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Title: SULFATION OF THE ISOFLAVONES GENISTEIN AND DAIDZEIN IN HUMAN AND RAT LIVER AND GASTROINTESTINAL TRACT

Author
item RONIS, MARTIN - ACNC/UAMS
item LITTLE, JOANNA - ACNC/UAMS
item BARONE, GARY - UAMS
item CHEN, GUANGPING - UAMS
item RADOMINSKA-PANDYA, ANNA - UAMS
item BADGER, THOMAS - ACNC/UAMS

Submitted to: Journal of Medicinal Foods
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/5/2006
Publication Date: 7/25/2006
Citation: Ronis, M.J., Little, J.M., Barone, G.W., Chen, G., Radominska-Pandya, A., Badger, T.M. 2006. Sulfation of the isoflavones genistein and daidzein in human and rat liver and gastrointestinal tract. Journal of Medicinal Foods. 9(3):384-355.

Interpretive Summary: There is a controversy over the safety of soy-based infant formula. This is largely because in addition to soy proteins, soy also has phytochemicals called isoflavones which are structurally similar to the female sex hormone estradiol bound to the protein. These so-called "phytoestrogens", gesinstein and daidzein, bind weakly to estrogen receptors and people are worried about estrogen exposure in early development when sex hormones are normally found at very low levels. An important aspect of this debate is how the body breaks these chemicals down. This will determine what concentration of bioactive phytoestrogens are present in target tissues and how "estrogenic" soy actually is. The major pathways by which isoflavones are broken down and removed from the body are attachment of water-soluble sugar and sulfate groups by the conjugating enzymes UDPGT and sulfotransferases found in liver and the gut. There are considerable differences between different experimental animals and humans in how isoflavones are conjugated. The current study compares isoflavone sulfation in the human and rat liver and gut and characterizes the human sulfotransferase enzymes involved in genistein and daidzein metabolism. The results demonstrate high conjugation of isoflavones as they cross the human gut, and help explain why only very low concentrations of bioactive isoflavones are found in human blood compared to experimental animals fed soy and why soy appears to have little estrogenic activity in people.

Technical Abstract: Phytoestrogens, in particular the isoflavone aglycones genistein and daidzein, are thought to be the bioactive components of soy. Like estrogens, isoflavones can be sulfur-conjugated. However, although isoflavones in the serum are found largely in the form of glucuronide and sulfur conjugates following soy consumption, little is known regarding the relative contributions of sulfotransferases in the liver and small intestine to isoflavone sulfation. Since the sulfates may be deconjugated in target tissues, circulating isoflavone sulfates may act as a source of tissue alglycones. In the current study genistein and daidzein sulfotransferase activities were measured in cytosol from human and rat liver and gastrointestinal tract. Isoflavone sulfation in the human (GI) was correlated with activities towards substrates for previously characterized human sulfotransferases. Western blots of human cytosols were also conducted using antisera towards human SULT1E1 and SULT2A1. Whereas rat liver was almost 4-fold more active than small intestine in sulfation of genistein, in the human, activities in the two tissues were comparable. In contrast, intestinal sulfation of daidzein was comparable to hepatic sulfation in the rat and significantly greater in the human. Genistein and daidzein sulfation occurred throughout the human GI tract, but with a different distribution and different inter-individual variability. Whereas genistein sulfation in the human GI tract correlated significantly with sulfation of the prototypical human phenolic SULT1A family substrate 2-naphthol (r2 = 0.71), daidzein sulfotransferase activity did not correlate with activities towards any prototypical sulfotransferase substrate or with genistein sulfation. Our results suggest that metabolism in the human GI tract has an important role in the generation of potentially bioactive isoflavone sulfates and a major role for the human phenolic SULT1A family in metabolism of genistein in the gut. However, human intestinal daidzein sulfation appears to be catalyzed by a separate enzyme.