Hexavalent chromium [
Cr(VI)] is a known etiological factor in human
lung cancer.
Cr(VI) exposure-related
lung cancer has a high mutation incidence in the p53 gene. Upon intake in human cells
Cr(VI) is reduced to Cr(III), which is able to conjugate with
amino acids and consequently form either binary Cr(III)-
DNA or ternary Cr(III)-
amino acid-
DNA adducts. Both binary and ternary Cr(III)-
DNA adducts are mutagenic. We have found that the Escherichia coli
nucleotide excision
enzyme UvrABC nuclease is able to incise Cr(III)- and Cr(III)-
histidine-modified plasmid
DNA and the extent of incision is proportional to the amount of Cr(III)-
DNA adducts in the plasmid. In order to determine the role of Cr(III)-
DNA adducts in the mutagenesis of the p53 gene in human
cancer using the
UvrABC nuclease incision method, we have mapped the Cr(III)-
DNA distribution in PCR
DNA fragments amplified from exons 5, 7 and 8 of the p53 gene. We have found that the sequence specificities of Cr(III)-
DNA and Cr(III)-
histidine-
DNA adducts in the p53 gene sequence are identical and that both types of adducts are preferentially formed at -NGG- sequences, including
codons 245, 248 and 249, the mutational hotspots in human
lung cancer. It has been found that Cr(III)-
DNA adducts induce mainly G to T mutations. Therefore, these results suggest that Cr(III)-
DNA adduct formation contributes to the p53 gene mutations in lung
carcinogenesis.