Formation, metabolism and physiologic importance of catecholestrogens

Ball, Peter; Knüppen, R.

doi:10.1016/0002-9378(90)90558-o

Cited by 60 publications

(40 citation statements)

References 28 publications

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“…2-Hydroxyestradiol (2OHE) is a metabolite of estradiol with low affinity for estrogen receptors (Ball and Knuppen, 1990). Our in vivo work demonstrates that 2OHE attenuates the development of obesity, the metabolic syndrome, and vascular and renal dysfunction in obese ZSF1 rats (Tofovic et al, 2001).…”

Section: Introductionmentioning

confidence: 84%

“…We could not detect 2OHE in plasma from rats receiving 2MEOE. We conclude that the conversion of 2OHE to 2MEOE is so efficient that in terms of 2MEOE exposure, administration of 2OHE is bioequivalent to administration of 2MEOE itself.2-Hydroxyestradiol (2OHE) is a metabolite of estradiol with low affinity for estrogen receptors (Ball and Knuppen, 1990). Our in vivo work demonstrates that 2OHE attenuates the development of obesity, the metabolic syndrome, and vascular and renal dysfunction in obese ZSF1 rats (Tofovic et al, 2001).…”

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confidence: 81%

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2-Hydroxyestradiol Is a Prodrug of 2-Methoxyestradiol

Zacharia¹,

Piché²,

Fielding³

et al. 2004

J Pharmacol Exp Ther

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Previous in vivo studies indicate that 2-hydroxyestradiol (2OHE) attenuates cardiovascular and renal diseases. In vitro studies suggest that the biological effects of 2OHE are mediated by 2-methoxyestradiol (2MEOE) after methylation of 2OHE by catechol-O-methyltransferase (COMT). This study tested the hypothesis that in vivo 2OHE is a prodrug of 2MEOE. We administered to male rats i.v. boluses of either 2OHE or 2MEOE and measured plasma levels of 2OHE and 2MEOE by gas chromatography-mass spectrometry at various time points after drug administration. After administration of 2OHE, plasma levels of 2OHE declined extremely rapidly [t 1/2(1) ϭ 0.94 min and t 1/2(2) ϭ 10.2 min] becoming undetectable after 45 min. Concomitant with the disappearance of 2OHE, 2MEOE occurred and then declined [t 1/2(1) ϭ 7.9 min and t 1/2(2) ϭ 24.9 min]. The peak concentration and total exposure (area under the curve) for 2OHE were much lower than for 2MEOE. 2OHE had a much higher plasma clearance (CL) and volume of distribution (V d ) compared with 2MEOE (2OHE: CL ϭ 1215 ml min Ϫ1 kg Ϫ1 and V d ϭ 17,875 ml/kg; 2MEOE: CL ϭ 50 ml min Ϫ1 kg Ϫ1 and V d ϭ 1760 ml/kg). After administration of 2MEOE, plasma levels of 2MEOE declined [t 1/2(1) ϭ 2.5 min and t 1/2(2) ϭ 20.2 min] with a plasma CL of 50 ml min Ϫ1 kg Ϫ1 and a V d of 1500 ml/kg. We could not detect 2OHE in plasma from rats receiving 2MEOE. We conclude that the conversion of 2OHE to 2MEOE is so efficient that in terms of 2MEOE exposure, administration of 2OHE is bioequivalent to administration of 2MEOE itself.2-Hydroxyestradiol (2OHE) is a metabolite of estradiol with low affinity for estrogen receptors (Ball and Knuppen, 1990). Our in vivo work demonstrates that 2OHE attenuates the development of obesity, the metabolic syndrome, and vascular and renal dysfunction in obese ZSF1 rats (Tofovic et al., 2001). Moreover, our more recent studies indicate that 2OHE protects against puromycin aminonucleoside-induced nephropathy (Tofovic et al., 2002), monocrotaline-induced pulmonary hypertension (Tofovic et al., 2003b), and angiotensin II-induced renal and cardiovascular injury (Tofovic et al., 2003a).Although the aforementioned in vivo studies were conducted with 2OHE, in point-of-fact 2OHE is readily oxidized and is therefore a poor candidate for drug development. 2-Methoxyestradiol (2MEOE), on the other hand, is less susceptible to oxidation, and in vitro evidence suggests that most of the cellular effects of 2OHE are mediated by 2MEOE, a metabolite of 2OHE that is devoid of estrogenic activity. In this regard, inhibition of catechol-O-methyltransferase (COMT), the enzyme that methylates 2OHE and converts it to 2MEOE, blocks the ability of 2OHE to inhibit growth of vascular smooth muscle cells (Dubey et al., 2000), cardiac fibroblasts (Dubey et al., 2002b), and renal mesangial cells (Dubey et al., 2002a). Moreover, 2OHE inhibits vascular smooth muscle cell growth in cells obtained from wild-type mice but not in cells cultured from COMT knockout mice (Zacharia et al., 2003b). In cont...

