On the impact of the molecule structure in chemical carcinogenesis.

Abstract

Cancer is as a highly complex and multifactorial disease responsible for the death of hundreds of thousands of people in the western countries every year. Since cancer is clonal and due to changes at the level of the genetic material, viruses, chemical mutagens and other exogenous factors such as short-waved electromagnetic radiation that alter the structure of DNA are among the principal causes. The focus of this present review lies on the influence of the molecular structure of two well-investigated chemical carcinogens from the group of polycyclic aromatic hydrocarbons (PAHs), benzo[a]pyrene (BP) and dibenzo[a,l]pyrene (DBP). Although there is only one additional benzo ring present in the latter compound, DBP exerts much stronger genotoxic and carcinogenic effects in certain tumor models as compared to BP. Actually, DBP has been identified as the most potent tumorigen among all carcinogenic PAHs tested to date. The genotoxic effects of both compounds investigated in mammalian cells in culture or in animal models are described. Comparison of enzymatic activation, DNA binding levels of reactive diol-epoxide metabolites, efficiency of DNA adduct repair and mutagenicity provides some clues on why this compound is about 100-fold more potent in inducing tumors than BP. The data published during the past 20 years support and strengthen the idea that compound-inherent physicochemical parameters, along with inefficient repair of certain kinds of DNA lesions formed upon metabolic activation, can be considered as strong determinants for high carcinogenic potency of a chemical.