Polymorphism of genes encoding drug-metabolizing enzymes is the major known genetic cause for the interindividual variability in drug response.[1-6] Based on the occurrence of mutations in these genes, gene deletions, and gene duplications, the populations can be divided into poor (PM), intermediate (IM), efficient (EM), or ultrarapid (UM) drug metabolizers. The PMs lack the enzyme in question, the IMs are heterozygous for a defect gene, the EMs have two functional alleles, whereas the UMs have multiple functional gene copies on a single allele.
All enzymes participating in the metabolism of drugs in phase I (functionalization) and phase II, where the modified drugs are conjugated to water-soluble end products usually excreted in the urine, are polymorphic. This genetic polymorphism can thus cause abolished, quantitatively or qualitatively altered or enhanced drug metabolism. The evolutionary basis for this variability is adaptation to the environment in the form of dietary habits and genetic drift, the founder effect. Because the genes usually are not essential for survival but of importance for detoxification of environmental constituents including dietary components, no selection pressure is put on the conservation of functionally active genes; subjects lacking one or several types of these genes usually have a normal physiological phenotype. The major part of the interethnic differences in the genetic constitution of these genes is a result of incidental mutations in the genes, amplified in certain areas because of population expansion. The lack of endogenous function of the gene products has thus allowed this extensive heterogeneity with respect to allelic distributions in different parts of the world.
The major influence of interindividual variability of drug metabolism is caused by polymorphism in the cytochrome P450 (CYP) genes. These enzymes are responsible for about 75-80% of the phase I-dependent drug metabolism, and this variation often influences the clearance of drugs to a great extent.
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