Genotoxicity of tobacco smoke-derived aromatic amines and bladder cancer: current state of knowledge and future research directions

Bladder cancer is a significant public health problem, worldwide. In the United States, bladder cancer is the fourth most common cancer in men, and its recurrence rate is the highest among all malignancies. Tobacco smoking is the leading risk factor for bladder cancer. The risk of bladder cancer is directly related to the intensity and duration of smoking, while quitting smoking reduces this risk. The increased risk of smokers for developing bladder cancer is attributable to their exposure to aromatic amines, which constitute a family of known bladder carcinogens present in tobacco smoke. The underlying mechanism of action of aromatic amines in the genesis of bladder cancer is not, however, fully delineated. Research has identified a genotoxic mode of action, specifically DNA adduction and mutagenicity, for aromatic amines, which may account for their carcinogenicity. The present review summarizes our current knowledge on the DNA adduction and mutagenicity of aromatic amines in relation to smoking-associated bladder cancer. For illustrative purposes, representative results from published research on aromatic amine-induced DNA adduction and mutagenesis are discussed. The direction of future research on the underlying mechanisms of tobacco smoke-associated bladder carcinogenesis is also outlined. Understanding the molecular mechanisms of bladder carcinogenesis is essential for improving future strategies for prevention, early detection, treatment, and prognosis of this malignancy.