Abstract
We investigated major determinants of the intracellular concentrations of methotrexate polyglutamates (MTXPGs) in patients with rheumatoid arthritis (RA). In 271 RA patients on stable oral low dose weekly pulse MTX therapy, the concentrations of MTXPGs in red blood cells (RBCs) were measured by liquid chromatography-electrospray ionization-tandem mass spectrometry. Polymerase chain reaction-restriction fragment length polymorphism analysis was performed to determine the genotypes of solute carrier family 19 member 1 (SLC19A1), folylpolyglutamate synthase (FPGS), and gamma-glutamyl hydrolase (GGH). The mean total MTXPG concentration and the concentrations of individual MTXPGs increased dose-dependently, but reached a plateau at MTX doses >10 mg weekly. The MTXPG3-5/1-2 ratio was lower in patients with adverse events related to MTX than in patients without adverse events. Three polymorphisms of FPGS significantly influenced the MTXPG3-5/1-2 ratio in RBCs, while polymorphisms of SLC19A1 and GGH had no impact. The minor allele frequencies of 2 FPGS genotypes were significantly increased in our patients compared with a Caucasian population. FPGS may have a major role in regulating intracellular polyglutamation of MTX in RA patients receiving low-dose weekly MTX therapy.
Highlights
MTX binds to a folate transporter in order to enter target cells[4]
To examine the association between the MTX polyglutamates (MTXPGs) concentration in red blood cells (RBCs) and polymorphism of the genes for enzymes involved in intracellular MTX metabolism, we investigated polymorphisms of SLC19A1, folylpolyglutamate synthetase (FPGS), and Gamma-glutamyl hydrolase (GGH) (Table 3)
The total MTXPG concentration in RBCs and the individual concentrations of MTXPG1-5 were analyzed after stratification by the weekly dose
Summary
MTX binds to a folate transporter (solute carrier family 19, member 1 [SLC19A1], known as reduced folate carrier 1) in order to enter target cells[4]. Intracellular MTXPGs are considered to have a major role in suppressing both cell-mediated immunity and humoral immunity, as well as exerting anti-inflammatory and immunosuppressive effects through inhibition of DNA synthesis or amino acid metabolism. For that reason and because of its known mechanism of action, attention has been directed toward the intracellular MTXPG concentration as a potential predictor of the response to MTX treatment. The cells that are considered to be direct targets of MTX (such as peripheral blood lymphocytes) are difficult to collect an adequate quantity, and measurement of the MTX concentration in these cells is not easy in human studies[9]. Researchers have measured the MTXPG concentration in red blood cells (RBCs) and have investigated its association with the clinical response to MTX9,10. We investigated polymorphism of the SLC19A1, FPGS, and GGH genes, which play a vital role in intracellular metabolism of MTX
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