Mechanisms of action of known human carcinogens

Abstract

Mutational mechanisms can be proposed for most, if not all, known human carcinogens. Many of these are electrophilic or metabolically activated to reactive molecules which can alter DNA, causing genetic damage and different types of mutations. Even some human carcinogens previously proposed to be nongenotoxic (e.g., hormones and asbestos) exhibit mutational activity in assays for chromosomal mutations. Since such chemicals are usually inactive in the Salmonella assay and other assays for gene mutation, more emphasis has been placed on their nonmutational mechanisms. Clear evidence exists that these carcinogens can alter gene expression and stimulate cell proliferation by epigenetic mechanisms. Such properties are undoubtedly important in their carcinogenic activity. Although they are less well studied, DNA reactive, genotoxic carcinogens also alter gene expression and increase cell turnover by epigenetic mechanisms. These findings are consistent with the current understanding of the molecular basis of multistep carcinogenesis. Most common human cancers evolve as the result of multiple mutational events. The molecular basis of these mutations is varied, and they include point mutations, deletion mutations, chromosomal rearrangements, gene amplification and chromosomal losses and gains. Therefore, different mutational activities of carcinogens can influence the carcinogenic process at different steps. Influences on gene expression and cell proliferation are also 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). The mechanisms of action of human carcinogens, and very probably many rodent carcinogens, include both genetic and epigenetic processes. Carcinogenesis is a multistep, multigenic, multicausal process (Barrett, 1987b), so both epigenetic and genetic factors are probably important.(ABSTRACT TRUNCATED AT 250 WORDS)