Methylation pharmacogenetics: Catechol O-methyltransferase, thiopurine methyltransferase, and histamine N-methyltransferase

Methyl conjugation is an important pathway in the biotransformation of many exogenous and endogenous compounds. Pharmacogenetic studies of methyltrans ferase enzymes have resulted in the identification and characterization of functionally important common genetic polymorphisms for catechol O-methyltr ansferase, thiopurine methyltransferase, and histamine N-methyltransferase. In recent years, characterization of these genetic polymorphisms has been extended to include the cloning of cDNAs and genes, as well as a determinat ion of the molecular basis for the effects of inheritance on these methyltr ansferase enzymes. The thiopurine methyltransferase genetic polymorphism is responsible for clinically significant individual variations in the toxici ty and therapeutic efficacy of thiopurine drugs such as B-mercaptopurine. P henotyping for the thiopurine methyltransferase genetic polymorphism repres ents one of the first examples in which testing for a pharmacogenetic varia nt has entered standard clinical practice. The full functional implications of pharmacogenetic variation in the activities of catechol O-methyltransfe rase and histamine N-methyltransferase remain to be determined. Finally, ex perimental strategies used to study methylation pharmacogenetics illustrate the rapid evolution of biochemical, pharmacologic, molecular, and genomic approaches that have been used to determine the role of inheritance in vari ation in drug metabolism, effect, and toxicity.