A77 1726 inhibits cell proliferation in activated lymphocytes in patients with active RA. In vitro data indicate that the drug inhibits the enzyme dihydro-orotate dehydrogenase (DHODH), which is the fourth enzyme utilized in the de novo purine synthesis pathway (70). By inhibiting uridine 5'-monophosphate (UMP) production, the levels of ribonucleo-tides and deoxyribonucleotides necessary for DNA and RNA synthesis are reduced. The interruption to DNA synthesis results in lymphocyte cell arrest (Fig. 4). The induction of arrest of activated autoimmune lymphocytes by leflunomide thereby reduces the autoimmune response in RA patients. When antirheumatic activity of leflunomide was observed, it was unclear as to whether it inhibited DHODH (71) or tyrosine kinases, which transfer ATPs terminal phosphate to a tyrosine residue on another protein. Davis et al. (71) established that leflunomide had no inhibitory effects on DHODH or tyrosine kinases but noted that A77 1726 had a concentration-dependent inhibitory effect on DHODH, with DHODH requiring both substrate and an electron acceptor. Although it was found that A77 1726 inhibits the activity of tyrosine kinases, the concentrations needed were much greater than the usual therapeutic concentrations seen in RA. DHODase inhibition is therefore potentially the main mechanism of action of this novel
Figure 4 Proposed inflammatory pathways for the active moiety of leflunomide, A77 1726, in rheumatoid arthritis. At pharmacological concentrations, inhibition of DHODH (gray box) appears to be the most important mechanism leading to a reduction in pyrimidine synthesis in proliferating lymphocytes and cell cycle. Abbreviations: NF-kB, nuclear factor-^B. DHODH, dihydro-orotate synthase.
immunosuppressive agent. DHODH has two redox sites, oxidation of dihydro-orotate to orotate, and the oxidation by ubiquinone of dihydroflavin mononucleotide (FMNH2) to flavin mononucleotide (FMN). The long N-terminal extension forms a helical membrane-associated motif. This forms the mouth of a hydrophobic tunnel leading into the FMNH2-ubiquinone redox site. A77 1726 binds to a narrow region of the tunnel. The DHODH sites resemble one another as they all carry out the same reaction. However, regions near the active sites can differ. The residues that interact with the inhibitors differ markedly from one organism to another, and a single residue change can lead to resistance (72). A77 1726 is also reported to possess other activities, such as concentration-dependent inhibition of nuclear factor kappa-B activation and nuclear factor kappa-B-dependent reporter gene expression (73). It also has inhibitory effects on oxygen radical, immunoglobulin (Ig)G, and IgM production (74) and interleukin (IL)-1b and IL-2 levels (75). Genetic variability of these pathways, especially of the DHODH enzyme, may therefore account for some of the variability in response to leflu-nomide observed in clinical practice.
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