Cytochromes 1A1/1B1- and Catechol-<i>O</i>-Methyltransferase-Derived Metabolites Mediate Estradiol-Induced Antimitogenesis in Human Cardiac Fibroblast

Dubey, Raghvendra K.; Jackson, Edwin K.; Gillespie, Delbert G.; Rosselli, Marinella; Barchiesi, Federica; Krust, Andrée; Keller, H. J.; Zacharia, Lefteris C.; Imthurn, Bruno

doi:10.1210/jc.2003-032154

Cited by 34 publications

(25 citation statements)

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“…As mentioned above, catechol O-methyltransferase can methylate hydroxylated estrogens, and it has been reported that the methylation products are important antiinflammatory estrogen metabolites (22). In the present study, we tested the relevance of 2MeO-17␤-estradiol and 4MeO-17␤-estradiol on TNF secretion.…”

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confidence: 83%

Estrone/17β‐estradiol conversion to, and tumor necrosis factor inhibition by, estrogen metabolites in synovial cells of patients with rheumatoid arthritis and patients with osteoarthritis

Schmidt

Hartung

Capellino

et al. 2009

Arthritis & Rheumatism

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Objective. The role of estrogens in rheumatoid arthritis (RA) is debated since both proinflammatory and antiinflammatory effects have been reported. Important evidence of the dual role of estrogens is conversion to various proinflammatory or antiinflammatory metabolites. This study was undertaken to examine the downstream conversion of estrogens in synovial cells from patients with RA or osteoarthritis (OA).Methods. We studied serum levels of estrone, estrone sulfate, and estrone sulfate membrane transporters, intracellular interconversion of estrone and 17␤-estradiol, and conversion of estrone/17␤-estradiol to various estrogen metabolites in RA and OA synovial cells. The effect of estrogen metabolites on tumor necrosis factor (TNF) secretion was also studied in RA and OA synovial cells.Results. Serum levels of estrone sulfate were similar in healthy controls and RA patients. Estrone sulfate transporters were present in synovial tissue. Interconversion of estrone and 17␤-estradiol and the expression of converting enzymes of the cytochrome P450 family were similar in RA and OA cells. Using estrone and 17␤-estradiol as substrates, RA and OA synovial cells produced 16␣-, 4-, and 2-hydroxylated estrogens and their 4-and 2-methylation products. The levels of 16␣-hydroxylated estrone/17␤-estradiol (16␣OH-estrone/16␣OH-17␤-estradiol) were higher than the levels of all other estrogen metabolites. RA synovial cells produced more 16␣OH-estrone than did OA synovial cells. Importantly, the 16␣OH estrogens did not inhibit TNF secretion, whereas all other estrogen metabolites had marked inhibitory effects.Conclusion. Our findings indicate that precursor estrogens are converted to proinflammatory metabolites, particularly in RA synovial cells. RA synovial cells mainly produce the proproliferative 16␣OH-estrone, which, in addition to 16␣OH-17␤-estradiol, is one of the only 2 estrogens studied that does not inhibit TNF secretion. A preponderance of 16␣-hydroxylated estrogens is an unfavorable sign in synovial inflammation.

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confidence: 83%

Estrone/17β‐estradiol conversion to, and tumor necrosis factor inhibition by, estrogen metabolites in synovial cells of patients with rheumatoid arthritis and patients with osteoarthritis

Schmidt

Hartung

Capellino

et al. 2009

Arthritis & Rheumatism

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“…Moreover, human female left ventricular cardiac fibroblasts cells (Dubey et al, 2005), human coronary artery SMCs (Dubey et al, 2003), and endothelial cells (Borlak et al, 2003) constitutively expressed CYP1B1 higher than CYP1A1 proteins, which were significantly induced after 3MC and phenobarbital (PB) treatments. CYP1A2 mRNA expression, however, was expressed at very low level (Dubey et al, 2003;Dubey et al, 2005).…”

Section: The Expression Of Phase I Ahr-regulated Genes In the Cvsmentioning

confidence: 99%

The Role of Aryl Hydrocarbon Receptor in the Pathogenesis of Cardiovascular Diseases

Korashy

El‐Kadi

2006

Drug Metabolism Reviews

159

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Numerous experimental and epidemiological studies have demonstrated that polycyclic aromatic hydrocarbons (PAHs), which are major constituents of cigarette tobacco tar, are strongly involved in the pathogenesis of the cardiovascular diseases (CVDs). Knowing that PAH-induced toxicities are mediated by the activation of a cytosolic receptor, aryl hydrocarbon receptor (AhR), which regulates the expression of a group of xenobiotic metabolizing enzymes (XMEs) such as CYP1A1, CYP1A2, CYP1B1, NQO1, and GSTA1, suggests a direct link between AhR-regulated XMEs and CVDs. Therefore, identifying the localization and expression of the AhR and its regulated XMEs in the cardiovascular system (CVS) is of major importance in understanding their physiological and pathological roles. Generally, it was believed that the levels of AhR-regulated XMEs are lower in the CVS than in the liver; however, it has been shown that similar or even higher levels of expression are demonstrated in the CVS in a tissue- and species-specific manner. Moreover, most, if not all, AhR-regulated XMEs are differentially expressed in most of the CVS, particularly in the endothelium cells, aorta, coronary arteries, and ventricles. Although the exact mechanisms of PAH-mediated cardiotoxicity are not fully understood, several mechanisms are proposed. Generally, induction of CYP1A1, CYP1A2, and CYP1B1 is considered cardiotoxic through generating reactive oxygen species (ROS), DNA adducts, and endogenous arachidonic acid metabolites. However the cardioprotective properties of NQO1 and GSTA1 are mainly attributed to the antioxidant effect by decreasing ROS and increasing the levels of endogenous antioxidants. This review provides a clear understanding of the role of AhR and its regulated XMEs in the pathogenesis of CVDs, in which imbalance in the expression of cardioprotective and cardiotoxic XMEs is the main determinant of PAH-mediated cardiotoxicity.

