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Рассматриваются данные по проблеме вклада полиморфизма генов белков и ферментов метаболизма альдостерона в патогенез артер...
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Рассматриваются данные по проблеме вклада полиморфизма генов белков и ферментов метаболизма альдостерона в патогенез артериальной гипертензии. На основе анализа научных публикаций (eLIBRARY.RU, PubMed) и открытых баз данных (NCBI, GeneCard, QIAGEN и связанные с ними ресурсы) оценено современное состояние представлений о генах метаболизма альдостерона (STAR, CYP11A1, HSD3B1, CYP21A2, CYP11B1, CYP11B2, UGT2B7), их экспрессии, полиморфизме и влиянии генетической вариабельности на кодируемый продукт. Проанализирована роль баланса предшественников альдостерона в регуляции давления крови ивзаимовлияния минералокортикоидов в процессе биогенеза альдостерона на конечный продукт реакции. Отмечены основные дискуссии по исследуемой проблеме.
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Diseases triggered by an abnormally high level of cortisol (hypercortisolism), such as the Cushing's and metabolic syndromes, could be successfully tackled by inhibitors of CYP11B1, a steroidal cytochrome P450 enzyme that catalyze...
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Diseases triggered by an abnormally high level of cortisol (hypercortisolism), such as the Cushing's and metabolic syndromes, could be successfully tackled by inhibitors of CYP11B1, a steroidal cytochrome P450 enzyme that catalyzes the last hydroxylation step of the cortisol biosynthesis. Structural optimization of 7-(benzyloxy)-4-(1H-imidazol-1-ylmethyl)-2H-chromen-2-one 2, a selective aromatase inhibitor, afforded the 4-(1H-imidazol-1-ylmethyl)-7-{[3-(trifluoromethoxy)benzyl]oxy}-2H-chromen-2-one 7, with improved inhibitory potency at human CYP11B1 (IC50 = 5 nM) and an enhanced selectivity over human CYP11B2 (SIB = 25) compared to lead compound 2 (IC50 = 72 nM, SIB = 4.0) and metyrapone (IC50 = 15 nM, SIB = 4.8), a non-selective drug used in the therapy of the Cushing's syndrome. Structure-activity relationship studies allowed the design and optimization of a novel series of potent and selective compounds, that can be regarded as open analogues of 2H-chromen-2-one derivatives. Compound 23, 2-(1H-imidazol-1-yl)-1-(4-{[3(trifluoromethoxy)benzyl]oxy}phenyl) ethanone, was the most interesting inhibitor of the series displaying a high potency at CYP11B1 (IC50 = 15 nM), increased selectivities over CYP11B2 (SIB = 33), CYP19 (SIB = 390) and CYP17 (5% inhibition at 2.5 mu M concentration). (C) 2014 Elsevier Masson SAS. All rights reserved.
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Abstract Background The chronic‐plus‐binge model of ethanol consumption, where chronically (8‐week) ethanol‐fed mice are gavaged a single dose of ethanol (E8G1), is known to induce steatohepatitis in mice. However, how chronic...
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Abstract Background The chronic‐plus‐binge model of ethanol consumption, where chronically (8‐week) ethanol‐fed mice are gavaged a single dose of ethanol (E8G1), is known to induce steatohepatitis in mice. However, how chronically ethanol‐fed mice respond to multiple binges of ethanol remains unknown. Methods We extended the E8G1 model to three gavages of ethanol (E8G3) spaced 24?h apart, sacrificed each group 9?h after the final gavage, analyzed liver injury, and examined gene expression changes using microarray analyses in each group to identify mechanisms contributing to liver responses to binge ethanol. Results Surprisingly, E8G3 treatment induced lower levels of liver injury, steatosis, inflammation, and fibrosis as compared to mice after E8G1 treatment. Microarray analyses identified several pathways that may contribute to the reduced liver injury after E8G3 treatment compared to E8G1 treatment. The gene encoding cytochrome P450 2B10 (Cyp2b10) was one of the top upregulated genes in the E8G1 group and was further upregulated in the E8G3 group, but only moderately induced after chronic ethanol consumption, as confirmed by RT‐qPCR and western blot analyses. Genetic disruption of Cyp2b10 worsened liver injury in E8G1 and E8G3 mice with higher blood ethanol levels compared to wild‐type control mice, while in vitro experiments revealed that CYP2b10 did not directly promote ethanol metabolism. Metabolomic analyses revealed significant differences in hepatic metabolites from E8G1‐treated Cyp2b10 knockout and WT mice, and these metabolic alterations may contribute to the reduced liver injury in Cyp2b10 knockout mice. Conclusion Hepatic Cyp2b10 expression is highly induced after ethanol binge, and such upregulation reduces acute‐on‐chronic ethanol‐induced liver injury via the indirect modification of ethanol metabolism.
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Исследовано влияние трифенилдиоксана на ферменты I фазы метаболизма ксенобиотиков в печени крыс и кроликов. Определено общее...
