Phenotypic and Genotypic Characterization of N-Acetylation

Variation among the human population in the ability to acetylate drugs has been known since the observations on individual variations in isoniazid toxicity in the 1950s. The genetic basis for this was soon appreciated and has come to be known as the N -acetylation polymorphism. This chapter provides as background a description of some key studies that showed that acetylation was variable in the human population, that it is inherited, and the molecular basis for this phenomenon. Since accurate determination of acetylator phenotype is critical to testing a number of important hypotheses, including the link between disease risk and acetylator phenotype, limitations and potential problems with various methods of phenotype determination are discussed. Similarly, procedures and approaches for determination of NAT1 and NAT2 genotype are described. The final section brings phenotype and genotype together by examining the relationship between variant alleles and disease incidence. Increasingly, these studies have relied solely on the measurement of genotype, with the assumption that phenotype may be accurately deduced from genotype. There is a fairly wide degree of variability in the frequency of discordance between genotype and phenotype, however, especially when caffeine is used as a probe for phenotype determination. The potential consequences of this discordance are discussed.