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This study was initiated on the hypothesis that aryl acetic acid and aryl carboxylic acid-containing drugs would inhibit human phenol sulfotransferase (SULT1A1), and that isoform selectivity would depend on the interaction of the aryl portion of the molecule with the acceptor binding site of the sulfotransferase. This hypothesis was based on results with the rat orthologue enzyme showing that oxidation of phenolic substrates to carboxylic acid derivatives resulted in competitive inhibition of rat phenol sulfotransferase. We chose nine structurally representative non-steroidal antiinflammatory agents and determined their inhibitory potency and selectivity toward human liver phenol sulfotransferase (SULT1A1) and expressed human estrogen sulfotransferase (SULT1E1).The results show that the tested agents reversibly inhibit human liver cytosolic phenol sulfotransferase activity with 50% inhibitory concentrations (IC 50 ) ranging from 0.1 μM to 3800 μM. These agents also inhibited SULT1E1 (IC 50 = 6 μM to 9000 μM). The agents were clearly isoform selective, with IC 50 ratios (1E1/1A1) ranging from 0.01 to 200. Nimesulide, meclofenamate, and piroxicam were more selective towards SULT1A1 inhibition, while sulindac and ibuprofen were more selective towards SULT1E1 inhibition. Two agents lacking a carboxylic acid functional group, nimesulide and piroxicam, showed that the carboxylate could be substituted by enolate or methylsulfonamide and retain sulfotransferase inhibitory characteristics. Kinetic studies determined the type of inhibition of SULT1A1 for three agents (meclofenamate, nimesulide, aspirin) to be noncompetitive or partial non-competitive versus both substrate (p-nitrophenol) and cofactor (PAPS). This inhibition mechanism indicates that meclofenamate, nimesulide and aspirin bind near enough to the substrate binding site to prevent catalysis but not affect dissociation of the substrate-enzyme complex. The inhibition of SULT1A1 by meclofenamate, nimesulide, salicylic acid and aspirin may be clinically relevant based on ratio of inhibition constant to predicted in vivo inhibitor concentration ([I]/IC 50 >1).

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