Mechanisms of human carcinogens.
Mutational mechanisms can be proposed as contributing to the activity of most human carcinogens. Many of these chemicals are electrophilic or are metabolically activated to reactive molecules that can alter DNA. Even human carcinogens that do not exhibit direct chemical interaction with DNA, e.g., hormones and asbestos, have been shown to induce genetic effects when in vitro assays for chromosomal mutations are employed. Since these chemicals are usually inactive in the Salmonella assay and other gene mutational assays, more emphasis has been placed on their nonmutational mechanisms. Evidence exists that these carcinogens alter gene expression and stimulate cell proliferation by epigenetic mechanisms; such properties almost certainly contribute to the carcinogenic activity of these chemicals. Although less well studied, DNA reactive, genotoxic carcinogens also alter gene expression and cell proliferation by epigenetic mechanisms. These findings are consistent with the current understanding of the molecular basis of multistep carcinogenesis. The neoplastic evolution of most common human cancers occurs as the result of multiple mutational events. The molecular basis for these mutations is varied and includes point mutations, deletion mutations, chromosome rearrangements, gene amplification, and chromosome losses and gains. Therefore, different mutational activities of carcinogens may influence the carcinogenic process at different steps. In addition, chemical influences on gene expression and cell proliferation are important in allowing clonal expansion of preneoplastic cells and in disrupting the suppressive effects of surrounding normal cells on preneoplastic cells (Dotto et al., 1988). Therefore, the mechanisms of action of human carcinogens, and very likely many rodent carcinogens, will include both genetic and epigenetic processes.
Barrett
J C
JC
Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709.
Shelby
M D
MD
D000818:Animals; D015197:Carcinogenicity Tests; D002273:Carcinogens / Q000494:pharmacology / Q000633:toxicity*; D016147:Genes, Tumor Suppressor; D006801:Humans; D009152:Mutagenicity Tests; D009369:Neoplasms / Q000139:chemically induced* / Q000235:genetics; D009374:Neoplasms, Experimental / Q000139:chemically induced*; D011519:Proto-Oncogenes
D002273:Carcinogens