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Section: Introductionmentioning

confidence: 84%

mentioning

confidence: 81%

2-Hydroxyestradiol Is a Prodrug of 2-Methoxyestradiol

Zacharia¹,

Piché²,

Fielding³

et al. 2004

J Pharmacol Exp Ther

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“…Metal ions and hydroxyl radicals are thought to be responsible for oxidative damage to macromolecules such as DNA or lipids (44,45). Conjugation of estrogens makes them water soluble to be readily excreted or much more lipophilic to confer longer half-lives than the parent estrogens (46)(47)(48). It has been reported that these metabolic conjugation reactions play a critical role in deactivation of the redox active estrogen metabolites and marked reduction of the classical estrogenic activities of the parent estrogens (49,50).…”

Section: Metabolism Of Estrogenmentioning

confidence: 99%

Dual roles of estrogen metabolism in mammary carcinogenesis

Chang

2011

BMB Reports

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A female hormone, estrogen, is linked to breast cancer incidence. Estrogens undergo phase I and II metabolism by which they are biotransformed into genotoxic catechol estrogen metabolites and conjugate metabolites are produced for excretion or accumulation. The molecular mechanisms underlying estrogen-mediated mammary carcinogenesis remain unclear. Cell proliferation through activation of estrogen receptor (ER) by its agonist ligands and is clearly considered as one of carcinogenic mechanisms. Recent studies have proposed that reactive oxygen species generated from estrogen or estrogen metabolites are attributed to genotoxic effects and signal transduction through influencing redox sensitive transcription factors resulting in cell transformation, cell cycle, migration, and invasion of the breast cancer. Conjuguation metabolic pathway is thought to protect cells from genotoxic and cytotoxic effects by catechol estrogen metabolites. However, methoxylated catechol estrogens have been shown to induce ER-mediated signaling pathways, implying that conjugation is not a simply detoxification pathway. Dual action of catechol estrogen metabolites in mammary carcinogenesis as the ER-signaling molecules and chemical carcinogen will be discussed in this review. [BMB reports 2011; 44(7): 423-434]

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“…In vivo metabolism of estradiol to 2-OHE accounts for 50% of the estradiol metabolites formed, 1,13,19 and the levels of catecholestradiols range between 0.12 to 0.3 mol/L in peripheral blood. Substantial amounts of 2-OHE are thus available to be converted to 2-methoxyestradiol.…”

Section: Discussionmentioning

confidence: 99%

“…5 In the present study, a direct effect of catecholamines on GMC growth was also ruled out because catecholamines did not markedly affect GMC proliferation in the absence of 2-OHE. This suggests that catecholamines block the antimitogenic effects of 2-OHE by inhibiting COMT and 2-methoxyestradiol formation.In vivo metabolism of estradiol to 2-OHE accounts for 50% of the estradiol metabolites formed, 1,13,19 and the levels of catecholestradiols range between 0.12 to 0.3 mol/L in peripheral blood. Substantial amounts of 2-OHE are thus available to be converted to 2-methoxyestradiol.…”

