Inhibition of human phenol and estrogen sulfotransferase by certain non-steroidal anti-inflammatory agents.
We hypothesized that aryl acetate- and aryl carboxylate-containing drugs would inhibit human phenol sulfotransferase (SULT1A1), and that selectivity would depend upon the interaction of the aryl portion of the molecule with the sulfotransferase acceptor binding site. This hypothesis was based on results with the rat orthologue showing that oxidation of phenolic substrates to carboxylate derivatives resulted in competitive inhibition of rat phenol sulfotransferase. We chose nine structurally representative non-steroidal anti-inflammatory agents and determined their inhibitory potency and selectivity toward SULT1A1 and expressed human estrogen sulfotransferase (SULT1E1). The results show that the tested agents reversibly inhibit SULT1A1 activity with IC(50) ranging from 0.1 microM to 3800 microM. These agents also inhibited SULT1E1 (IC(50) = 6 microM to 9000 microM). 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. Sulfotransferase inhibition was maintained after substituting the carboxylate with enolate (nimesulide) or methylsulfonamide (piroxicam). Kinetic studies determined the type of inhibition of SULT1A1 for three agents (meclofenamate, nimesulide, aspirin) to be non-competitive 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, salicylate and aspirin may be clinically relevant based on ratio of inhibition constant to predicted in vivo inhibitor concentration ([I]/IC(50) > 1).
King
Roberta S
RS
Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI 02881, USA. rking@uri.edu
Ghosh
Anasuya A
AA
Wu
Jinfang
J
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D015239:Arylsulfotransferase / Q000037:antagonists & inhibitors*; D002264:Carboxylic Acids; D003600:Cytosol; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D008099:Liver; D015238:Sulfotransferases / Q000037:antagonists & inhibitors*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D002264:Carboxylic Acids; D004791:Enzyme Inhibitors; D015238:Sulfotransferases; D015239:Arylsulfotransferase; C117544:SULT1A1 protein, human; C020122:estrone sulfotransferase