Low 2‐methoxyestradiol levels at the first trimester of pregnancy are associated with the development of pre‐eclampsia

Pérez-Sepúlveda, Alejandra; Torres, María José; Valenzuela, Francisco; Larraín, Raimundo; Figueroa‐Diesel, H.; Galaz, José; Nien, Jyh Kae; Serra, Ramón; Michea, Luis; Illanes, Sebastián E.

doi:10.1002/pd.3954

Cited by 28 publications

(15 citation statements)

References 27 publications

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“…More recently, Lee et al have described that 2-methoxyestradiol (2-ME), a natural metabolite of 17- β -estradiol synthesized by Cathechol-O-Methyltransferase (COMT), induces the differentiation of the endovascular cytotrophoblast cells into its invasive phenotype in the presence of hypoxia [8]. Kanasaki et al have reported low levels of circulating 2-ME during the third trimester of pregnancy in patients that would later develop PE as compared with controls [9] and our group found the same trend during the early first trimester of pregnancy [10]. With COMT being responsible for methylating 2-Hydroxyestradiol (2-HE) into 2-ME, it has been proposed that the low activity or expression of this enzyme could be involved in the pathogenesis of PE.…”

Section: Introductionsupporting

confidence: 57%

Levels of Key Enzymes of Methionine-Homocysteine Metabolism in Preeclampsia

Pérez-Sepúlveda

España-Perrot

et al. 2013

BioMed Research International

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Objective. To evaluate the role of key enzymes in the methionine-homocysteine metabolism (MHM) in the physiopathology of preeclampsia (PE). Methods. Plasma and placenta from pregnant women (32 controls and 16 PE patients) were analyzed after informed consent. Protein was quantified by western blot. RNA was obtained with RNA purification kit and was quantified by reverse transcritase followed by real-time PCR (RT-qPCR). Identification of the C677T and A1298C methylenetetrahydrofolate reductase (MTHFR) single-nucleotide polymorphisms (SNPs) and A2756G methionine synthase (MTR) SNP was performed using PCR followed by a high-resolution melting (HRM) analysis. S-adenosyl methionine (SAM) and S-adenosyl homocysteine (SAH) were measured in plasma using high-performance liquid chromatography-tandem mass spectrometry (HPLC/MS/MS). The SNP association analysis was carried out using Fisher's exact test. Statistical analysis was performed using a Mann-Whitney test. Results. RNA expression of MTHFR and MTR was significantly higher in patients with PE as compared with controls. Protein, SAM, and SAH levels showed no significant difference between preeclamptic patients and controls. No statistical differences between controls and PE patients were observed with the different SNPs studied. Conclusion. The RNA expression of MTHFR and MTR is elevated in placentas of PE patients, highlighting a potential compensation mechanism of the methionine-homocysteine metabolism in the physiopathology of this disease.

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Section: Introductionsupporting

confidence: 57%

Levels of Key Enzymes of Methionine-Homocysteine Metabolism in Preeclampsia

Pérez-Sepúlveda

España-Perrot

et al. 2013

BioMed Research International

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“…24 Recent data from our laboratory have shown that 2-ME levels in early pregnancy may also be able to predict the subsequent development of PE, since plasma 2-ME levels at 11 to 14 weeks of gestation were decreased in women who later developed PE (PE: 1.87 + 2 pg/mL vs normotensive controls: 61.73 + 27 pg/mL, P < .05). 36 Despite these differences, the mechanisms responsible for this reduction are not known. This last step is essential in order to determine whether 2-ME can be used as a potential therapeutic intervention to prevent or treat PE.…”

Section: -Methoxyestradiol and Its Relationship With Pementioning

confidence: 99%

Metabolic Pathways Involved in 2-Methoxyestradiol Synthesis and Their Role in Preeclampsia

et al. 2013

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Preeclampsia (PE) remains a major cause of maternal/fetal morbidity-mortality worldwide. The first stage of PE is characterized by placental hypoxia due to a relative reduction in uteroplacental blood flow, resulting from restricted trophoblast invasion. However, hypoxia is also an essential element for the success of invasion. Under hypoxic conditions, 2-methoxyestradiol (2-ME) could induce the differentiation of cytotrophoblast cells into an invasive phenotype in culture. 2-Methoxyestradiol is generated by catechol-O-methyltransferase, an enzyme involved in the metabolic pathway of estrogens. During pregnancy, circulating 2-ME levels increase significantly when compared to the menstrual cycle. Interestingly, plasma levels of 2-ME are lower in women with PE than in controls, and these differences are apparent weeks or even months before the clinical manifestations of the disease. This article reviews the metabolic pathways involved in 2-ME synthesis and discusses the roles of these pathways in normal and abnormal pregnancies, with particular emphasis on PE.

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“…A mouse model of COMT knockout exhibits a preeclampsialike phenotype due to lack of 2-ME, and supplementation of 2-ME ameliorated the preeclampsia features including reducing placental HIF1a level and expression of sFlt-1 [8]. Additionally, a recent report showed that women with preeclampsia exhibit lower levels of 2-ME during the first trimester suggesting a possible role for 2-ME in the development of preeclampsia [14] or as a marker of abnormal placental development. Another recent report correlated decreased plasma levels of 2-ME in third trimester patients with increased risk and severity of PE symptoms and markers, including systolic arterial pressure, proteinuria and altered sFlt-1 and placental growth factor levels [15].…”

Section: Discussionmentioning

confidence: 94%