Diet, genetic polymorphisms, detoxification, and health risks.

Modulation of detoxification enzymes is one mechanism by which diet may influence risk of cancer and other diseases. However, genetic differences in taste preference, food tolerance, nutrient absorption, and metabolism and response of target tissues all potentially influence the effect of diet on disease risk. Thus, disease prevention at the individual and population level needs to be evaluated in the context of the totality of genetic background and exposures to both causative agents and chemopreventive compounds. Polymorphisms in the detoxification enzymes that alter protein expression and/or function can modify risk in individuals exposed to the relevant substrates. Diet is a mixture of carcinogens, mutagens, and protective agents that are all metabolized by detoxification enzymes. Genotypes associated with more favorable handling of carcinogens may be associated with less favorable handling of phytochemicals. For example, glutathione S-transferases (GST) detoxify polycyclic aromatic hydrocarbons present in grilled meats. GSTs also conjugate isothiocyanates, the chemopreventive compounds found in cruciferous vegetables. Polymorphisms in the GSTM1 and GSTT1 genes result in complete lack of GSTM1-1 and GSTT1-1 proteins, respectively. In some observational studies of cancer, cruciferous vegetable intake confers greater protection in individuals with these polymorphisms; however, in other studies, the converse is observed. A recent study of sulforaphane pharmacokinetics suggests that lack of the GSTM1 enzyme is associated with more rapid excretion of sulforaphane. Many phytochemicals are also conjugated with glucuronide and sulfate moieties, and are excreted in urine and bile. Polymorphisms in UDP-glucuronosyltransferases (UGT) and sulfotransferases (SULT) may contribute to the variability in phytochemical clearance and efficacy. The effects of UGT polymorphisms on flavonoid clearance have not been examined, but UGT polymorphisms affect glucuronidation of several drugs and steroid hormones. Genetic polymorphisms in detoxification enzymes may account in part for individual variation in disease risk but have to be considered in the context of other aspects of human genetics, gut bacterial genetics, and environmental exposures.