Pathway Estrogen Metabolism Pathway

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The liver is a site for biosynthesis of estrogens but it is also the main site for further biotransformation of them. Once the estrogens are synthesized by aromatase in peripheral tissues including the liver, they will be released to the circulation. Estrone is in equilibrium with estradiol and 17-b-hydroxysteroid dehydrogenase (17bHSD) in this respect. The estrogens are taken up by the liver where they will be biotransformed further in to different metabolites. The major oxidative routes of estrone and estradiol are 2- and 4-hydroxylation by cytochrome P450 (CYP) 2B1, 1A and 3A. Other minor oxidative pathways are also identified (not shown in the pathway). The 2- and 4-hydroxy derivatives (and other metabolites) will be further converted to 2- and 4-methoxy metabolites by catechol-O-methyltransferase (COMT). While the hydroxylated metabolites appear to result in DNA damage and contribute to the tumerogenic effect of estrogen, the methoxy-derivatives appear to exhibit beneficial cardiovascular effects. Estrone and estradiol and their metabolites undergo sulfation by sulfotransferases (SULTs) and glucuronidation by glucoronyltransferases (UGTs). Estrone and estradiol sulfates could be deconjugated by sulfatases (STs).

Authors: Zeruesenay Desta, Anne Nguyen, David Flockhart, Todd Skaar, Rebecca Fletcher, Richard Weinshilboum, Dorit S. Berlin, Teri E. Klein, Russ B. Altman.
M. Whirl-Carrillo, E.M. McDonagh, J. M. Hebert, L. Gong, K. Sangkuhl, C.F. Thorn, R.B. Altman and T.E. Klein. "Pharmacogenomics Knowledge for Personalized Medicine" Clinical Pharmacology & Therapeutics (2012) 92(4): 414-417. Full text
Therapeutic Categories:
  • Physiological mechanisms

Entities in the Pathway

Genes (16)

Relationships in the Pathway

Arrow FromArrow ToControllersPMID
2-hydroxy-estradiol 2-methoxy-estradiol COMT 10963623, 14657266
4-hydroxy-estradiol 4-methoxy-estradiol COMT 10963623, 14657266
Androstenedione Estrone CYP19A1 12700178
Androstenedione Testosterone HSD17B1 12700178
Estradiol 4-hydroxy-estradiol CYP1A1, CYP1A2, CYP1B1, CYP3A 11861789, 12865317, 14623547, 14657266, 15784278, 16024767
Estradiol Estradiol sulfate SULT1A1, SULT1E1, SULT2A1 10963623, 12922923, 15860265
Estradiol Estrone
Estrone 2-hydroxy-estradiol CYP1A1, CYP1A2, CYP1B1, CYP3A 11861789, 12865317, 14623547, 14657266, 15784278, 16024767
Estrone Estradiol HSD17B1 12700178
Estrone Estrone sulfate SULT1A1, SULT1E1, SULT2A1 10963623, 12922923, 15860265
Testosterone Androstenedione
Testosterone Estradiol CYP19A1 12700178

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