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SULFOTRANSFERASE 1E1 IS A LOW K_M ISOFORM MEDIATING THE 3-O-SULFATION OF ETHINYL ESTRADIOL

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

Sulfation of ethinyl estradiol (EE) is a major pathway of first pass metabolism in both the intestine and liver. Consequently, we sought to identify the human sulfotransferases (SULTs) involved in the 3-O-sulfation of EE (EE-SULT). Based on the results described herein, cDNA-expressed human cytosolic SULT1A3 and SULT1E1 were identified as low K_m isoforms (18.9 and 6.7 nM, respectively) mediating the sulfation of EE. In contrast, the EE-SULT catalyzed by other recombinant SULTs (SULT1A1 and 2A1) was a relatively high K_m process (K_m 230 nM). The kinetics of EE-SULT in human intestine (K_m1 = 24 nM; K_m2 = 1206 nM) and liver (K_m1 = 8 nM; K_m2 = 2407 nM) cytosol was biphasic and conformed to a two-K_m model with both low and high K_m components. At a low EE concentration (3 nM), inhibition of EE-SULT activity (intestinal) was characterized with 2,6-dichloro p-nitrophenol (DCNP) (IC₅₀ = 15.6 µM) and quercetin (IC₅₀ = 0.4 µM). When these IC₅₀ values were compared with those derived from expressed enzyme, inhibition of EE-SULT was consistent with the SULT1E1 (DCNP, IC₅₀ = 20 µM; quercetin, IC₅₀ = 0.6 µM), but not SULT1A3 (DCNP, IC₅₀ = 12.4; quercetin, IC₅₀ = 7 µM). Moreover, when estrone (which selectively inhibits expressed SULT1E1 and SULT1A3) was included in intestinal incubations, the high-affinity component of the Eadie-Hofstee plot for EE sulfation was inhibited, converting the plot from biphasic to monophasic. Collectively, these data are consistent with SULT1E1 as the primary sulfotransferase involved in EE sulfation at clinically relevant concentrations (<10 nM).

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