Gene Approach

2.1.1. 6-Mercaptopurine and TPMT

The thiopurine S-methyltransferase (TPMT) genetic polymorphism has long served as a prototype of the clinical potential of pharmacogenetics. TPMT is a cytosolic metabolizing enzyme that catalyzes the S-methylation of thiopurine drugs such as 6-mercaptopurine (6-MP), 6-thioguanine, and azathioprine. In patients with exceptionally low TPMT activity (~1 in 300 individuals), thiopurine drugs may cause severe and sometimes life-threatening hematopoietic toxicity (9,10,11,12,13). Therefore, substantial (~ 10-fold) dosage reduction is required in patients with the homozygous mutant TPMT genotypes to avoid toxicity (13,14,15).

In Caucasians, the three most common variant genotypes, TPMT*3A (Ala154Thr and Tyr240Cys), TPMT*3C (Tyr240Cys), and TPMT*2 (Ala80Pro), account for >95% of the low-activity phenotypes. The U.S. FDA has added TPMT genetic information to the package inserts of thiopurine drugs, which recommends TPMT testing (genotypic testing for TPMT*3A, *3C, and *2 and/or phenotypic testing of thiopurine nucleotides and TPMT activity in erythrocytes) if patients exhibit clinical or laboratory evidence of severe toxicity, particularly myelosuppression.

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