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“…Indeed, the inhibitory effect of estradiol on BV2 proliferation is enhanced by phenobarbital and 3-MC (CYP450 inducers) (14) and reduced by ABT (broad-spectrum CYP450 inhibitor) (14) and pyrene (selective inhibitor of CYP1B1) (13,14). Moreover, the COMT inhibitor OR486 significantly abrogates the inhibitory effect of estradiol and completely blocks the effects of 2-OE.…”

Section: Discussionmentioning

confidence: 99%

“…The medium was harvested after 2 h of treatment, and 16-␣-hydroxyestradiol (100 l of 2.5 mol/l) was added as an internal standard. Steroids were extracted with chloroform, dried, resuspended in H 2O formation is well established to provide a reliable estimate for the conversion of estradiol to 2-OE (6,14). Briefly, BV2 cells grown to 80% confluence in 33-mm culture dishes were pretreated for 24 h with 5 mol/l of 3-MC and subsequently fed 2 ml of medium supplemented with 1 Ci/ml of 17␤- [2-3 H(N)]estradiol (specific activity, 20 Ci/mmol; ANAWA/American Radiolabeled Chemicals, St. Louis, MO) in the presence of ABT or pyrene.…”

Section: Methodsmentioning

confidence: 99%

2-Methoxyestradiol, an endogenous 17β-estradiol metabolite, inhibits microglial proliferation and activation via an estrogen receptor-independent mechanism

Schaufelberger

Rosselli

Barchiesi

et al. 2016

American Journal of Physiology-Endocrinology and Metabolism

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Jackson EK, Dubey RK. 2-Methoxyestradiol, an endogenous 17␤-estradiol metabolite, inhibits microglial proliferation and activation via an estrogen receptor-independent mechanism. Am J Physiol Endocrinol Metab 310: E313-E322, 2016. First published January 5, 2016 doi:10.1152 doi:10. /ajpendo.00418.2015 inhibits microglia proliferation. 2-Methoxyestradiol (2-ME) is an endogenous metabolite of estradiol with little affinity for estrogen receptors (ERs). We hypothesize that 2-ME inhibits microglial proliferation and activation and contributes to estradiol's inhibitory effects on microglia. We compared the effects of estradiol, 2-hydroxyestradiol [2-OE; estradiol metabolite produced by cytochrome P450 (CYP450)], and 2-ME [formed by catechol-O-methyltransferase (COMT) acting upon 2-OE] on microglial (BV2 cells) DNA synthesis, cell proliferation, activation, and phagocytosis. 2-ME and 2-OE were approximately three-and 10-fold, respectively, more potent than estradiol in inhibiting microglia DNA synthesis. The antimitogenic effects of estradiol were reduced by pharmacological inhibitors of CYP450 and COMT. Inhibition of COMT blocked the conversion of 2-OE to 2-ME and the antimitogenic effects of 2-OE but not 2-ME. Microglia expressed ER␤ and GPR30 but not ER␣. 2,3-Bis(4-hydroxyphenyl)-propionitrile (ER␤ agonist), but not 4,4=,4==-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol (ER␣ agonist) or G1 (GPR30 agonist), inhibited microglial proliferation. The antiproliferative effects of estradiol, but not 2-OE or 2-ME, were partially reversed by ICI-182,780 (ER␣/␤ antagonist) but not by 1,3-bis(4-hydroxyphenyl)-4-methyl-5-[4-(2-piperidinylethoxy)phenol]-1H-pyrazole (ER␣ antagonist) or G15 (GPR30 antagonist). Lipopolysaccharide increased microglia iNOS and COX-2 expression and phagocytosing activity of microglia; these effects were inhibited by 2-ME. We conclude that in microglia, 2-ME inhibits proliferation, proinflammatory responses, and phagocytosis. 2-ME partially mediates the effects of estradiol via ER-independent mechanisms involving sequential metabolism of estradiol to 2-OE and 2-ME. 2-ME could be of potential therapeutic use in postischemic stroke injuries. Interindividual differences in estradiol metabolism might affect the individual's ability to recover from stroke. stroke; microglia; 17␤-estradiol; 2-hydroxyestradiol; 2-methoxyestradiol

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Cytochromes 1A1/1B1- and Catechol-O-Methyltransferase-Derived Metabolites Mediate Estradiol-Induced Antimitogenesis in Human Cardiac Fibroblast

Cited by 34 publications

References 55 publications

Estrone/17β‐estradiol conversion to, and tumor necrosis factor inhibition by, estrogen metabolites in synovial cells of patients with rheumatoid arthritis and patients with osteoarthritis

Estrone/17β‐estradiol conversion to, and tumor necrosis factor inhibition by, estrogen metabolites in synovial cells of patients with rheumatoid arthritis and patients with osteoarthritis

The Role of Aryl Hydrocarbon Receptor in the Pathogenesis of Cardiovascular Diseases

2-Methoxyestradiol, an endogenous 17β-estradiol metabolite, inhibits microglial proliferation and activation via an estrogen receptor-independent mechanism

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