[Interindividual differences in the reaction to drugs and poisons]

Two major groups of factors influence the kinetics and dynamics of drugs and chemicals, namely environmental factors such as cigarette smoking, nutrition, drug-interaction, etc., and genetic factors. The major site of variation is the biotransformation of these compounds in the liver, i.e. the enzyme systems involved in the metabolism of xenobiotics into inactive, active and toxic metabolites. Of particular importance are inherited polymorphisms of these enzymes which lead to subgroups in the population with a deficit in certain biotransformation reactions. These subgroups are at higher risk to develop adverse reactions with certain drugs or chemicals, including chemicals with mutagenic and carcinogenic potential. Deficient individuals are designated as 'poor metabolizers' or 'slow metabolizers' as compared to the normal 'extensive' or 'rapid metabolizers'. Two of the genetic polymorphisms of drug biotransformation have been elucidated in this laboratory at the molecular level, and simple DNA tests can now identify these risk populations. This applies to the debrisoquine polymorphism and the acetylation polymorphism. 5 to 10% of the population in Europe and North America are poor metabolizers of debrisoquine and 25 other drugs. They have an increased risk to develop adverse reactions to these drugs. 40 to 70% of this population are slow acetylators, and they may have an increased risk to develop certain cancers when exposed to arylamine chemicals. Both polymorphisms are inherited as autosomal recessive traits.