Chlorotrianisene

Description:

ED50: 2.0 μM

Glandular kallikrein, a trypsin-like serine protease, has been identified as a major estrogen-induced protein in the rat anterior pituitary. This induction appears to be mediated by increased gene expression since glandular kallikrein mRNA is also estrogen-induced. Chlorotrianisene is classified as an estrogen agonist.

In vitro: The ED50 of chlorotrianisene were lowered by 3.9-fold. Chlorotrianisene inhibited the growth of both P388 and P388/ADR cells in a concentration-dependent manner [1].

In vivo: Chlorotrianisene markedly varied in its ability to elicit agonist responses on the three measures. On uterine weight and anterior pituitary prolactin, chlorotrianisene behaved as partial agonists. Chlorotrianisene also exhibited strikingly less agonist activity on glandular kallikrein than on PRL or the uterus. Further, the small agonist activity of chlorotrianisene on glandular kallikrein induction differed from that on the uterus or prolactin [2].

Clinical trial: Chlorotrianisene is a estrogen which is highly effective in the suppression of postpartum lactation when given orally in dosage of 48 mg/day for seven days. Recurrence of symptoms and appearance of withdrawal bleeding are virtually eliminated, probably because of the storage of chlorotrianisene in the body fat and its gradual release after cessation of therapy [3].

Reference:
[1] Ramu A, Glaubiger D, Fuks Z.  Reversal of acquired resistance to doxorubicin in P388 murine leukemia cells by tamoxifen and other triparanol analogues. Cancer Res. 1984 Oct;44(10):4392-5.
[2] Powers CA, Hatala MA, Pagano PJ.  Differential responses of pituitary kallikrein and prolactin to tamoxifen and chlorotrianisene. Mol Cell Endocrinol. 1989 Sep;66(1):93-100.
[3] NULSEN RO, CARMON WB, HENDRICK HO.  TACE (chlorotrianisene), a new estrogen for inhibition of lactation. Am J Obstet Gynecol. 1953 May;65(5):1048-51.


Inactivation of the uterine estrogen receptor binding of estradiol during P-450 catalyzed metabolism of chlorotrianisene (TACE). Speculation that TACE antiestrogenic activity involves covalent binding to the estrogen receptor.[Pubmed:2307235]

FEBS Lett. 1990 Feb 12;261(1):59-62.

Chlorotrianisene (TACE) exhibits in vitro little or no binding to the uterine estrogen receptor (ER) but demonstrates potent estrogenic activity in vivo, indicating that TACE is a proestrogen/proantiestrogen. Our earlier studies demonstrated that the incubation of TACE with rat liver microsomes and NADPH generates a reactive intermediate (T*) which binds covalently to proteins. The current study examined the possibility that T* may inactivate the uterine ER. The incubation of TACE with rat liver microsomes and NADPH in the presence of rat uteri, under conditions which generate T*, markedly decreased the binding capacity of the ER for [3H]estradiol (E2). The evidence indicates that ER inactivation was probably due to irreversible (covalent) binding of T* to the E2 binding site. The possibility that the antiestrogenic action of TACE and of other triphenylethylenes involves such a novel mechanism is discussed.

[Prevention of bone loss by chlorotrianisene in oophorectomized rats].[Pubmed:9639753]

Zhonghua Fu Chan Ke Za Zhi. 1997 Sep;32(9):535-7.

OBJECTIVE: To determine the influence of Chlorotrianisene on bone metabolism in oophorectomized rats. METHODS: Forty-eight Wistar female rats, 70 days of age, were randomly divided into four groups: SV group (sham operation + vehicle), OV group (oophorectomy + vehicle), SE group (sham (operation + Chlorotrianisene) and OE group (oophorectomy + Chlorotrianisene). Chlorotrianisene or vehicle 4 ml/kg was given i.p. daily for 45 days from day 7 of being ovariectomized or sham operated. At the time of death, uterine weight was measured, and the thoracic vetebra 12, left tibia were collected and made into decalcified bone specimens for histomorphometry. RESULTS: There were significant difference in the uterine weight among each group. Significant different appearance by bone histomorphometry was seen between OV and the other three groups, but not shown between SV and SE, OE groups. CONCLUSION: These results suggest Chlorotrianisene could inhibit bone loss and delay the atrophy of uterus induced by ovariectomy in Wistar female rats. It has protective effects on bone like other estrogen preparations.

