Z. Smolenska et al., Effect of methotrexate on blood purine and pyrimidine levels in patients with rheumatoid arthritis, RHEUMATOLOG, 38(10), 1999, pp. 997-1002
Objective. The mechanism of anti-inflammatory effects of methotrexate (MTX)
at low dose may relate to a decrease in availability of the purine precurs
or or it may depend on accumulation of 5-aminoimidazole-4-carboxamide (AICA
R) and the anti-inflammatory nucleoside adenosine. The aim of this study wa
s to evaluate the possible mechanism of action by analysis of changes in bl
ood concentrations of purine and pyrimidine metabolites during MTX treatmen
t.
Methods. Venous blood samples were collected from rheumatoid arthritis pati
ents before and at different times for up to 7 days after the start of MTX
treatment. Whole blood concentrations of adenosine, uridine, hypoxanthine,
uric acid and erythrocyte nucleotides were measured by HPLC.
Results. The initial blood adenosine concentration was 0.073 +/- 0.013 mu M
and no differences were observed during MTX treatment. However, a decrease
in uric acid concentration was observed from 205.5 +/- 13.5 to 160.9 +/- 1
3.5 mu M (P < 0.05) within 24 h after MTX administration. The hypoxanthine
concentration decreased in parallel with uric acid, while the uridine conce
ntration decreased 48 h after MTX administration. Nb accumulation of AICAR-
triphosphate (ZTP) was observed in the erythrocytes.
Conclusions. MTX decreases circulating purine and pyrimidine concentrations
, and their availability for DNA and RNA synthesis, which may affect immune
cell proliferation and protein (cytokine) expression. The absence of adeno
sine concentration changes and lack of ZTP formation is evidence against an
AICAR/adenosine mechanism; although localized adenosine concentration chan
ges cannot be excluded.