Carcinogenesis Advance Access originally published online on July 28, 2005
Carcinogenesis 2005 26(12):2172-2178; doi:10.1093/carcin/bgi197
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Carcinogenesis vol.26 no.12 © Oxford University Press 2005; all rights reserved.
Isoflavones modulate the glucuronidation of estradiol in human liver microsomes
Institute of Applied Biosciences, Section of Food Chemistry and Toxicology, University of Karlsruhe, Germany
* To whom correspondence should be addressed at: Institute of Applied Biosciences, University of Karlsruhe, PO Box 6980, D-76128 Karlsruhe, Germany. Tel: +49 721 608 2132; Fax: +49 721 608 7255; Email: Manfred.Metzler{at}chemie.uni-karlsruhe.de
Soy food has been associated with a reduced incidence of hormonal cancer in Asian countries, and the soy isoflavones daidzein and genistein are believed to protect against tumors induced by the endogenous hormone 17ß-estradiol (E2). In the present study, we have examined if daidzein and genistein as well as several structurally related isoflavones are able to modulate the in vitro glucuronidation of E2 in human hepatic microsomes. It is known that different isoforms of UDP-glucuronosyltransferase (UGT) are involved in E2 glucuronidation: UGT1A1 leads exclusively to the 3-glucuronide and is stimulated by E2 via homotropic kinetics, whereas UGT2B7 gives rise to the 17-glucuronide of E2 following Michaelis–Menten kinetics. In our study, daidzein markedly stimulated the 3-glucuronidation, thereby enhancing the metabolic clearance of E2. In contrast, genistein inhibited the 3-glucuronidation. The 17-glucuronidation of E2 was not affected by either compound. Formononetin and the daidzein metabolites equol, 3'-hydroxy-daidzein, 6-hydroxy-daidzein and glycitein behaved similar to daidzein, whereas biochanin A resembled genistein. The effect of daidzein on the 3-glucuronidation of E2 in human hepatic microsomes was also obtained with human recombinant UGT1A1. Since the only other compound known to stimulate E2 glucuronidation via allosteric kinetics is 17
-ethynylestradiol, our study is the first report of the heterotropic stimulation of a UGT by a non-steroidal and naturally occurring compound. An enhanced rate of glucuronidation of E2 by daidzein and its metabolites may contribute to the putative protection of soy against hormonal cancer.
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