Phenotypes of TPMT activity:
(1) low
(2) intermediate
(3) high (normal)
(4) very high
TPMT alleles
(1) TPMT*1
(2) TPMT*2
(3) TPMT*3A: most prevalent in Whites
(4) TPMT*3C: most prevalent in Blacks
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TPMT Genotype
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Enzyme Activity
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homozygous TPMT*1
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high
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heterozygous TPMT*1 (with any of the other alleles)
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intermediate
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homozygous for any of the other alleles
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low
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Azathrioprine is converted to 6-mercaptopurine which is then either (1) inactivated by xanthine oxidase or TPMT, or (2) activated to cytotoxic 6-thioguanine nucleotides. Deficient activity in xanthine oxidase or TPMT results in higher concentrations of the 6-thioguanine nucleotides with a higher rate of adverse side effects.
Activity is measured in assays erythrocytes, with results reported in units of activity per mL of RBCs. 1 unit of TPMT is equivalent to conversion of 1 nmol of 6-mercaptopurine to 6-methyl-mercaptopurine per hour. The assay is performed on RBC lysates, and the hemoglobin of the lysates is used to report the activity per mL of RBCs.
Patients with low or intermediate TPMT activity tend to be intolerant of azathioprine therapy, with development of:
(1) nausea or vomiting
(2) pancreatitis
(3) bone marrow suppression, with neutropenia or pancytopenia
(4) flu-like illness
Patients with very high activity are often non-responders to azathioprine therapy at standard doses, and may require higher doses for therapeutic effect. However, the metabolite 6-methyl-mercaptopurine may be hepatotoxic this may limit the AZA dose that can be administered.
Limitations:
• Adverse effects to AZT are multifactorial. A person with high TPMT activity may develop myelosuppression or gastrointestinal toxicity, while a person with intermediate TPMT may tolerate therapy at a lower dose.
