EFFECT OF SULPHASALAZINE AND ITS METABOLITES ON MITOGEN INDUCED TRANSFORMATION OF LYMPHOCYTES--CLUES TO ITS CLINICAL ACTION?

The effects of sulphasalazine (SASP), sulphapyridinc (SP), and5-aminosalicylic acid (5-ASA) have been studied on mouse spleencells cultured in the presence of phytohaemagglutmin (PHA),concanavalin A (Con A), pokeweed mitogen (PWM) and lipopolysaccharide(LPS). SASP exhibited a significant degree of suppression, at dosesin the range 25–100 .µg/ml (p < 0.01), this suppressionbeing >50% at 50 µg/ml. SP exhibited only a minor degreeof suppression (10% at 75 µg/ml. p < 0.01). Coadministrationof a non-steroidal anti-inflammatory drug (NSAID), indomethacin,produced no evidence of further suppression in the presenceof SASP or SP. Administration of SP plus 5-ASA to parallel culturesthat were profoundly suppressed by the molecular equivalentamount of SASP resulted in no suppression. This implied requirementof the intact parent molecule (SASP) to produce this effect,at these concentrations. The concentration of SASP required to produce more than 50%suppression was higher than that ever attained in the peripheralblood of humans receiving therapeutic doses of the drug. Humanlymphocytes are similarly suppressed by SASP, but only at higherconcentrations than are required for murine cells. Thus, ifthe parent drug is the active moiety and requires these concentrationsto be effective in vivo, it follows that the site where theseeffects may be mediated is likely to be the intestinal tract.The effects described would suggest the gut associated lymphoidtissue as a likely target. KEY WORDS: 5-Aminosalicylic acid, Small intestine, Rheumatoid arthritis, Reactive arthritis, Ankylosing spondylitis