Gene Number: 7172

Location: 6p22.3

Key Functions: Thiopurine metabolism, drug detoxification, TPMT enzymatic activity

The TPMT gene, located on chromosome 6p22.3, encodes thiopurine S-methyltransferase, a cytosolic enzyme that plays a pivotal role in the metabolism and detoxification of thiopurine drugs—a class of medications widely used in the treatment of leukemia, autoimmune diseases, and organ transplant rejection. This enzyme catalyzes the S-methylation of thiopurine compounds such as azathioprine, 6-mercaptopurine (6-MP), and thioguanine, converting them into inactive metabolites that are less cytotoxic.

In pharmacogenetic terms, TPMT is a cornerstone example of how genetic variation dictates drug response. The enzyme’s activity is highly polymorphic, with common variants—such as TPMT*2 (rs1800462, G238C), TPMT*3A (rs1800460, A719G; rs1142345, G460A), and TPMT*3C (rs1142345, G460A)—leading to markedly reduced or absent enzyme function. Individuals carrying two nonfunctional alleles (homozygous poor metabolizers) accumulate excessive thioguanine nucleotides in bone marrow cells when treated with standard thiopurine doses, resulting in life-threatening myelosuppression.

Conversely, individuals with intermediate activity (heterozygous carriers) show partial enzymatic function and require substantial dose adjustments to balance efficacy and toxicity. Only about 90% of the population possess fully functional TPMT activity, underscoring the enzyme’s clinical relevance in personalized medicine.

Mechanistically, TPMT competes with hypoxanthine-guanine phosphoribosyltransferase (HGPRT) and other metabolic enzymes that activate thiopurines into cytotoxic 6-thioguanine nucleotides (6-TGNs). By methylating these intermediates, TPMT acts as a biochemical “safety valve,” maintaining a therapeutic equilibrium between anticancer efficacy and hematologic toxicity.

Clinically, TPMT genotyping or phenotyping is now standard practice prior to initiating thiopurine therapy, preventing avoidable adverse reactions and optimizing dosing precision. In this way, TPMT exemplifies the growing integration of pharmacogenomics into modern medicine—where one’s genetic code guides the safe and effective use of powerful chemotherapeutic and immunosuppressive agents.