Regioselective Monosulfation and Disulfation of the Phytoestrogens Daidzein and Genistein by Human Liver Sulfotransferases

• Published in: DRUG METABOLISM AND PHARMACOKINETICS Vol. 19; no. 3; pp. 216 - 226
• Main Authors: Nakano, Hiroaki, Ogura, Kenichiro, Takahashi, Eriko, Harada, Tomokazu, Nishiyama, Takahito, Muro, Kei, Hiratsuka, Akira, Kadota, Shigetoshi, Watabe, Tadashi
• Format: Journal Article
• Language: English; Japanese
• Published: England Elsevier Ltd 2004; Japanese Society for the Study of Xenobiotics
• Subjects: Adult; Aged; Arylsulfotransferase - metabolism; Female; Genistein - chemistry; Genistein - metabolism; human; Humans; isoflavone; Isoflavones - chemistry; Isoflavones - metabolism; kinetic parameter; Liver - enzymology; Male; Middle Aged; phytoestrogen; Phytoestrogens - chemistry; Phytoestrogens - metabolism; Stereoisomerism; Sulfates - metabolism; sulfotransferase; Sulfotransferases - metabolism; phytoestrogen; isoflavone; sulfotransferase; human; kinetic parameter
• ISSN: 1347-4367; 1880-0920
• DOI: 10.2133/dmpk.19.216

Regioselective sulfation of the phytoestrogens daidzein (DZ, 7,4′-dihydroxyisoflavone) and genistein (GS, 5,7,4′-trihydroxyisoflavone) was investigated using human liver cytosol and purified recombinant human sulfotransferase (SULT) isoforms, SULT1A1, SULT1A3, SULT2A1, and SULT1E1. 7-Position-preferential sulfation of DZ and GS was observed in human hepatic cytosols from 3 male and 3 female subjects. Average ratios for 7- to 4′-sulfate formation were 4.5:1 from DZ and 8.4:1 from GS in these human liver cytosols. Apparent Km values for the 7- and 4′-sulfation of DZ and GS by these cytosols were similar and in a range from 0.46 to 0.66 μM. All recombinant human SULTs had activity for 7- and 4′-sulfation of these phytoestrogens except for 7-sulfating activity of SULT1A3. SULT1A1 and SULT1E1 exhibited much higher catalytic efficiency, kcat /Km , for 7- and 4′-sulfation of these substrates than did the other two, SULT1A3 and SULT2A1. SULT1A1 showed Km values of 0.47 and 0.52 μM for the mono-sulfation of DZ and GS, respectively, which were very similar to those of human cytosol. The observed kcat /Km indicated that SULT1A1 catalyzed 7-sulfation of DZ and GS at rates 4.4- and 8.8-fold higher, respectively, than such 4′-sulfation. However, with SULT1E1, catalytic efficiency was very similar for the sulfation of both positions. These data strongly suggest that SULT1A1 plays a major role in monosulfation of the phytoestrogens and determines the regioselectivity of sulfation in human hepatic cytosol. A kinetic study for 7,4′-disulfate formation of DZ and GS from their 7- and 4′-monosulfates indicated that SULT1E1 most efficiently catalyzed both reactions among human SULTs.