Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues

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Azathioprine Treatment [T88.7]

OMIM numbers: 610460, 187680 (TPMT)

Dipl.-Biol. Birgit Busse

Scientific Background

The enzyme thiopurine S-methyltransferase (TPMT) catalyzes the addition of a methyl group to the respective sulfhydryl group of thiopurine such as azathioprine (AZA), 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG). This methylation prevents the incorporation of the nucleotide analogs into the DNA/RNA during the nucleic acid synthesis and is thus a crucial reaction for the inactivation of cytotoxic compounds.

Variants in the TPMT gene lead to an enzyme deficiency, which results in impairment of the inactivation of the thiopurines. Accumulation of thioguanine nucleotides in the hematopoietic tissue may lead to fatal myelosuppressions. The alleles TPMT*2, *3A, *3B and *3C are the most frequent cause for a genetically caused TPMT deficiency. Determination of the TPMT genotype prior to treatment with TPMT substrates allows for individual dosage adjustment and prevention of undesired side-effects. The FDA has already included the association of enzyme activity, genotype and dosage into the warnings/precautions section in the prescribing information.