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Estradiol metabolism
Estradiol metabolism

Object List (links open in MetaCore):

COMT, CYP1A1, 2.8.2.15, 17 beta-estradiol, Estradiol 3-glucuronide, SULT1A3, 1.14.14.1, 2.4.1.17, 17beta-estra-1,3,5-trien-3,17-diol 3-sulfate, 1.14.14.1, UGT2B11, UGT1A10, methoxyestradiol, 2.1.1.6, 4-hydroxy- estradiol, CYP2C9, UGT2B28, SULT1E1, CYP3A4, CYP1B1, 2-hydroxy-Estradiol, SULT1A1, CYP2D6, 17beta-estra-1,3,5-trien-3,4,17-triol 4-methyl ether, 1.14.14.1, 16alpha,17beta-estra-1,3,5-trien-3,16,17-triol 16-D-glucuronoside, CYP2C8, 2.1.1.6, estriol, SULT2A1, CYP3A5, CYP2C19, 2.4.1.17, UGT1A1, CYP1A2

Description

Estradiol metabolism.

Endogenous and exogenous estrogens undergo oxidative metabolism by hepatic microsomal cytochrome P-450. Aromatic hydroxylation at either the C2 or C4 position is a major route of Estradiol metabolism in humans and other mammals, although there is less 4-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 of Estradiol to 2-Hydroxyestradiol or/and 4-Hydroxyestradiol. Furthermore, Catechol-O-methyltransferase ( COMT ) catalyzes the methylation of 2-Hydroxyestradiol and 4-Hydroxyestradiol to 2-Methoxyestradiol and 4-Metoxyestradiol, respectively [4].

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

Other pathways of Estradiol metabolism include formation of glucuronide conjugates and sulfation. UDP glucuronosyltransferase 1 family, polypeptides A1 ( UGT1A1 ) [6] and A10 ( UGT1A10 ) [6], and UDP glucuronosyltransferase 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-diol 3-sulfate.

References:

  1. Lee AJ, Cai MX, Thomas PE, Conney AH, Zhu BT
    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
  2. Badawi AF, Cavalieri EL, Rogan EG
    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
  3. Hayes CL, Spink DC, Spink BC, Cao JQ, Walker NJ, Sutter TR
    17 beta-estradiol hydroxylation catalyzed by human cytochrome P450 1B1. Proceedings of the National Academy of Sciences of the United States of America 1996 Sep 3;93(18):9776-81
  4. Dawling S, Roodi N, Mernaugh RL, Wang X, Parl FF
    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
  5. Jin CJ, Miners JO, Lillywhite KJ, Mackenzie PI
    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
  6. Lepine J, Bernard O, Plante M, Tetu B, Pelletier G, Labrie F, Belanger A, Guillemette C
    Specificity and regioselectivity of the conjugation of estradiol, estrone, and their catecholestrogen and methoxyestrogen metabolites by human uridine diphospho-glucuronosyltransferases expressed in endometrium. The Journal of clinical endocrinology and metabolism 2004 Oct;89(10):5222-32
  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
  11. Falany CN, Wheeler J, Oh TS, Falany JL
    Steroid sulfation by expressed human cytosolic sulfotransferases. The Journal of steroid biochemistry and molecular biology 1994 Mar;48(4):369-75