Abstract
17β‐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.