title: Folylpolyglutamate synthase is a major determinant of intracellular methotrexate polyglutamates in patients with rheumatoid arthritis.
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.
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, School of Medicine, Faculty of Medicine, Toho University, Tokyo 143-8541, Japan.
authors.forename: Tatsuhiro
authors.initials: T
authors.lastname: Yamamoto
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, School of Medicine, Faculty of Medicine, Toho University, Tokyo 143-8541, Japan.
authors.forename: Kotaro
authors.initials: K
authors.lastname: Shikano
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, School of Medicine, Faculty of Medicine, Toho University, Tokyo 143-8541, Japan.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Nanki
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, School of Medicine, Faculty of Medicine, Toho University, Tokyo 143-8541, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Kawai
mesh_terms: D000368:Aged; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000235:genetics; D004912:Erythrocytes / Q000378:metabolism; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D007564:Japan; D008297:Male; D008727:Methotrexate / Q000031:analogs & derivatives* / Q000378:metabolism / Q000627:therapeutic use; D008875:Middle Aged; D010453:Peptide Synthases / Q000235:genetics / Q000378:metabolism*; D011099:Polyglutamic Acid / Q000031:analogs & derivatives* / Q000378:metabolism / Q000627:therapeutic use; D011110:Polymorphism, Genetic; D058978:Reduced Folate Carrier Protein / Q000235:genetics*; D011623:gamma-Glutamyl Hydrolase / Q000235:genetics*
chemical_list: D058978:Reduced Folate Carrier Protein; C548699:SLC19A1 protein, human; D011099:Polyglutamic Acid; C014085:methotrexate polyglutamate; D011623:gamma-Glutamyl Hydrolase; D010453:Peptide Synthases; C023103:folylpolyglutamate synthetase; D008727:Methotrexate