Mechanisms of Carcinogenicity

Chemical carcinogens induce neoplasia by a wide range of mechanisms involving either interaction with the hereditary material of the organism or interference with one of the many cellular control systems. The former compounds, known as geno-toxic carcinogens, interact directly with DNA, resulting in a permanent heritable change to a cell following replication (i.e., an altered genotype). In contrast, nongenotoxic (epigenetic) carcinogens do not interact directly with DNA but cause cancer by other mechanisms.

Chemicals that react with DNA are invariably electrophiles (i.e., they possess one or more electron-deficient centers in the molecule) that target the nucleophilic (electron-rich) sites in the DNA. The electrophilic center may be present in the molecule itself (activation independent) as in ^-propiolactone, dimethyl sulfate, and a,/3-unsaturated aldehydes or be generated following metabolism (activation dependent) in the target species.

Examples of classes of compounds that are converted to reactive electrophiles by oxidative metabolism include nitrosamines, chlorinated alkanes, hydrazines, and polycyclic aromatic hydrocarbons. Because of the inherent reactivity of these species, they react not only with DNA, but also with other cellular macromolecules such as RNA and proteins. These reactions protect the cell against the carcino-genicity of the chemical by reducing the amount of electrophile available to react with DNA, but may lead to other forms of damage and ultimately cell death.

The enzyme system considered to be mainly involved in the activation of chemicals to carcinogenic species is the so-called mixed function oxidase system. This enzyme complex is centered on cytochrome P450 and is present in most, if not all, of the organs of the body. The enzyme system consists of a very large family of related isoenzymes of differing substrate specificity and has a widespread distribution in the animal kingdom. Early work with this enzyme system suggested that only certain isoenzymes were responsible for the activation of carcinogens, although it is now clear that different isoenzymes may activate the same compound in different species.

Most chemical carcinogens appear to be substrates of one particular isoenzyme called CYP1A1. Molecular modeling has shown that only relatively flat (planar) molecules are oxygenated by this cytochrome. Common carcinogens activated by this isoenzyme include PAHs, afla-toxin, and 9-hydroxyellipticine, whereas the related isoenzyme CYP1A2 activates arylamines and amides such as 2-acetylaminofluorene and the cooked food mutagens. Other subfamilies of cyto-chromes involved in activating carcinogens include CYP2E1, which is known to act on a wide range of small molecules such as dialkylnitrosamines, urethane, vinyl monomers and haloalkanes, and CYP3A, which also activates PAHs, aflatoxins, and cooked food mutagens.

The chemistry of the activation process varies with the type of carcinogen. The oxidation of afla-toxin B1, for example, results in the formation of the 8,9-epoxide in a single step whereas the activation of PAHs, such as benzo(a)pyrene, is a multistep process involving an epoxide that is converted to a diol by epoxide hydrolase, which is then converted to the proximate carcinogenic species, a diol-epoxide. Activation of arylamines and amides to DNA reactive species, in contrast, frequently involves an initial oxidation step to an N-hydroxy derivative, which is then further metabolized to a highly reactive N-O-ester. This latter reaction is catalyzed by a transferase enzyme, usually sulfo-transferase or acetyltransferase for arylamines and glucuronotransferase for arylamides. Other oxida-tive reactions result in the formation of unstable compounds that decompose spontaneously to the ultimate carcinogenic species. Thus, simple nitro-samines are oxidized by CYP2E1 to an a-hydroxy intermediate, which breaks down to the electro-philic alkyldiazonium ion.

Enzyme systems other than the mixed function oxidase system may also be involved in the metabolic activation of carcinogens. Thus, for aflatoxins, there is evidence that prostaglandin H synthetase can activate this group of compounds and for arylamines, oxidation may be carried out by prosta-glandin peroxidase, myeloperoxidase, or by flavin-containing monooxygenases.

The direct metabolic activation of compounds to carcinogenic species by phase II metabolism, a process normally associated with detoxification, can also occur. Thus safrole and related compounds are converted to their sulfate esters, the ultimate carcinogenic species by the phase II enzyme, sulfotransferase.

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