CARCINOGENS

Chemical carcinogens increase tumor incidence and cancer, often by direct interactions with DNA as DNA damage and genomic mutations are key factors in mutagenesis. There are several mechanisms underlying chemical carcinogenesis. Alkylating agents have electrophilic centers that enable the covalent addition of methyl or ethyl groups to the N⁷ atom of guanosine. Aromatic moieties of aralkylating agents can form adducts with DNA. Some chemicals become carcinogenic only after being metabolized by cytochrome P450 enzymes. Some carcinogens do not cause DNA damage directly but induce the intracellular production of reactive oxygen species such as peroxide (H₂/O₂), superoxide anion (O₂•) and peroxynitrite (ONOO•), that may result in gene mutations. Polymerases may misread altered DNA, inducing point mutations. Alternatively, the presence of adducts or other modifications may increase the incidence of chromosomal breakage and rearrangement. When DNA repair mechanisms fail, these mutations, deletions, and rearrangements become part of the somatic cell genome that is replicated during cell division. The transformation of a normal cell to a cancerous cell can occur when a mutated or translocated oncogene or tumor suppressor gene is expressed. A mutated gene may produce no protein or a mutant protein with altered function. Alternatively, a normally silent gene may become dissociated from its control sequences and be expressed constitutively. When these processes lead to cell immortalization and unchecked proliferation rather than to apoptosis or cellular senescence, tumorigenesis may result. Chemical carcinogens are often used to model tumorigenesis in animals or cultured cell lines. Researchers use these models not only to study the intervention of chemopreventive and therapeutic agents, but also to discover the mechanisms underlying cancer progression and metastasis.