The 21-aminosteroid U74389G prevents the down-regulation and decrease in activity of CYP1A1, 1A2 and 3A6 induced by an inflammatory reaction

Taherzadeh, Mehrzad; Fradette, Caroline; Bleau, Anne-Marie; Jomphe, Claudia; Trudeau, Louis-Éric; Souich, Patrick du

doi:10.1016/j.bcp.2005.10.040

Cited by 9 publications

(5 citation statements)

References 54 publications

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“…Hypoxia, and oxidative stress in general, play significant roles in experimental and human PAH (62), and both hypoxia and oxidative stress down-regulate expression of CYP1A1/2 (63, 64), key enzymes controlling the 2-hydroxylation pathway . Hypoxia not only affects E2 metabolism, but also has significant influence on pulmonary vascular remodeling, stimulating proliferation of pulmonary ECs, VSMCs, and adventitial fibroblasts (65), and hypoxia and E2 have synergistic mitogenic effects in endothelial cells (66).…”

Section: Estradiol Metabolism and Pulmonary Arterial Hypertensionmentioning

confidence: 99%

Estrogens and Development of Pulmonary Hypertension: Interaction of Estradiol Metabolism and Pulmonary Vascular Disease

Tofovic

2010

Journal of Cardiovascular Pharmacology

102

113

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Severe pulmonary arterial hypertension (PAH) is characterized by clustered proliferation of endothelial cells in the lumina of small size pulmonary arteries resulting in concentric obliteration of the lumina and formation of complex vascular structures known as plexiform lesions. This debilitating disease occurs more frequently in women, yet both animal studies in classical models of PAH and limited clinical data suggest protective effects of estrogens: the estrogen paradox in pulmonary hypertension. Little is known about the role of estrogens in PAH, but one line of evidence strongly suggests that the vascular protective effects of 17β-estradiol (estradiol; E2) are mediated largely by its downstream metabolites. Estradiol is metabolized to 2-hydroxyestradiol (2HE) by CYP1A1/CYP1B1, and 2HE is converted to 2-methoxyestradiol (2ME) by catechol-Omethyl transferase. 2ME is extensively metabolized to 2-methoxyestrone, a metabolite that lacks biologic activity but which may be converted back to 2ME. 2ME has no estrogenic activity and its effects are mediated by estrogen receptors-independent mechanism(s). Notably, in systemic and pulmonary vascular endothelial cells, smooth muscle cells, and fibroblasts 2ME exerts stronger anti-mitotic effects than E2 itself. E2 and 2ME, despite having similar effects on other cardiovascular cells, have opposing effects on endothelial cells; that is, in endothelial cells, E2 is pro-mitogenic, pro-angiogenic and anti-apoptotic, whereas 2ME is antimitogenic, anti-angiogenic and pro-apoptotic. This may have significant ramifications in severe PAH that involves uncontrolled proliferation of monoclonal, apoptosis resistant endothelial cells. Based on its cellular effects, 2ME should be expected to attenuate the progression of disease and provide protection in severe PAH. In contrast, E2, due to its mitogenic, angiogenic, and anti-apoptotic effects (otherwise desirable in normal, quiescent endothelial cells), may even adversely affect endothelial remodeling in PAH and this may be even more significant if the E2's effects on injured endothelium are not opposed by 2ME (e.g., in the event of reduced E2 conversion to 2ME due to hypoxia, inflammation, drugs, environmental factors, or genetic polymorphism of metabolizing enzymes). This review focuses on the effects of estrogens and their metabolites on pulmonary vascular pathobiology and the development of experimental PAH, and offers potential explanation for the estrogen paradox in PAH. Furthermore, we propose that unbalanced estradiol metabolism may lead to the development of PAH. Recent animal data and studies in patients with PAH support this concept.Corresponding Author: Stevan P. Tofovic M.D., Ph.D. FAHA FASN Division of Pulmonary, Allergy and Critical Care Medicine and Vascular Medicine Institute, Department of Medicine University of Pittsburgh School of Medicine Bridge side 542 100 Technology Drive, Pittsburgh, PA 15219 FAX +412-624-5070 Phone +412-648-3363 tofovic@dom.pitt.edu. This is a PDF file of an unedited manuscript that ...

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Section: Estradiol Metabolism and Pulmonary Arterial Hypertensionmentioning

confidence: 99%

Estrogens and Development of Pulmonary Hypertension: Interaction of Estradiol Metabolism and Pulmonary Vascular Disease

Tofovic

2010

Journal of Cardiovascular Pharmacology

102

113

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“…As a antioxidant, inhibitory effect of U-74389G on NF-kB activation has been demonstrated by various studies [16,44,45]. In a previous study on rabbits, Taherzadeh et al found that IL-1b did activate NF-kB translocation, and the effect was abrogated by U-74389G [46]. Many evidences suggest that the anti-inflammatory effect elicited by U-74389G suppresses the degradation of IkB proteins and consequently, prevents the activation NF-kB nuclear translocation [15,16,37].…”

Section: 3mentioning

confidence: 93%

Lazaroid U-74389G inhibits the osteoblastic differentiation of IL-1β-indcued aortic valve interstitial cells through glucocorticoid receptor and inhibition of NF-κB pathway

Sun

Shi

Chen

et al. 2015

The Journal of Steroid Biochemistry and Molecular Biology

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“…B8 inhibited the cysteine protease calpain-dependent lipid peroxidation in a mouse model of traumatic brain injury in a dose-dependent manner (21). B9 has been shown to reduce the levels of IL-1b and other inflammatory cytokines (22). Due to their relevant activities in inflammatory pathways and high potencies, B8 and B9 were studied in more detail to characterize their interactions with caspase-1.…”

mentioning

confidence: 99%

Lazaroids U83836E and U74389G are Potent, Time‐Dependent Inhibitors of Caspase‐1

2015

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Caspase-1 is involved in inflammatory processes and is overactive in autoimmunity and autoinflammation. Antioxidant small molecules also play a role in the immune response by decreasing inflammation. An 84-membered library of pro- and antioxidant small molecules was screened for potential inhibitors of caspase-1. Thirteen compounds were discovered to reduce the activity of caspase-1 below 30%. The most potent inhibitors were lazaroid antioxidant molecules, U83836E (B8) and U74389G (B9), displaying apparent Ki values of 48.0 and 50.0 nm, respectively. Both demonstrated a time-dependent and reversible inhibition.

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The 21-aminosteroid U74389G prevents the down-regulation and decrease in activity of CYP1A1, 1A2 and 3A6 induced by an inflammatory reaction

Cited by 9 publications

References 54 publications

Estrogens and Development of Pulmonary Hypertension: Interaction of Estradiol Metabolism and Pulmonary Vascular Disease

Estrogens and Development of Pulmonary Hypertension: Interaction of Estradiol Metabolism and Pulmonary Vascular Disease

Lazaroid U-74389G inhibits the osteoblastic differentiation of IL-1β-indcued aortic valve interstitial cells through glucocorticoid receptor and inhibition of NF-κB pathway

Lazaroids U83836E and U74389G are Potent, Time‐Dependent Inhibitors of Caspase‐1

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