Differential effects of thiopurine methyltransferase (TPMT) and multidrug resistance-associated protein gene 4 (MRP4) on mercaptopurine toxicity.

Abstract

PURPOSE:

Mercaptopurine plays a pivotal role in treatment of acute lymphoblastic leukemia (ALL) and autoimmune diseases, and inter-individual variability in mercaptopurine tolerance can influence treatment outcome. Thiopurine methyltransferase (TPMT) and multi-drug resistant Protein 4 (MRP4) have both been associated with mercaptopurine toxicity in clinical studies, but their relative contributions remain unclear.

METHODS:

We studied the metabolism of and tolerance to mercaptopurine in murine knockout models of Tpmt, Mrp4, and both genes simultaneously.

RESULTS:

Upon mercaptopurine treatment, Tpmt -/- Mrp4 -/- mice had the highest concentration of bone marrow thioguanine nucleotides (8.5 pmol/5 × 106 cells, P = 7.8 × 10-4 compared with 2.7 pmol/5 × 106 cells in wild-types), followed by those with Mrp4 or Tpmt deficiency alone (6.1 and 4.3 pmol/5 × 106 cells, respectively). Mrp4-deficient mice accumulated higher concentrations of methylmercaptopurine metabolites compared with wild-type (76.5 vs. 23.2 pmol/5 × 106 cells, P = 0.027). Mice exposed to a clinically relevant mercaptopurine dosing regimen displayed differences in toxicity and survival among the genotypes. The double knock-out of both genes experienced greater toxicity and shorter survival compared to the single knockout of either Tpmt (P = 1.7 × 10-6) or Mrp4 (P = 7.4 × 10-10).

CONCLUSIONS:

We showed that both Tpmt and Mrp4 influence mercaptopurine disposition and toxicity.

• Authors: Chengcheng Liu, Laura J Janke, Jun J Yang, William E Evans, John D Schuetz, Mary V Relling
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 80 Issue 2 Pg. 287-293 (Aug 2017) ISSN: 1432-0843 [Electronic] Germany
• PMID: 28623449 (Publication Type: Journal Article)

Chemical References

• Abcc4 protein, mouse
• Antimetabolites, Antineoplastic
• Multidrug Resistance-Associated Proteins
• 6-methylthiopurine
• Mercaptopurine
• Methyltransferases
• thiopurine methyltransferase

Topics

• Animals
• Antimetabolites, Antineoplastic (administration & dosage, pharmacokinetics, toxicity)
• Female
• Genotype
• Male
• Mercaptopurine (administration & dosage, analogs & derivatives, metabolism, pharmacokinetics, toxicity)
• Methyltransferases (genetics)
• Mice, Knockout
• Multidrug Resistance-Associated Proteins (genetics)