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 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.

Identification of MRP4/ABCC4 as a Target for Reducing the Proliferation of Pancreatic Ductal Adenocarcinoma Cells by Modulating the cAMP Efflux

“…Nevertheless, these mice did not show major physiologic alterations (Russel et al, 2008), indicating that MRP4 inhibition could be a feasible therapeutic approach. Also, exposition of the knockout mice to several drugs highlighted MRP4 role in the excretion of such agents, as they presented altered cytotoxicity and tissue distribution compared with wild-type animals (Leggas et al, 2004;Zamek-Gliszczynski et al, 2006;Takenaka et al, 2007;Liu et al, 2017). Moreover, several FDA-approved drugs inhibit MRP4 activity without showing any serious adverse effects (Yaneff et al, 2017).…”

The genetic vulnerability to cisplatin ototoxicity: a systematic review

“…It was recently demonstrated that HEI-OC1 and UB / OC-1 cells derived from the cochlea are more sensitive to cisplatin when expressing the TPMT *3A variant instead of the wild-type Tpmt 65 . In contrast, Tpmt knock-out mice do not display an increased sensitivity to cisplatin when administered at comparable levels as found in humans 66 , however this result might not be surprising given the known resistance of mice to cisplatin ototoxicity when compared to rats or guinea pigs 67 .…”

Pharmacogenomic and Pharmacotranscriptomic Profiling of Childhood Acute Lymphoblastic Leukemia: Paving the Way to Personalized Treatment

“…Pharmacogenes that encode transporters and enzymes involved in the clearance of thiopurine drugs have been in the focus, in particular ITPA and ABCC4 . The ITPA enzyme catalyzes hydrolysis of the pyrophosphate group from purine analogs triphosphates, which interferes with their incorporation into DNA [127], while the ABCC4 transporter exports thiopurine drugs and their metabolites [128]. Lower activity variants of ITPA and ABCC4 [129] genes have been associated with a diminished tolerance of thiopurine therapy, however, this is inconsistent [130,131].…”