Inhibition of human liver phenol sulfotransferase by nonsteroidal anti-inflammatory drugs

Objective: The aim of this investigation was to study the inhibition of 11 nonsteroidal anti-inflammatory drugs (NSAIDs) on the human liver phenol sul fotransferases (HL-PST) and catechol sulfotransferase (HL-CST). Methods: The activities of HL-PST and HL-CST were measured with 4 mu M 4-ni trophenol and 60 mu M dopamine (the sulfate accepters) and 0.4 mu M 3'-phos phoadenosine-5'-phosphosulfate [S-35] (the sulfate donor). Samples of liver were obtained from five patients, aged 55-79 years, undergoing clinically indicated hepatectomy. The inhibition curves were constructed with at least five concentrations of the inhibitor. Results: With the exception of piroxicam, NSAIDs inhibited HL-PST, and the estimates of the inhibitory concentration for 50% of responses (IC50; mu M) were: 0.02 (mefenamic acid), 3.7 (diflunisal), 5.4 (nimesulide), 9.5 (dicl ofenac), 30 (salicylic acid), 41 (ketoprofen), 74 (indomethacin), 159 (ibup rofen), 245 (ketoralac) and 473 (naproxen). With 4-nitrophenol as the varia ble substrate, the inhibition of salicylic acid on HL-PST was non-competiti ve and the K-i and K-ies were 18 mu M and 21 mu M (n = 5; P = 0.548), respe ctively. HL-CST was less susceptible than HL-PST to inhibition by NSAIDs, w ith only five drugs inhibiting this enzyme. The IC50 estimates for these dr ugs (mu M) were 76 (mefenamic acid), 79 (diflunisal), 103 (indomethacin), 6 09 (salicylic acid) and 753 (diclofenac). Conclusion: The comparison of the IC50 estimates of HL-PST with the therape utic plasma concentrations of NSAIDs corrected for the plasma unbound fract ion was consistent with the view that mefenamic acid and salicylic acid, wh en administered at therapeutic doses, should impair the hepatic sulfation o f those compounds that are substrates of phenol sulfotransferase.