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J Biol Chem, Vol. 273, Issue 34, 21682-21691, August 21, 1998
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From the The mode of action of Leflunomide, an
immunomodulatory drug used in rheumatoid arthritis, is debated. This
study, using 14C-labeled de novo purine
and pyrimidine synthesis precursors, proves conclusively that the prime
target in proliferating human T-lymphocytes is pyrimidine biosynthesis
at the level of dihydroorotic-acid dehydrogenase. Leflunomide (25 and
50 µM), like Brequinar (0.5 and 1 µM), a
demonstrated dihydroorotic-acid dehydrogenase inhibitor, was
cytostatic, not cytotoxic, with proliferation being halted in the
G1 phase. Both drugs restricted the normal 4-8-fold
mitogen-induced expansion of pyrimidine pools over 72 h to
concentrations found in nonstimulated T-cells and
[14C]bicarbonate incorporation into UTP, ATP, and GTP.
Uridine (50 µM) restored expansion of all pools, but
[14C]bicarbonate incorporation into ATP and GTP only, not
UTP. [14C]Hypoxanthine salvage was also restricted,
indicating that purine salvage pathways are compromised likewise by
both inhibitors. [14C]Glycine studies confirmed that
restriction of de novo purine synthesis occurred secondary
to inhibition of proliferation since this was reversed by uridine
rescue, except at 100 µM Leflunomide. 100 µM Leflunomide markedly depleted ATP and GTP pools also,
which would have serious consequences for ATP-dependent
enzymes essential to the immune response, thereby explaining
non-pyrimidine-related effects reported for Leflunomide at 100 µM and above.
Purine Research Laboratory and the
¶ Department of Allergy and Respiratory Medicine, United Medical
and Dental Schools of Guy's and St. Thomas' Hospitals, London Bridge
SE1 9RT, Great Britain, the § Department of Biochemistry and
Molecular Biology, Royal Free Hospital School of Medicine, London NW3
2PF, Great Britain, and Hoechst Marion Roussel, Frankfurt
D-65926, Germany
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