Estrogen receptor metabolites

In vivo studies in animals suggest that endosulfan may disrupt normal reproductive hormone levels in male animals, but that it is not an endocrine disrupter in females. Persistent depressed testicular testosterone was seen in male rats after intermediate duration oral exposures to endosulfan. In ovariectomized female rats, orally administered endosulfan did not induce normal development of female reproductive tissues, and in female mice and immature female rats, acute parenteral exposure to endosulfan did not affect several endocrine-related end points. In vitro studies have evaluated endosulfan for estrogen receptor (ER) and cytosolic protein binding affinity, ER-mediated reporter gene expression, estrogenic induction of cell proliferation, and alteration of relative abundance of active estradiol metabolites. Overall, in vitro evidence in favor of endosulfan estrogenicity indicates relatively weak potency compared to 17[3-estradiol. Apparently contradictory results were reported in different... 

Toremifene is an estrogen receptor antagonist. The pharmacokinetics of toremifene are best described by a two-compartment model, with an a half-life of 4 hours and an elimination half-life of 5 days. Peak plasma concentrations are achieved approximately 3 hours after an oral dose. Toremifene is metabolized extensively, with metabolites found primarily in the feces. Toremifene is used for the treatment of metastatic breast cancer in postmenopausal women with estrogen-receptor-positive or unknown tumors. Toremifene causes hot flashes, vaginal bleeding, thromboembolism, and visual acuity changes. 

Schafer JI, Liu H, Tonetti DA, Jordan VC (1999) The interaction of raloxifene and the active metabolite of the antiestrogen EM-800 (SC 5705) with the human estrogen receptor. Cancer Res 59 4308-4313... 

Mueller SO, Simon S, Chae K, Metzler M, Korach KS. Phytoestrogens and their human metabolites show distinct agonistic and antagonistic properties on estrogen receptor (alpha) and ER(beta) in human cells. Toxicol ScL 81, 530-531, 2004. 

J. A. (2005) Isocoumarins as estrogen receptor beta selective ligands isomers of isoflavone phytoestrogens and their metabolites. Bioorg Med Chem 13, 6529-6542. 

Setchell KD, Clerici C, Lephart ED, Cole SJ, Heenan C, Castellani D, Wolfe BE, Nechemias-Zimmer L, Brown NM, Lund, TD, Handa RJ, Heubi JE. 2005. S-equol, a potent ligand for estrogen receptor beta, is the exclusive enantiomeric form of the soy isoflavone metabolite produced by human intestinal bacterial flora. Am J Clin Nutr 81 1072-1079. 

Wu X et al (2009) The tamoxifen metabolite, endoxifen, is a potent antiestrogen that targets estrogen receptor alpha for degradation in breast cancer cells. Cancer Res 69 1722-1727... 

Murdter TE et al (2011) Activity levels of tamoxifen metabolites at the estrogen receptor and the impact of genetic polymorphisms of phase I and II enzymes on their concentration levels in plasma. Clin Pharmacol Ther 89 708-717... 

It is very likely that the polybrominated biphenyls are metabohzed in fish, sea mammals, and human to debrominated and hydroxylated polybrominated biphenyls. It is suggested by the authors that some of these polybrominated metabolites can bind to the estrogen receptor and act hke xenoestrogens, as was shown for hydroxy polychlorinated biphenyls (HO-PCBs) by Korach et al. [256], McKinney and Waller [257], and Waller et al. [258]. Especially the chemical structure of para-substituted hydroxylated metabohtes of polybrominated biphenyls would be similar to that of estradiol, preferably in the presence of... 

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