Cancer risk related to genetic polymorphisms in carcinogen metabolism and DNA repair.

Chemical carcinogenesis involves metabolism in the body of the carcinogen to the ultimate carcinogen and its interaction with DNA. There is considerable interindividual variation in the metabolic ability to activate as well as detoxify the carcinogens and in the ability to repair the carcinogen-DNA adducts. In many cases such differences occur as genetic polymorphisms and form the basis for variation in susceptibility to carcinogens and thereby to cancer risk. The activation mechanism is particularly related to the cytochromes P-450 (CYPs), and four of these are known to activate carcinogens: CYP1A1, CYP1A2, CYP2E1, and CYP3A4. Increased cancer risk has been related to polymorphisms in the CYPs and other activating enzymes. The DNA repair mechanisms show considerable complexity, and deficient repair mechanisms in certain human disorders are clearly related to increased cancer risk. Yet, there is no unambiguous epidemiological evidence available for cancer risk among individuals in general. In vivo methods have to be refined and developed for use in epidemiological studies.