Interethnic differences of drug-metabolizing enzymes

Polymorphisms exhibited by drug-metabolizing enzymes are well known and have been investigated for many years. Recently, the exploding field of pharmacogenetics has focused not only on the characterization of enzymes responsible for drug biotransformation but also, on describing the sources of variability in enzyme activity. While initial observations and studies focused on populations of Caucasian origin, reports for other populations followed. The incidence of a poor or slow metabolizer phenotype for a given enzyme caused by allelic variants may vary significantly between populations. The question arises as to whether a prediction of the phenotype (i.e. distribution and/or enzyme activity) can be accurately ascertained from genotype information gathered in a related population. This is exemplified by NAD(P):quinone oxidoreductase (NQO1) investigated in Canadian Native Indian (CNI), Inuit and Chinese populations and the cytochromes P4502C19 and 2D6. While the two North American Native populations are genetically distinct, they are both descendants from northern Asia. Consequently, one might suspect that on a pharmacogenetic basis, CNI and Inuit would be more comparable to Chinese as opposed to Caucasian populations. This is certainly not the case as demonstrated for all three enzymes. Also, for a reliable phenotype prediction, one needs to pay attention to ethnic "mixing" which occurs between certain populations. Ethnic diversity constitutes both a challenge and an opportunity to prudently apply pharmacogenetics so that variability in both drug disposition and effect may be better understood.