The TPMT Polymorphism

Krynetski E, Evans WE. Drug methylation in cancer therapy lessons from the TPMT polymorphism. 

Population studies have found that approximately ll Pbof Caucasians are heterozygous and 0.3% homozygous for TPMT deficiency (73). For the TPMT polymorphism, all patients who inherit two non-functional TPMT alleles will develop dose-limiting hematopoi-... 

Tai HI, Krynetski EY, Schuetz EG, Ya-shinevski Y, Evans WE. Enhanced proteolysis of thiopurine S-methyltransferase (TPMT) encoded by mutant alleles in human (TPMT 3A, TPMT 2) mechanism for the genetic polymorphism of TPMT activity. Proc Natl Acad Sci USA 1997 94 6444-6449. 

The activity of TPMT is influenced by genetic polymorphisms that can alter the rate of 6-MP metabolism by TPMT. The enzyme activity of TPMT varies among patients 86.6% of the Caucasian population has high TPMT activity, 11.1% has intermediate activity, and 0.3% are deficient in TPMT (42-44). The TPMT found in patients with normal TPMT activity is classified as the wild-type TPMT 1. 

AZA because of toxicity. Of the 6 patients with severe GI toxicity, 3 were heterozygous for the TPMT3A allele the remainder possessed the wild-type TPMT allele. The correlation between the TPMT allele and AZA toxicity was significant, p =0.018. Based on the resnlts of this stndy, the positive predictive valne for a TPMT polymorphism carrier was 60% (49). 

Moreover, it was shown that ehaperone proteins, espeeially hsp90, are involved in targeting TPMT 3A (176) and very reeently the assumption that the TPMT 3A polymorphisms might result in misfolding and protein aggregation with ag-gresome formation was elueidated (177). 

In 155 Chinese kidney transplant recipients, the allele frequency of the 94C>A polymorphism, which leads to reduced ITPA activity, was 0.12 [169. Patients with the ITPA 94C>A homozygous allele are at high risk of azathioprine-related gastrointestinal toxicity and flu-like symptoms. The TPMT wild-type/homozygous ITPA variant is closely related to azathioprine-induced adverse reactions. 

In vivo azathioprine is rapidly converted into its active metabolite 6-mercaptopurine by the enzyme thiopurine methyltransferase (TPMT). The active agent inhibits IMPDH function. Furthermore, it also acts as antimetabolite of the RNA and DNA synthesis particularly in T-lymphocytes leading to cell death. Due to genetic polymorphism of TPMT, therapy may fail, thus it is currently discussed whether individual patients should be monitored before the use of azathioprine. 

Mercaptopurine (6-MP) is an oral purine analog that is converted to a ribonucleotide to inhibit purine synthesis. Mercaptopurine is converted into thiopurine nucleotides, which are catabolized by thiopurine S-methyltransferase (TPMT), which is subject to genetic polymorphisms and may cause severe myelosuppression. TPMT status may be assessed prior to therapy to reduce drug-induced morbidity and the costs of hospitalizations for neutropenic events. Mercaptopurine is poorly absorbed, with a time to peak concentration of 1 to 2 hours after an oral dose. The half-life is 21 minutes in pediatric patients and 47 minutes in adults. Mercaptopurine is used in the treatment of acute lymphocytic leukemia and chronic myelogenous leukemia. Significant side effects include myelosuppression, mild nausea, skin rash, and cholestasis. When allopurinol is used in combination with 6-MP, the dose of 6-MP must be reduced by 66% to 75% of the usual dose because allopurinol blocks the metabolism of 6-MP. 

Seki T, Tanaka T, Nakamura Y. Genomic stmcture and multiple single-nucleotide polymorphisms (SNPs) of the thio-purine S-methyltransferase (TPMT) gene. J Hum Genet 2000 45 299-302. 

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