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Pharmacogenomics: Catechol O-Methyltransferase to Thiopurine S-Methyltransferase

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1. Pharmacogenomics is the study of the role of inheritance in variation in the drug response phenotype—a phenotype that can vary from adverse drug reactions at one end of the spectrum to lack of therapeutic efficacy at the other.

2. The thiopurine S-methyltransferase (TPMT) genetic polymorphism represents one of the best characterized and most clinically relevant examples of pharmacogenomics. This polymorphism has also served as a valuable “model system” for studies of the ways in which variation in DNA sequence might influence function.

3. The discovery and characterization of the TPMT polymorphism grew directly out of pharmacogenomic studies of catechol O-methyltransferase (COMT), an enzyme discovered by Julius (Julie) Axelrod and his coworkers.

4. This review will outline the process by which common, functionally significant genetic polymorphisms for both COMT and TPMT were discovered and will use these two methyltransferase enzymes to illustrate general principles of pharmacogenomic research—both basic mechanistic and clinical translational research—principles that have been applied to a series of genes encoding methyltransferase enzymes.

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ACKNOWLEDGMENTS

I thank Mrs. Luanne Wussow for her assistance with the preparation of this manuscript. Supported in part by NIH grants R01 GM28157, R01 GM35720 and U01 GM61388 (The Pharmacogenetics Research Network).

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  1. Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Mayo Clinic, Rochester, Minnesota, 55905, USA

    Richard M. Weinshilboum

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Weinshilboum, R.M. Pharmacogenomics: Catechol O-Methyltransferase to Thiopurine S-Methyltransferase. Cell Mol Neurobiol 26, 537–559 (2006). https://doi.org/10.1007/s10571-006-9095-z

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