Smoking and lung cancer--a new role for an old toxicant?

Abstract

Denissenko et al. (1) reported in 1996 that benzo[a]pyrene-7,8-diol-9,10-epoxide (BPDE), a metabolite of the widely studied polycyclic aromatic hydrocarbon (PAH) carcinogen benzo[a]pyrene (BaP), produced a characteristic pattern of DNA damage in the p53 tumor suppressor gene of lung cells. This pattern was remarkably similar to that observed in the commonly mutated p53 gene isolated from lung tumors in smokers. In view of the central role of the p53 gene in carcinogenesis, the results of this widely quoted study, which were reproduced subsequently with related PAH metabolites and by other methods (2, 3), have been described as a “smoking gun,” confirming that PAHs were the major carcinogenic agents in cigarette smoke. But life is not so simple. Cigarette smoke contains >4,000 compounds and >60 established carcinogens (4). In addition to PAH, there are carcinogenic nitrosamines, aromatic amines, aldehydes, volatile organic compounds, oxidants, and metals. As discussed in refs. 5 and 6, some of these compounds or their metabolites, similar to BPDE and other PAH diol epoxides, cause G-to-T transversions in DNA, as commonly observed in the p53 and K-ras genes in smoking-induced lung tumors. These other agents might also cause patterns of DNA damage in the p53 gene similar to those seen with BPDE. Confirming this possibility, Feng et al. (7) report in a recent issue of PNAS that acrolein, a toxic compound occurring in cigarette smoke at levels up to 10,000 times greater than those of BaP, produces essentially the same spectrum of DNA damage in the p53 gene of …