Stimulation of estradiol glucuronidation: a protective mechanism against estradiol-mediated carcinogenesis?
17beta-Estradiol (E2) and its catechol and methoxy metabolites are believed to play important roles in the mechanism of E2-mediated tumor formation. Because conjugation with glucuronic acid lowers tissue levels by facilitating excretion, we have determined the kinetic parameters of the glucuronidation of E2, estrone (E1), and seven phase I metabolites using human liver microsomes. The catechol estrogens 2- and 4-hydroxy-E2/E1 exhibited the highest clearance, exceeding that of E2, E1, and the methoxy metabolites by factors of 6-44. Homotropic activation kinetics were observed for the 3-glucuronidation of E2 but not for any of the metabolites. None of the metabolites affected the kinetics of the 3-glucuronidation of E2. In contrast, the isoflavone daidzein stimulated the formation of E2-3-glucuronide, as has been reported previously. This heterotropic activation by daidzein appears to be specific for the glucuronidation of E2 because daidzein did not affect the glucuronidation of the 2- and 4-hydroxy metabolites of E2. However, daidzein may lower the glucuronidation of 2-methoxy-E2 in vivo due to its preferential glucuronidation. The decreased tissue levels of E2 and increased concentrations of 2-methoxy-E2, as implied by this study and the previous one, may contribute to the protective effect of daidzein against breast and endometrial cancer.
Pfeiffer
Erika
E
Section of Food Chemistry and Toxicology, Department of Chemistry and Biosciences, Institute of Applied Biosciences, University of Karlsruhe, Germany.
Graf
Eva
E
Gerstner
Silke
S
Metzler
Manfred
M
D001943:Breast Neoplasms / Q000517:prevention & control; D016889:Endometrial Neoplasms / Q000517:prevention & control; D004958:Estradiol / Q000009:adverse effects* / Q000378:metabolism*; D004970:Estrone / Q000378:metabolism; D005260:Female; D020719:Glucuronides / Q000378:metabolism*; D006801:Humans; D007529:Isoflavones / Q000494:pharmacology; D007700:Kinetics; D008862:Microsomes, Liver / Q000378:metabolism; D009369:Neoplasms / Q000209:etiology* / Q000517:prevention & control*
D020719:Glucuronides; D007529:Isoflavones; D004970:Estrone; D004958:Estradiol; C004742:daidzein