Deficiency in TPMT causes life-threatening myelosuppression after thiopurines?

• A. TPMT
• B. CYP2D6
• C. G6PD
• D. GSTP1

Answer: (A)

Thiopurines such as azathioprine and 6-mercaptopurine are inactivated by TPMT through methylation. When TPMT activity is deficient, this inactivation pathway is reduced, so more active thioguanine nucleotide metabolites accumulate in bone marrow cells. Those cytotoxic metabolites disrupt DNA synthesis in rapidly dividing cells, leading to severe, potentially life-threatening myelosuppression. This is why TPMT testing or genotyping is important before starting thiopurines, so dosing can be adjusted to minimize toxicity. The other enzymes listed aren’t the primary determinants of this toxicity: CYP2D6 handles many other drugs, not the key thiopurine inactivation; G6PD deficiency mainly predisposes to oxidative hemolysis with certain drugs; GSTP1’s detox role isn’t the main factor driving TPMT-related myelosuppression.