Inhibition by sulfasalazine of LTC synthetase and of rat liver glutathione S-transferases.

Sulfasalazine inhibited the formation of sulfidopeptide leukotrienes in ionophore A23187-challenged rat basophil leukemia cells in a dose-dependent fashion (EC50 = 0.11 mM). This compound also inhibited the solubilized, particulate LTC synthetase of RBL cells (EC50 = approximately 0.4 mM in the presence of a standard substrate mixture). The inhibition of LTC synthetase was paralleled by the capacity of sulfasalazine to potently inhibit several subfractions of the cytosolic rat liver glutathione S-transferases. The kinetics of the inhibition of the glutathione S-transferases, with 2,4-dinitrochlorobenzene as the substrate, were consistent with competitive inhibition with respect to glutathione (Ki values 0.21 +/- 0.05 to 0.46 +/- 0.096 microM in three discrete fractions). Inhibition with respect to the chromophoric substrate was uncompetitive in two of the three fractions examined (K'i values 0.61 +/- 0.13 and 1.05 +/- 0.14 microM) and non-competitive in the third (Ki = 0.72 microM). The inhibition of the LTC synthetase of RBL cells was also competitive with respect to glutathione (Ki = 120 microM). Both 5-aminosalicyclic acid and N'-2-pyridylsulfanilamide inhibited the one glutathione S-transferase fraction which was examined, and N'-2-pyridylsulfanilamide also inhibited the LTC synthetase. However, the kinetics of the inhibition of the liver enzyme by these compounds were not consistent with a competitive mechanism relative to glutathione, and the Ki values were at least 100 times greater than the ones for sulfasalazine on the same enzyme.