A patient on 6-mercaptopurine develops profound myelosuppression at a standard dose. Genotyping reveals absent activity of thiopurine methyl methyltransferase (TPMT). What is the initial biochemical step required for 6-mercaptopurine cytotoxicity, and how does TPMT normally interact with the drug pathway?

• A Activation by adenosine kinase to thio-ATP; TPMT deaminates the drug, so its absence increases potency safely
• B Activation by xanthine oxidase to thio-IMP; TPMT transports the drug into cells, so its absence reduces efficacy
• C Activation by HGPRT to thio-IMP; TPMT methylates and inactivates the drug, so its absence causes toxicity ✓
• D Direct binding to ribonucleotide reductase without activation; TPMT excretes the drug, so its absence prolongs half-life harmlessly

Explanation

6-Mercaptopurine is a prodrug converted intracellularly by HGPRT into thioinosinic acid (TIMP), which blocks purine synthesis. TPMT normally S-methylates and thereby detoxifies thiopurines; homozygous TPMT deficiency allows excessive active thioguanine nucleotide accumulation, producing severe marrow suppression. Allopurinol coadministration also raises toxicity risk because it blocks xanthine oxidase, another inactivating route, but the genotoxicity here is specifically TPMT related.

Reference: Robbins and Cotran Pathologic Basis of Disease, 10th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.