ABSTRACT
The antiproliferative effect of the leflunomide metabolite is due to a change in the de novo synthesis of pyrimidines and is reversed by the addition of uridine to in vitro culture systems. It is also partially reversed by the addition of cytidine. It appears that the metabolite binds to a key enzyme in the pyrimidine pathway, which is termed dihydro-orotate dehydrogenase. As a consequence of enzyme inhibition, there is a reduction in uridine triphosphate (UTP) levels, and to a lesser
extent other high-energy phosphates (CTP, ATP, and GTP). In vivo pyrimidine synthesis by lymphocytes and other rapidly dividing cells may therefore be reduced, leading to changes in DNA and RNA synthesis, cell proliferation, and glycosylation.
