The ability of chemical carcinogens to induce cancer results from the DNA damage they cause as well as the errors introduced into DNA during the cells’ efforts to repair that damage. Thus carcinogens are also mutagens. The strongest evidence that carcinogens act through mutagenesis comes from the observation that cellular DNA altered by the exposure of cells to carcinogens can change cultured cells or cells implanted in mice into fast-growing cancer-like cells. The mutagenic effect of a carcinogen is roughly proportional to its ability to transform cells and induce cancer in animal models.

Although substances identified as chemical carcinogens have a broad range of chemical structures with no obvious unifying features, they can be classified into two general categories. Direct-acting carcinogens, of which there are only a few, are mainly reactive electrophiles (compounds that seek out and react with electron-rich centers in other compounds). By chemically reacting with nitrogen and oxygen atoms in DNA, these compounds can modify bases in DNA so as to distort the normal pattern of base pairing. If the modified nucleotides are not repaired, they allow an incorrect nucleotide to be incorporated during replication. This class of carcinogens includes ethylmethane sulfonate (EMS), dimethyl sulfate (DMS), and nitrogen mustards.

In contrast, indirect-acting carcinogens are generally unreactive, often water-insoluble compounds that can act as potent cancer inducers only after the introduction of electrophilic centers. In animals, cytochrome P-450 enzymes are located in the endoplasmic reticulum of most cells and at especially high levels in liver cells. P-450 enzymes normally function to add electrophilic centers, such as OH groups, to nonpolar foreign chemicals, such as certain insecticides and therapeutic drugs, in order to solubilize them so that they can be excreted from the body. However, P-450 enzymes can also turn otherwise harmless chemicals into carcinogens. Indeed, most chemical carcinogens have little mutagenic effect until they have been modified by cellular enzymes.