Chemoprevention by phytochemical modifiers of carcinogen metabolism

A variety of carcinogens, such as polycyclic aromatic hydrocarbons, aro-matic amines, heterocyclic aromatic amines, N-nitroso compounds, and aflatoxins, are believed to be causes of major human cancers (Baird and Ralston, 1997; Delelos and Kadlubar, 1997; Adamson et al., 1995; Hecht, 1998a; Kensler and Groopman, 1997). Virtually all carcinogens to which humans are exposed require enzymatic transformation to exert their carcinogenic effects. The most common enzymatic process is addition of oxygen, catalyzed by cytochrome P450 enzymes (Guengerich, 1997). This generally increases the polarity of the molecule facilitating excretion. This type of transformation is referred to as Phase 1 metabolism. Some of the intermediates formed in this process may be electrophiles, which can react with nucleophilic sites in critical macromolecules, such as DNA, RNA, and protein. The DNA adducts that are formed can persist if they escape cellular repair mechanisms. These adducts have the potential to cause miscoding, thus producing permanent mutations in critical genes, such as oncogenes and tumor suppressor genes (Bowden, 1997; Balmain, 1997). Multiple mutations of this type are involved in cancer induction. The conversion of a carcinogen to a macromolecular adduct is called metabolic activation. Competing with metabolic activation is detoxification. A second group of enzymes, Phase 2 enzymes, are important in detoxification. These enzymes, typified by glutathione-S-transferases, UDP glucuronosyl transferases, and sulfotransferases, add polar moieties to the oxygenated carcinogen, generally producing highly polar molecules that are readily excreted (Armstrong, 1997; Burchell et al., 1997; Duffel, 1997).