Possible mechanisms for the agonist actions of tamoxifen and the antagonist actions of MER-25 (ethamoxytriphetol) in the mouse uterus.

Experiments were conducted to determine why tamoxifen, a non-steroidal antiestrogen, is uterotrophic in mice, whereas MER-25 (ethamoxytriphetol), a structurally related compound, is antiuterotrophic. Initial experiments indicated that the pituitary was not required for a uterotrophic response in mice to either estradiol (E2), tamoxifen (TAM), or 4-hydroxytamoxifen (4-OH-TAM) MER-25 was not uterotrophic in mice but was capable of completely inhibiting the uterotrophic responses of mice to estrogens (E2) as well as antiestrogens (TAM and 4-OH-TAM); this inhibition was reversible by increasing the dose of the antiestrogen (TAM). The relative binding affinities (RBA) of TAM, 4-OH-TAM, and MER-25 to mouse uterus estrogen receptor (ER) and mouse liver antiestrogen binding sites (AEBS) were compared to determine whether either (or both) of these sites mediate the biological effects of these compounds. E2 is arbitrarily assigned an RBA of 100 for ER; similarly, TAM is assigned an RBA of 100 for AEBS. MER-25 bound to AEBS with an RBA of 8.9 and to ER with an RBA of less than 0.06; in contrast, TAM and 4-OH-TAM bound to AEBS with RBAs of 100 and 53, respectively, and to ER with RBAs of 2 and 131, respectively. Five other compounds that had similar RBAs as MER-25 for AEBs (RBAs in the range 4-9) and for ER (RBAs less than 0.06) were tested for their antiuterotrophic activities in vivo against both estrogen (E2) and antiestrogen (TAM) in ovariectomized mice. None of these compounds were antiuterotrophic against either estradiol or tamoxifen (P less than 0.01), nor were any of the compounds uterotrophic in mice. These data suggest that differences in the biological actions of tamoxifen and MER-25 in mice are not mediated through AEBS and are most likely due to differences in their interactions with ER.