). ESR spectroscopic study demonstrated that
carbon-centered radicals and
nitrogen-centered radicals were generated in the reaction mixture of DMF, H(2)O(2), and Cu(II). Inhibitory effects of scavengers on radical formation and DNA damage suggest that
carbon-centered radicals and/or
nitrogen-centered radicals may contribute to the DNA damage. These results suggest that H(2)O(2) generation during DMF degradation is related to the possible carcinogenic activity of DMF.