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SECOND INTERNATIONAL SYMPOSIUM
ON THE ROLE OF SOY
IN PREVENTING AND TREATING CHRONIC DISEASESeptember 15-18, 1996
Brussells, Belgium
POSTER ABSTRACTSIn Vitro Metabolism of the soybean isoflavonoid genistein in rat liver: implication on its canalicular excretion.
Thalhammer, B. Halper, A. Salamon, O. Winter, K. Schaufler, J. Graf, G.Theyer and W.Jäger.
Dept. Gen. Exptl. Pathology and Dept. Pharm. Chemistry.
University of Vienna, Vienna, Austria
Previous studies from our lab showed that genistein (GEN) reduces the biliary secretion of substrates of the canalicular Multispecific Organic Anion Transporter (cMOAT), such as glucuronides of bilirubin and rhodamine or bromosulfophthalein-glutathione. However, it has no influence on the secretion of a P- glycoproteinsubstrate (untransformed rhodamine 123).
The aim of this study was to determine whether GEN and/or its possible anionic metabolites are inhibiting cMOAT mediated transport by competition with the carrier. Therefore we studied biotransformation and excretion of GEN in vitro using the isolated perfused rat liver of control and mutant TR-rats, a strain deficient in the cMOAT.
Metabolite formation and secretion into bile and the effluent perfusate was assessed every 5 min. using an HPLC-assay. In livers of control and TR-rats GEN is extensively metabolized into six biotransformation products, appearing in bile in a time dependent manner. Five of these are glucuronides and one (metabolite6) is a sulfate conjugate. Glucuronide formation is inhibited by application of salicylamide, an inhibitor of UDP-glucuronytransferase. However, in TR-rats, the excretion of the parent compound and of all GEN metabolites (due to the anionic nature of GEN and its metabolites) is significantly decreased to 3-35% of control values. In addition in the effluent perfusate the main metabolite M2 is enriched to more than 200%.
The data indicate that the elimination of GEN and its conjugates is mediated by the cMOAT resulting in a competitive inhibition of other cMOAT substrates.
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