Historical Overview of Chemical Carcinogenesis

Abstract

There is increasing evidence that carcinogens play a major role in causation of human cancer. This chapter reviews the advances in carcinogenesis research from a historical perspective. The classes of carcinogens surveyed include polycyclic aromatic hydrocarbons, aromatic amines and amides, nitroarenes, heterocyclic amines formed in cooking, N-nitroso compounds, aflatoxins, natural oils such as safrole, and other natural products, such as the pyrrolizidine alkaloids. For each of these categories, information is presented on historical developments, environmental occurrence, the identities of the active metabolites, the pathways of enzymatic activation, and the structures of the adducts formed with DNA. Despite the chemical and structural diversity of the carcinogens, the evidence indicates that their mechanisms of tumorigenesis are fundamentally similar. The active metabolites of most carcinogens are electrophiles (or reactive oxygen species) that react with DNA to induce mutations and/or other genotoxic changes.

DNA Damage, Mutagenesis and Cancer

“…Extensive investigations were performed to establish how each carcinogenic agent, either directly or following metabolic changes in their structures, damage DNA or form DNA adducts. As for example, B[ a ]P is converted to 7 S ,8 R -B[ a ]P oxide by cytochrome P-450 (CYP) 1A1/1B1, which is hydrolyzed by microsomal epoxide hydrolase to form the (−)-7 R ,8 R -dihydroxydihydro-B[ a ]P [ 26 , 27 ] ( Figure 1 ). This trans dihydrodiol is then oxidized again by the same CYP 1A1/1B1 enzymes to form predominantly (+)- anti -B[ a ]P-7,8-dihydrodiol-9,10-epoxide, the most mutagenic and tumorigenic metabolite of B[ a ]P. The major adduct formed by this B[ a ]P metabolite is the (+)- trans-anti -B[ a ]PDE ( Figure 1 ).…”

Disinfection of water using pulsed power technique: Effect of system parameters and kinetic study

“…However, application of this technique is reducing because of the formation of carcinogenic disinfection by-products like trihalomethanes, haloacetic acids and organo-chlorine compounds in water [4][5][6]. Other disinfection processes like UV irradiation, ozonation and gamma irradiation are expensive.…”

Current and Future Methodology for Quantitation and Site-specific Mapping the Location of DNA Adducts

“…Since identification of the first DNA adduct by Reiner, B. and Zamenhof in 1957 [2], several thousand studies on DNA adducts have been reported and are reviewed from different perspectives [3][4][5][6][7][8][9][10]. The ability of a compound to form DNA adducts, directly or after metabolic activation, is considered a critical event in chemical carcinogenesis [11] and a key event for genotoxic mode of action of toxicants [12,13]. The binding to DNA, has been widely used as biomarker of exposure in molecular epidemiology studies to link exposure to adverse health outcomes [14][15][16].…”