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METABOLISM, TRANSPORT, AND PHARMACOGENOMICS

Involvement of ST1B Subfamily of Cytosolic Sulfotransferase in Kynurenine Metabolism to Form Natriuretic Xanthurenic Acid Sulfate

Division of Drug Metabolism and Molecular Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sondai, Miyagi, Japan

Natriuretic substances are a group of molecules affecting sodium homeostasis in the body. Recently, two new molecules having natriuresis effects, xanthurenic acid 8-O-β-D-glucoside and xanthurenic acid 8-O-sulfate (XA sulfate), have been isolated from human urine. In the present study, we have investigated the sulfation of xanthurenic acid (XA) in mouse tissues to assess the contribution of specific sulfotransferases (STs) to the reaction. Cytosols from tissues of both sexes of C57BL/6N mice (liver, stomach, jejunum, colon, and kidney) were capable of forming XA sulfate, with various K_m values. Jejunum cytosol showed the lowest K_m value, and its V_max/K_m value was much greater than those of other tissues. The kinetic analyses with recombinant mouse (m) STs (Sult1a1, Sult1b1, Sult1c2, and Sult1d1) showed the lowest K_m value for mSult1b1, and the value was comparable with that for jejunum cytosol. The highest expression of mSult1b1 in small intestine was confirmed at the mRNA and protein levels. mSult1b1 is thus suggested as a major enzyme responsible for XA sulfation in jejunum. Similar to mSult1b1, human SULT1B1 and rat Sult1b1 mediated XA sulfation efficiently. Thus, XA is likely to be an endogenous substrate for ST1B members. In contrast to XA, an XA-related compound, kynurenic acid strongly inhibited mSult1b1-mediated sulfations, with IC₅₀ values at a micromolar range. These results indicate the functional role of ST1B subfamily of ST in XA sulfate formation in the body.

Address correspondence to: Dr. Kouichi Yoshinari, Division of Drug Metabolism and Molecular Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aramaki-aoba, Aoba-ku, Sendai, Miyagi 980-8578, Japan. E-mail: kyoshina{at}mail.pharm.tohoku.ac.jp