Metabolic activation and inactivation of chemical carcinogens.

Chemical carcinogens are metabolized by numerous pathways catalyzed by enzymes in endoplasmic reticulum and other parts of the cell. Reactions in which functional groups are created (epoxidation and epoxide hydration, catalyzed by cytochrome P-450-linked monooxygenase and epoxide hydratase, respectively) are especially important in the activation of polycyclic hydrocarbon carcinogens to ultimate carcinogenic forms, although other enzymes may also participate in the activation of other chemical carcinogens. Numerous factors, genetic as well as environmental, affect the activities and the balance of different enzymes that participate in carcinogen activation and detoxification. The reasons why carcinogens act on specific target tissues are incompletely understood, although differences in enzyme profiles between tissues certainly contribute to the target tissue variability. Also, the location in the cell (endoplasmic reticulum, nuclear membrane, or other organelle) where the activation takes place is not known. It has been demonstrated that conjugated metabolites of carcinogens may be activated by spontaneous or enzymatic hydrolysis, and this raises the possibility of transport of metabolites to distant target tissues. The concept of metabolic activation of carcinogens by body's own enzymes has led to the development of short-term assay systems, which essentially measure the production of biologically active metabolites from potential carcinogens.