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Abstract
Leflunomide [HWA 486 or RS-34821, 5-methyl-N-(4-trifluoromethylphenyl)-4-isoxazole
carboximide] is an immunosuppressive agent effective in the treatment of rheumatoid
arthritis. In spite of its clinical potential, its mechanism of action has not been
elucidated. Recent studies suggest that leflunomide may interfere with the metabolism
of pyrimidine nucleotides. In our studies, the active metabolite of leflunomide, RS-61980
(A77 1726, 2-hydroxyethylidene-cyanoacetic acid-4-trifluoromethyl anilide), was cytostatic
towards a human T-lymphoblastoma cell line (A3.01). The inhibition of growth could
be overcome completely by uridine. The other nucleosides, cytidine, adenosine and
guanosine, did not overcome the effect of the compound. Since uridine is a precursor
for the salvage synthesis of UMP, we propose that RS-61980 may be inhibiting the de
novo pathway of UMP synthesis. Using human cells, the six enzymes catalyzing de novo
UMP biosynthesis were tested for their sensitivity towards RS-61980. Only one of the
enzymes, dihydroortate dehydrogenase (DHODH, EC 1.3.3.1) was inhibited by RS-61980
with a Ki value of 2.7 +/- 0.7 microM. The other five enzymes were not affected. The
inhibition exhibited mixed-type kinetics towards both substrates, dihydroorotic acid
and coenzyme Q. These results suggest that the molecular target of leflunomide action
is DHODH. The immunomodulating activity may be related to the inhibition of UMP synthesis
in proliferating lymphocytes.