Tamoxifen antiestrogens. A comparison of the activity, pharmacokinetics, and metabolic activation of the cis and trans isomers of tamoxifen

David W. Robertson, John A. Katzenellenbogen, Deborah J. Long, Ellen A. Rorke, Benita S. Katzenellenbogen

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Pages (from-to)1-13
Number of pages13
JournalJournal of Steroid Biochemistry
Issue number1
StatePublished - Jan 1982

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology


Dive into the research topics of 'Tamoxifen antiestrogens. A comparison of the activity, pharmacokinetics, and metabolic activation of the cis and trans isomers of tamoxifen'. Together they form a unique fingerprint.

Cite this