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:
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- Tseng L, Lee LY, Mazella J
Estrogen sulfotransferase in human placenta.
Journal of steroid biochemistry 1985 May;22(5):611-5
- 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