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).
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
If you would like to reproduce this PharmGKB pathway diagram:
Entities in the Pathway
Relationships in the Pathway
|Arrow From||Arrow To||Controllers||PMID|
|Estradiol||4-hydroxy-estradiol||CYP1A1, CYP1A2, CYP1B1, CYP3A||11861789, 12865317, 14623547, 14657266, 15784278, 16024767|
|Estradiol||Estradiol sulfate||SULT1A1, SULT1E1, SULT2A1||10963623, 12922923, 15860265|
|Estrone||2-hydroxy-estradiol||CYP1A1, CYP1A2, CYP1B1, CYP3A||11861789, 12865317, 14623547, 14657266, 15784278, 16024767|
|Estrone||Estrone sulfate||SULT1A1, SULT1E1, SULT2A1||10963623, 12922923, 15860265|
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