Potential molecular mechanisms of oxidant-induced carcinogenesis.

Chronic exposure to oxidants is associated with an increased incidence of malignancy; however, the mechanism(s) by which oxidants contribute to carcinogenesis is unknown. Since oncogene activation plays an important role in carcinogenesis, we hypothesized that hydroxyl radical-induced DNA damage might contribute to carcinogenesis by causing oncogene activation. The studies reported herein demonstrate that hydroxyl radical-induced DNA damage can activate the K-ras 4B and C-Raf-l oncogenes by causing point mutations and deletions, respectively. In addition, our results indicate that a) hydroxyl radical-induced DNA damage causes selective base substitutions; b) the four DNA bases have different susceptibilities to hydroxyl radical-induced mutations; and c) hydroxyl radical-induced mutations are not randomly distributed among oncogene codons. Our studies suggest that oncogene activation could be one potential mechanism by which oxidants contribute to carcinogenesis.