Molecular mechanisms of genetic polymorphisms of drug metabolism

One of the major causes of interindividual variation of drug effects is generic variation of drug metabolism. Genetic polymorphisms of drug-metabolizing enzymes give rise to distinct subgroups in the population that differ in their ability to perform certain drug biotransformation reactions. Polymorphisms are generated by mutations in the genes for these enzymes, which cause decreased, increased, or absent enzyme expression or activity by multiple molecular mechanisms. Moreover, the variant alleles exist in the population at relatively high frequency. Genetic polymorphisms have been described for most drug metabolizing enzymes. The molecular mechanisms of three polymorphisms are reviewed here. The acetylation polymorphism concerns the metabolism of a variety of arylamine and hydrazine drugs, as well as carcinogens by the cytosolic N-acetyltransferase NAT2. Seven mutations of the NAT2 gene that occur singly or in combination define numerous alleles associated with decreased function. The debrisoquine-sparteine polymorphism of drug oxidation affects the metabolism of more than 40 drugs. The poor metabolizer phenotype is caused by several ''loss of function'' alleles of the cytochrome P450 CYP2D6 gene. On the other hand, ''ultrarapid'' metabolizers are caused by duplication or amplification of an active CYP2D6 gene. Intermediate metabolizers are often heterozygotes or carry alleles with mutations that decrease enzyme activity only moderately. The mephenytoin polymorphism affects the metabolism of mephenytoin and several other drugs. Two mutant alleles of CYP2C19 have so far been identified to cause this polymorphism. These polymorphisms show recessive transmission of the poor or slow metabolizer phenotype, i.e. two mutant alleles define the genotype in these individuals. Simple DNA tests based on the primary mutations have been developed to predict the phenotype. Analysis of allele frequencies in different populations revealed major differences, thereby tracing the molecular history and evolution of these polymorphisms.