Role of Methotrexate Polyglutamation and Reduced Folate Carrier 1 (RFC1) Gene Polymorphisms in Clinical Assessment Indexes

Abstract

The aims of the present study were to define inter-individual differences in response to methotrexate (MTX) through MTX polyglutamate (MTX-PG) levels in red blood cells (RBC) and MTX-related gene polymorphisms. A total of 145 rheumatoid arthritis patients were recruited. MTX-PG1-5 concentrations in RBC were measured, and 11 single nucleotide polymorphisms, all in MTX-related genes involved in the folate pathway, were analyzed. Disease activity was also assessed. There was no direct relationship between any MTX-PG concentration and the patient's disease condition, but detectability of MTX-PG5 was extracted as a candidate marker for response to MTX. When disease activity was compared between patients in which MTX-PG5 was detectable and undetectable, all indexes except the visual analog scale (VAS) and C-reactive protein (CRP) were found to be significantly lower in the former patients. Reduced folate carrier 1 (RFC1) 80G>A was significantly associated with the detectability of MTX-PG5; detectability of MTX-PG5 was lower in patients with the A mutant allele. The present study suggests that detectability of MTX-PG5 in RBC is a possible biomarker for response to MTX, and the RFC1 80G>A mutation is associated with low detectability of MTX-PG5. Prospective studies with a sufficient number of patients are needed to confirm the present findings.

Weekly split‐dose regimen for oral methotrexate reduced polyglutamation in red blood cells in patients with rheumatoid arthritis compared with single‐dose regimen: Results from a multicentered randomized control trial

“…According to non‐clinical studies, higher polymerization in MTX‐PGs led to stronger enzyme‐inhibiting activities 14‐16 . However, according to some previous reports of clinical analysis data, the treatment effects of MTX were correlated with total concentrations of MTX‐PGs, 17‐22 whereas the correlation between total MTX‐PG concentrations and effectiveness was not clear in other reports 23,24 . In this study, there was no considerable difference in the increase of MTX‐PG 2–5 concentrations between dose regimens.…”

Impact of genetic variants of RFC1, DHFR and MTHFR in osteosarcoma patients treated with high-dose methotrexate

“…Wang et al 34 concluded that RFC1 80 homozygote AA was significantly associated with increased risk of esophageal cancer in a Chinese population. Ando et al 35 observed that the level of PGMTX (PG-5) in red blood cells was lower in rheumatoid arthritis with 80 A allele. The common feature in these studies appears to be that the lower the concentration or retention of PGMTX in tumor cells is, the less the efficacy of the MTX and worse patient response.…”

Contribution of genetic polymorphism of methylene tetrahydrofolate reductase on the effect of methotrexate in ectopic pregnancy patients

“…As a transporter of folacin, RFC1 plays a critical role in membrane transport of MXT and its metabolites. RFC1 participates in regulating cellular uptake of MTX and cellular efflux of MTX‐PGs . RFC1 G80A impairs transporting of MTX into cells caused a lower level of MTX .…”

“…Intercellular MTX is converted to more active MTX‐PGs with up to seven glutamyl residues (MTX‐PG 1 to MTX‐PG 7 ). Longer chain polyglutamates have longer antifolate effects, with better retained in cells . Dervieux et al concluded that there was a higher level of intracellular MTX‐PG 5 in patients with RFC1 80AA genotype .…”