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Исследовано влияние трифенилдиоксана на ферменты I фазы метаболизма ксенобиотиков в печени крыс и кроликов. Определено общее содержание цитохрома Р450, содержание белка и каталитические активности CYP2B, CYP3A и CYP2C изоформ. Трифе-нилдиоксан значительно увеличивал специфичные активности, ассоциированные с CYP2B в печени крыс и CYP2C в печени кроликов. При иммуноблот-анализе микро-сомалъных препаратов печени животных показано, что увеличение CYP-специфич-ных активностей обусловлено увеличением содержания апоферментов. У крыс и кроликов впервые выявлены видоспецифичные различия индукции изоформ цитохрома Р450 под действием трифенилдиоксана.
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Генетический полиморфизм ферментов синтеза и метаболизма эстрогенов может вносить вклад в предрасположенность к раку молоч...
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Генетический полиморфизм ферментов синтеза и метаболизма эстрогенов может вносить вклад в предрасположенность к раку молочной .железы (РМЖ). Цель настоящего исследования ~ анализ ассоциации полиморфных локусов CYPlBlrslOS6836, CYP] A Irs 1048943 CYPlA2rs762551, CYP19Aln2470152 u CYP17Alrs743572 с риском развития РМЖ у русских .жителей Западно-Сибирского региона России. Частоты аллелей и генотипов данных локусов были определены в выборке .женщин, больных РМЖ (670 человек), и в группе контроля (480 человек без онкологических заболеваний). Подгруппы больных РМЖ в пре- и постменопаузе были проанализированы отдельно. Показана пограничная ассоциация локуса CYP17Alrs743572 с увеличением риска РМЖ в пременопаузе (аллель С: ОШ = 1,45, р = 0,04). Для остальных полиморфных локусов ассоциации не выявлено.
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Background: Structural studies on CYP2B enzymes identified some of the features that are related to their high plasticity. The aim of this work was to understand further the possible relationships between combinations of structura...
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Background: Structural studies on CYP2B enzymes identified some of the features that are related to their high plasticity. The aim of this work was to understand further the possible relationships between combinations of structural elements and functions by linking shift in substrate specificity with sequence element swaps between CYP2B6 and CYP2B11.
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Excess aldosterone production and signaling are primary contributors to numerous cardiovascular disorders including primary aldosteronism and resistant hypertension. Recently, inhibition of aldosterone synthesis via the enzyme ald...
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Excess aldosterone production and signaling are primary contributors to numerous cardiovascular disorders including primary aldosteronism and resistant hypertension. Recently, inhibition of aldosterone synthesis via the enzyme aldosterone synthase (CYP11B2) has been pursued to ameliorate the negative effects of elevated aldosterone. Herein, we report the development of aldosterone synthase inhibitors using a pyrimidine-based metal binding group leading to the highly selective CYP11B2 inhibitor 22. Superior selectivity combined with robust pharmacokinetics afforded highly selective in vivo aldosterone suppression in a monkey model of adrenal steroidogenesis, demonstrating the potential for selective aldosterone lowering in humans with pyrimidine 22.
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摘要 :? 2019 American Chemical Society.? 2019 American Chemical Society. Excess aldosterone production and signaling are primary contributors to numerous cardiovascular disorders including primary aldosteronism and resistan...
展开? 2019 American Chemical Society.? 2019 American Chemical Society. Excess aldosterone production and signaling are primary contributors to numerous cardiovascular disorders including primary aldosteronism and resistant hypertension. Recently, inhibition of aldosterone synthesis via the enzyme aldosterone synthase (CYP11B2) has been pursued to ameliorate the negative effects of elevated aldosterone. Herein, we report the development of aldosterone synthase inhibitors using a pyrimidine-based metal binding group leading to the highly selective CYP11B2 inhibitor 22. Superior selectivity combined with robust pharmacokinetics afforded highly selective in vivo aldosterone suppression in a monkey model of adrenal steroidogenesis, demonstrating the potential for selective aldosterone lowering in humans with pyrimidine 22.Excess aldosterone production and signaling are primary contributors to numerous cardiovascular disorders including primary aldosteronism and resistant hypertension. Recently, inhibition of aldosterone synthesis via the enzyme aldosterone synthase (CYP11B2) has been pursued to ameliorate the negative effects of elevated aldosterone. Herein, we report the development of aldosterone synthase inhibitors using a pyrimidine-based metal binding group leading to the highly selective CYP11B2 inhibitor 22. Superior selectivity combined with robust pharmacokinetics afforded highly selective in vivo aldosterone suppression in a monkey model of adrenal steroidogenesis, demonstrating the potential for selective aldosterone lowering in humans with pyrimidine 22.
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Data on the contribution of gene polymorphism of proteins and enzymes of aldosterone metabolism to arterial hypertension are considered. On the basis of the analysis of scientific papers (eLIBRARY.RU, PubMed) and open databases (N...
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Data on the contribution of gene polymorphism of proteins and enzymes of aldosterone metabolism to arterial hypertension are considered. On the basis of the analysis of scientific papers (eLIBRARY.RU, PubMed) and open databases (NCBI, GeneCard, QIAGEN, and related resources), the current status of ideas about the aldosterone metabolism genes (STAR, CYP11A1, HSD3B1, CYP21A2, CYP11B1, CYP11B2, UGT2B7), their expression, polymorphism, and the effect of the genetic variability on the encoded product was assessed. The role of the balance of aldosterone precursors in the regulation of blood pressure and the mutual influence of mineralocorticoids during aldosterone biogenesis on the final product of the reaction were analyzed. The main discussions on the studied issue were noted.
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