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confidence: 99%

Catecholamines Block 2-Hydroxyestradiol-Induced Antimitogenesis in Mesangial Cells

Zacharia¹,

Jackson²,

Gillespie³

et al. 2002

Hypertension

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Abstract-Methylation of 2-hydroxyestradiol to 2-methoxyestradiol by catechol-O-methyl transferase (COMT) mediates the antimitogenic effects of 2-hydroxyestradiol on vascular smooth muscle cells. Moreover, 2-hydroxyestradiol inhibits growth of glomerular mesangial cells (GMCs). Because catecholamines are substrates for COMT, which is expressed in GMCs, we hypothesize that catecholamines may abrogate the antimitogenic effects of 2-hydroxyestradiol on GMCs by competing for COMT and inhibiting 2-methoxyestradiol formation. To test this hypothesis, we investigated the antimitogenic effects of 2-hydroxyestradiol on rat GMCs in the presence and absence of catecholamines. The capability of GMCs to methylate 2-hydroxyestradiol in the presence and absence of catecholamines was also evaluated. GMCs metabolized 2-hydoxyestradiol in a concentration-dependent manner with a V max of 12.03Ϯ0.32 pmol/10 6 cells/min and an apparent K m of 0.23Ϯ0.04 mol/L. Norepinephrine (10 mol/L) and epinephrine (10 mol/L) significantly inhibited methylation of 0.25 mol/L 2-hydroxyestradiol. Norepinephrine concentration-dependently abrogated the ability of 2-hydroxyestradiol to inhibit 3 H-thymidine incorporation (index of DNA synthesis). In the presence of 5, 10, and 40 mol/L norepinephrine, the inhibitory effect of 0.1 mol/L 2-hydroxyestradiol on 3 H-thymidine incorporation was reduced from 51Ϯ0.7% to 46Ϯ0.4%, 39Ϯ0.3%, and 25Ϯ0.7%, respectively. Similar to DNA synthesis, the inhibitory effects of 2-hydroxyestradiol on cell number and 3 H-proline incorporation (index of collagen synthesis) on GMCs were abrogated by catecholamines. Our findings provide evidence that methylation of 2-hydroxyestradiol inhibits GMC proliferation and extracellular matrix synthesis and may in part protect against renal proliferative diseases. Moreover, catecholamines may abrogate the renoprotective effects of 2-hydroxyestradiol in the glomeruli by inhibiting COMT and 2-methoxyestradiol formation. Key Words: estrogen Ⅲ catecholamines Ⅲ metabolism Ⅲ sympathetic nervous system Ⅲ renal disease Ⅲ glomerulosclerosis E stradiol may have protective effects in the kidney. Compared with age-matched men, the rate of progression of renal disease is lower in premenopausal women. With the onset of menopause and the reduction in 17␤-estradiol (estradiol) synthesis, the progression of renal disease accelerates, and estradiol replacement therapy slows the progression of renal disease. [1][2][3] The mechanisms by which estradiol affords renoprotection are unknown. However, it is known that estradiol inhibits pathological responses (cell proliferation and extracellular matrix production) to vascular injury in part by conversion to 2-hydroxyestradiol, which in turn is methylated by catechol-O-methyl transferase (COMT) to 2-methoxyestradiol. 1,4 -6 Our results suggest that 2-methoxyestradiol importantly contributes to estradiol-induced vascular protection via estrogen receptor (ER)-independent mechanisms. 1,4 -6 Glomerulosclerosis engages mechanisms in glomerular mesangial cells (GMCs)...

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Formation, metabolism and physiologic importance of catecholestrogens

Cited by 60 publications

References 28 publications

2-Hydroxyestradiol Is a Prodrug of 2-Methoxyestradiol

2-Hydroxyestradiol Is a Prodrug of 2-Methoxyestradiol

Dual roles of estrogen metabolism in mammary carcinogenesis

Catecholamines Block 2-Hydroxyestradiol-Induced Antimitogenesis in Mesangial Cells

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