Antifolate actions of sulfasalazine on intact lymphocytes.
SASP, the drug most widely used for the treatment of Crohn's disease and ulcerative colitis, is a competitive inhibitor of intestinal folate metabolism and transport. Some of the therapeutic effects of the drug could be related to antifolate actions on lymphocytes, which predominate in the inflammatory reaction in inflammatory bowel diseases. Experiments were designed to examine the effect of SASP on folate-dependent systems in cultured lymphocytes. In rat spleen lymphocytes, THF-dependent conversion of glycine to serine was inhibited by SASP, with 50% inhibition occurring at 0.1 mM. Further evidence of folate antagonism was obtained with the dU suppression test, which depends on the function of a folate-dependent pathway in the de novo synthesis of DNA. Folate antagonists like methotrexate or folate depletion reduces the incorporation of dU into DNA and thus favors incorporation of [3H]thymidine into DNA by an alternate pathway. SASP inhibited the folate-dependent pathway in proliferating virally transformed human lymphocytes (Raji cells). To confirm that SASP acts as a folate antagonist in this system, THF was demonstrated to partly reverse the action of SASP. The significance of this antifolate action by SASP in intact lymphocytes deserves further study in relation to the actions of SASP in patients with inflammatory bowel disease.
D000818:Animals; D002051:Burkitt Lymphoma; D002460:Cell Line; D004247:DNA / Q000378:metabolism; D003857:Deoxyuridine / Q000494:pharmacology; D005493:Folic Acid Antagonists; D005561:Formates / Q000378:metabolism; D008214:Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D012694:Serine / Q000378:metabolism; D012460:Sulfasalazine / Q000494:pharmacology*; D013936:Thymidine / Q000378:metabolism
D005493:Folic Acid Antagonists; D005561:Formates; D012460:Sulfasalazine; D012694:Serine; D004247:DNA; D013936:Thymidine; D003857:Deoxyuridine