Ethnic and genetic differences in metabolism genes and risk of toxicity and cancer

Abstract

Individual risk of toxicity or cancer can be affected by one's exposure to sufficiently high doses of particular environmental agents (or mixtures), combined with each person's underlying genetic predisposition. The development of unequivocal DNA tests for genetic susceptibility to toxicity and cancer and the identification of individuals at increased risk, would revolutionize the fields of public health and preventive medicine. A growing number of human genetic polymorphisms in drug-metabolizing enzymes (DMEs) and the receptors controlling DME expression, are being characterized, some of these have been shown to be correlated with risk of toxicity or cancer, whereas, others presently remain equivocal and require further study. ‘Phase I’ DMEs, many of which represent cytochromes P450, sometimes metabolically activate pro-carcinogens to genotoxic electrophilic intermediates and other times are involved in detoxification. ‘Phase II’ DMEs are sometimes activating, but usually they conjugate Phase I intermediates to water-soluble derivatives, to complete the detoxification cycle. Genetic differences in the regulation, expression and activity of genes coding for Phase I and Phase II DMEs and DME receptors that control DME activity levels, can be crucial factors in defining cancer susceptibility and the toxic or carcinogenic power of environmental chemicals. In this review, our current knowledge about polymorphisms in several of these genes is summarized.