Benz(a)anthraceneBenzo(a)pyreneDibenz(a,h)anthracene3-Methylcholanthrene7,12-Dimethylbenz(a)anthracene
Aromatic Amines,Amides,Azo Dyes
NitrosamineandamidesVinylchloride,nickel,chromiumInsecticides,fungicidesPolychlorinatedbiphenyls http://ebooksmedicine.net metabolized to epoxides, which form covalent adducts (addition products) with molecules in the cell, principally DNA, but also with RNA and proteins.
The aromatic amines and azo dyes constitute another class of indirect-acting carcinogens. Before its carcinogenicity was recognized, β-naphthylamine was responsible for a 50-fold increased incidence of bladder cancers in heavily exposed workers in the aniline dye and rubber industries. Examples of other occupational carcinogens are listed in
Table 6.5 . Because indirect-acting carcinogens require metabolic activation for their conversion to DNA-damaging agents, much interest is focused on the enzymatic pathways that are involved, such as that mediated by the cytochrome P-450–dependent monooxygenases. The genes that encode these enzymes are polymorphic, and enzyme activity varies among individuals. It is widely believed that the susceptibility to chemical carcinogenesis depends at least in part, on the specific allelic form of the enzyme that is inherited. Thus, it may be possible in the future to assess cancer risk in a given individual by genetic analysis of enzyme polymorphisms.
A few other agents merit brief mention. Aflatoxin B1 is of interest because it is a naturally occurring agent produced by some strains of Aspergillus, a mold that grows on improperly stored grains and nuts. A strong correlation has been found between the dietary level of this food contaminant and the incidence of hepatocellular carcinoma in some parts of Africa and the Far East. Additionally, vinyl chloride, arsenic, nickel, chromium, insecticides, fungicides, and polychlorinated biphenyls are potential carcinogens in the workplace and about the house. Finally, nitrites used as food preservatives have caused concern, since they cause nitrosylation of amines contained in food. The nitrosamines thus formed are suspected to be carcinogenic.
Mechanisms of Action of Chemical Carcinogens
Because malignant transformation results from mutations, it should come as no surprise that most chemical carcinogens are mutagenic. Indeed, all direct and ultimate carcinogens contain highly reactive electrophile groups that form chemical adducts with DNA, as well as with proteins and RNA. Any gene may be the target of chemical carcinogens, but understandably it is the mutation of important cancer genes, such as RAS and TP53, that is responsible for carcinogenesis. Indeed, specific chemical carcinogens, such as aflatoxin B1, produce characteristic mutations in TP53, such that detection of mutations within particular codons strongly points toward aflatoxin as the causative agent. Such specific “mutational signatures” also exist for cancers caused by UV light, tobacco smoke, and other environmental carcinogens and are proving to be useful tools in epidemiologic studies of carcinogenesis.
Carcinogenicity of some chemicals is augmented by subsequent administration of promoters (e.g., phorbol esters, hormones, phenols, certain drugs), which are by themselves nontumorigenic. To be effective, repeated or sustained exposure to the promoter must follow the application of the mutagenic chemical, or initiator (
Fig. 6.32 ). The initiation-promotion sequence of chemical carcinogenesis raises an important question: Since promoters are not mutagenic, how do they contribute to tumorigenesis? Although the effects of tumor promoters are pleiotropic,