Estradiol metabolism

Estradiol metabolism.

Endogenous and exogenous estrogens undergo oxidative metabolism by hepatic microsomalcytochrome P-450. Aromatic hydroxylation at either the C2 or C4 position is a major routeof Estradiol metabolism in humans and other mammals, although there is less4-hydroxylation than 2-hydroxylation. 

Several cytochrome P450 isoforms including Cytochrome P450, family 2, subfamily C,polypeptides 8 ( CYP2C8 ) [1] and 9 ( CYP2C9 ) [1], Cytochrome P450, family 3, subfamily A, polypeptides 4 ( CYP3A4 )[2] and 5 ( CYP3A5 ) [1], Cytochrome P450, family 2,subfamily D, polypeptide 6 ( CYP2D6 ) [1], Cytochrome P450, family 1,subfamily A, polypeptides 1 ( CYP1A1 ) [2] and 2 ( CYP1A2 )[2], Cytochrome P450, family 1, subfamily B, polypeptide 1 ( CYP1B1 )[3] and Cytochrome P450, family 2, subfamily C, polypeptide 19 (CYP2C19 ) [1] were shown to catalyze hydroxylation ofEstradiol to 2-Hydroxyestradiol or/and 4-Hydroxyestradiol.Furthermore, Catechol-O-methyltransferase ( COMT ) catalyzes the methylation of2-Hydroxyestradiol and 4-Hydroxyestradiol to 2-Methoxyestradiol and4-Metoxyestradiol, respectively [4].

Cytochrome 450 isoforms CYP1A2 and CYP3A4 catalyzes the16alpha-hydroxylation of Estradiol forming Estriol [2].Estriol is glucuronidated to Estriol 16-D-glucuronoside by UDPglucuronosyltransferase 2 family, polypeptide B11 ( UGT2B11 ) [5].

Other pathways of Estradiol metabolism include formation of glucuronideconjugates and sulfation. UDP glucuronosyltransferase 1 family, polypeptides A1 (UGT1A1 ) [6] and A10 ( UGT1A10 ) [6], and UDPglucuronosyltransferase 2 family, polypeptide B28 ( UGT2B28 ) [7]convert Estradiol to Estradiol 3-glucuronide.

Several sulfotransferases including Sulfotransferase family, cytosolic, 1A,phenol-preferring, members 1 ( SULT1A1 ) [8] and 3 ( SULT1A3 )[9], Sulfotransferase family 1E, estrogen-preferring, member 1 (SULT1E1 ) [10] and Sulfotransferase family, cytosolic, 2A,dehydroepiandrosterone (DHEA)-preferring, member 1 ( SULT2A1 ) [11]catalyze sulfation of Estradiol to 17beta-Estra-1,3,5-trien-3,17-diol3-sulfate.

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   Characterization of the oxidative metabolites of 17beta-estradiol and estrone formed by 15 selectively expressed human cytochrome p450 isoforms. Endocrinology 2003 Aug;144(8):3382-98
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   Role of human cytochrome P450 1A1, 1A2, 1B1, and 3A4 in the 2-, 4-, and 16alpha-hydroxylation of 17beta-estradiol. Metabolism: clinical and experimental 2001 Sep;50(9):1001-3
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   Catechol-O-methyltransferase (COMT)-mediated metabolism of catechol estrogens: comparison of wild-type and variant COMT isoforms. Cancer research 2001 Sep 15;61(18):6716-22
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   cDNA cloning and expression of two new members of the human liver UDP-glucuronosyltransferase 2B subfamily. Biochemical and biophysical research communications 1993 Jul 15;194(1):496-503
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7. Levesque E, Turgeon D, Carrier JS, Montminy V, Beaulieu M, Belanger A
   Isolation and characterization of the UGT2B28 cDNA encoding a novel human steroid conjugating UDP-glucuronosyltransferase. Biochemistry 2001 Apr 3;40(13):3869-81
8. Falany JL, Lawing L, Falany CN
   Identification and characterization of cytosolic sulfotransferase activities in MCF-7 human breast carcinoma cells. The Journal of steroid biochemistry and molecular biology 1993 Oct;46(4):481-7
9. Fujita K, Nagata K, Yamazaki T, Watanabe E, Shimada M, Yamazoe Y
   Enzymatic characterization of human cytosolic sulfotransferases; identification of ST1B2 as a thyroid hormone sulfotransferase. Biological & pharmaceutical bulletin 1999 May;22(5):446-52
10. Tseng L, Lee LY, Mazella J
    Estrogen sulfotransferase in human placenta. Journal of steroid biochemistry 1985 May;22(5):611-5
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    Steroid sulfation by expressed human cytosolic sulfotransferases. The Journal of steroid biochemistry and molecular biology 1994 Mar;48(4):369-75