Role of P-450c in the formation of a reactive intermediate of chlorotrianisene (TACE) by hepatic microsomes from methylcholanthrene-treated rats.[Pubmed:1971562]

Drug Metab Dispos. 1990 Mar-Apr;18(2):131-7.

A previous study has shown that Chlorotrianisene is metabolized by hepatic microsomal cytochrome P-450 monooxygenase(s) to a reactive intermediate that binds covalently to microsomal proteins [Juedes, Bulger, and Kupfer: Drug Metab. Dispos. 15, 786 (1987)]. Covalent binding of Chlorotrianisene in hepatic microsomes is dramatically stimulated by treatment of rats with methylcholanthrene (MC), which is known to induce two major P-450 isozymes, P-450c (IA1) and P-450d (IA2). To determine whether P-450c and/or P-450d are involved in catalysis of covalent binding of Chlorotrianisene, antibodies to P-450c and P-450d were used. Incubations of Chlorotrianisene were conducted with liver microsomes from MC-treated rats (MC microsomes) and a monoclonal antibody (mAb) raised to the major MC-induced isozyme P450c, mAb 1-7-1, or a polyclonal monospecific antibody (pAb) to P-450d, pAb anti-d (-c). At a 5:1 ratio of antibody to microsomal protein, mAb 1-7-1 inhibited covalent binding by 67%, whereas pAb anti d (-c) showed a 10% inhibition. Maximal inhibition by mAb 1-7-1 was 89% at a 100:1 ratio of antibody to microsomal protein. From these findings it was concluded that P-450c is the major isozyme responsible for the metabolism of Chlorotrianisene to the covalently binding reactive intermediate in MC microsomes. Additionally, it was observed that potentiation of covalent binding occurred with the noninhibitory mAbs used in these incubations. Substituting bovine serum albumin (BSA) for antibodies showed that this increase in binding is probably due to an increase in acceptor sites.(ABSTRACT TRUNCATED AT 250 WORDS)

Differential responses of pituitary kallikrein and prolactin to tamoxifen and chlorotrianisene.[Pubmed:2583366]

Mol Cell Endocrinol. 1989 Sep;66(1):93-100.

Glandular kallikrein, a trypsin-like serine protease, and prolactin (PRL) are both estrogen-induced proteins in rat anterior pituitary lactotrophs. The estrogen agonist and antagonist effects of tamoxifen (TAM, a triphenylethylene antiestrogen) and Chlorotrianisene (TACE, a triphenylethylene estrogen) on anterior pituitary glandular kallikrein and PRL were examined to see if TAM and TACE differentially affect these estrogen response of lactotrophs after in vivo dosing of rats. TAM and TACE acted as partial agonists on PRL and uterine weight induction. In contrast, on glandular kallikrein induction TAM acted as a pure estrogen antagonist and TACE acted as an almost pure antagonist. The results document that both TAM and TACE exhibit protein-specific estrogen agonist and antagonist efficacies in lactotrophs, with the estrogen induction of glandular kallikrein being particularly sensitive to antagonism by TAM in vivo. The marked antiestrogen character of TACE was surprising since TACE has been classified and clinically used as an estrogen.

Chlorotrianisene is a long-acting non-steroidal estrogen and an orally active estrogen receptor modulator. Chlorotrianisene exhibits antiestrogenic activity. Chlorotrianisene potently inhibits the enzyme COX-1 and inhibits platelet aggregation in whole blood.

Chlorotrianisene,569-57-3,Natural Products,Estrogen/progestogen Receptor, buy Chlorotrianisene , Chlorotrianisene supplier , purchase Chlorotrianisene , Chlorotrianisene cost , Chlorotrianisene manufacturer , order Chlorotrianisene , high purity Chlorotrianisene