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0090-9556/04/3211-1260-1264$20.00
DMD 32:1260-1264, 2004

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HETEROTROPIC MODULATION OF SULFOTRANSFERASE 2A1 ACTIVITY BY CELECOXIB: PRODUCT RATIO SWITCHING OF ETHYNYLESTRADIOL SULFATION

Donghui Cui, Catherine L. Booth-Genthe, Edward Carlini, Brian Carr, and Michael L. Schrag

Drug Metabolism Department, Merck Research Laboratories, West Point, Pennsylvania

The major sulfated product of 17{alpha}-ethynylestradiol (EE) after incubations with 3'-phosphoadenosine-5'-phosphosulfate and recombinant human sulfotransferase 2A1 (SULT2A1), or liver cytosol, is the 3-O-sulfate of EE. However, when celecoxib is also present in the incubation, sulfation is switched (in a concentration-dependent manner) from the 3-O-position to the 17ß-O-position of ethynylestradiol. In incubations with recombinant SULT2A1, increasing concentrations of celecoxib decreased the Vmax of 3-O-sulfate product formation by 3- to 4-fold, with no major change in the Km value. For 17ß-O-sulfate formation, increasing concentrations of celecoxib resulted in an 8-fold decrease in the Km and a 7-fold increase in Vmax. Celecoxib not only modulated the regioselectivity of the enzyme, but also activated the enzyme such that total sulfated product exceeded product formation by the native enzyme, 3- to 4-fold (at 250 µM celecoxib). Finally, IC50 values obtained by varying celecoxib concentrations (0–250 µM) at fixed concentrations of EE showed that 3-O-sulfation was inhibited by celecoxib to the same extent, independent of the concentration of EE. In addition, the apparent kinetic constant for celecoxib (as measured by EE 17ß-O-sulfation) decreased 2-fold in the presence of high concentrations of EE, consistent with the potential for celecoxib to bind to either the enzyme-EE complex or to free enzyme. Taken as a whole, these data suggest that celecoxib is acting as a heterotropic modulator of SULT2A1 activity, most likely involving a separate noncompetitive binding site.

Address correspondence to: Dr. Michael Schrag, Amgen, One Amgen Center Drive, 1-1-A, Thousand Oaks, CA 91320-1799. E-mail: mschrag{at}amgen.com




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