In the rat uterus, trans-tamoxifen (ICI-47,699, 1-[4-(2-dimethylaminoethoxy)phenyl]-1,2-diphenylbut-1(E)-ene) is a full estrogen agonist, while trans-tamoxifen (ICI-46,474, 1-[4-(2-dimethylaminoethoxy)phenyl]-1,2-diphenylbut-1(Z)-ene is a partial antagonist-partial agonist. In this investigation, we have compared the bioactivity of the tamoxifen isomers in the rat, and utilizing these isomers in tritium-labeled form, we have examined their metabolism and pharmacodynamics. In immature rats, trans-tamoxifen is a partial agonist-partial antagonist in terms of uterine weight stimulation, while cis-tamoxifen is a pure agonist; both isomers give little stimulation of uterine peroxidase, while only trans-tamoxifen is able to antagonize peroxidase stimulation by estradiol. After administration of [3H]-trans-tamoxifen to rats in vivo, there is a progressive accumulation of trans-hydroxytamoxifen and a yet more polar metabolite in the nuclear fraction of the uterus. With [3Hcis-tamoxifen, on the other hand, there is no accumulation of these metabolites in the uterus: in the nuclear fraction, there is a metabolite that is slightly less polar than cis-hydroxytamoxifen, and in the cytosol, a metabolite slightly more polar than cis-tamoxifen (but different from the nuclear metabolite). There is no evidence for isomerization of the isomers of tamoxifen or hydroxytamoxifen. In in vitro incubations with rat liver microsomes, both [3H]-trans-tamoxifen and [3H]-cis-tamoxifen undergo hydroxylation and to a lesser extent demethylation. Thus, the selective accumulation of trans-hydroxytamoxifen in the uterus appears to result from its greater affinity tor the estrogen receptor (285%, vs estradiol = 100%) relative to that of cis-hydroxytamoxifen (5%). The different metabolites that accumulate in the uterus following treatment with trans or cis tamoxifen may account for their different agonist-antagonist character.
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