Which enzyme deficiency would cause severe toxicity during thiopurine treatment if reduced?

Which enzyme deficiency would cause severe toxicity during thiopurine treatment if reduced?

• A. CYP450
• B. TPMT
• C. N-acetyltransferase
• D. Glutathione S-transferase

Answer: (B)

Thiopurines are activated inside cells and then split into active toxic metabolites and inactive forms. The enzyme TPMT is responsible for converting thiopurines into inactive, methylated compounds, which keeps the level of active thioguanine nucleotides (TGNs) under control. When TPMT activity is reduced or absent, there is less inactivation, so TGNs accumulate and cause marked suppression of bone marrow, leading to severe toxicity at standard doses. That is why TPMT deficiency is the strongest predictor of serious toxicity with thiopurine therapy. In clinical practice, TPMT activity or genotype is checked before starting treatment, and dosing is adjusted accordingly or alternative therapies are considered if activity is low. The other enzymes listed aren’t the key determinants of thiopurine inactivation, so their deficiencies wouldn’t explain the same risk of severe toxicity.

Thiopurines are activated inside cells and then split into active toxic metabolites and inactive forms. The enzyme TPMT is responsible for converting thiopurines into inactive, methylated compounds, which keeps the level of active thioguanine nucleotides (TGNs) under control. When TPMT activity is reduced or absent, there is less inactivation, so TGNs accumulate and cause marked suppression of bone marrow, leading to severe toxicity at standard doses. That is why TPMT deficiency is the strongest predictor of serious toxicity with thiopurine therapy. In clinical practice, TPMT activity or genotype is checked before starting treatment, and dosing is adjusted accordingly or alternative therapies are considered if activity is low. The other enzymes listed aren’t the key determinants of thiopurine inactivation, so their deficiencies wouldn’t explain the same risk of severe toxicity.