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Молекулярные механизмы дидрогестерона (Дюфастон®). Полногеномное исследование транскрипционных эффектов рецепторов прогестерона, андрогенов и эстрогенов
Молекулярные механизмы дидрогестерона (Дюфастон®). Полногеномное исследование транскрипционных эффектов рецепторов прогестерона, андрогенов и эстрогенов
Материалы доступны только для специалистов сферы здравоохранения. Авторизуйтесь или зарегистрируйтесь.
Аннотация
Дидрогестерон – высокоселективный прогестаген, использующийся при широком спектре гинекологических заболеваний. Из всех стероидных рецепторов дидрогестерон значительно взаимодействует только с прогестерон-рецепторами. Результаты проведенного нами ранее исследования моделей структур комплекса прогестин–рецептор позволяют предположить, что ключевым моментом высокой селективности и специфичности дидрогестерона является уникальное для этой молекулы позиционирование метильной группы С19. Некоторые другие препараты прогестинов взаимодействуют и с другими типами рецепторов и как следствие приводят к нежелательным побочным эффектам. Побочными эффектами применения некоторых прогестинов являются вирилизация, являющаяся результатом активации андрогенных рецепторов, а также нежелательная активация эстрогеновых рецепторов. В настоящей работе мы приводим результаты полногеномного исследования транскрипционных эффектов активации прогестероновых, андрогенных и эстрогеновых рецепторов. Результаты показывают, что эти три типа рецепторов активируют существенно разные группы генов. Путем анализа функционального связывания установлены гены, предположительно влияющие на вирилизацию или феминизацию плода. Результаты исследования подчеркивают, что использование разновидностей прогестинов, побочно активирующих эстрогеновые или андрогеновые рецепторы, нежелательно при беременности и вмешивается в гормональные процессы развития плода. И, наоборот, применение во время беременности высокоселективных прогестинов (например, дидрогестерона) является безопасным для правильного развития плода как женского, так и мужского пола.
Полный текст
Список литературы
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2. Сухих Г.Т., Торшин И.Ю., Громова О.А. Молекулярные механизмы дидрогестерона (Дюфастона). Часть 1: исследование селективности взаимодействия дидрогестерона с прогестероновыми рецепторами методами молекулярной механики. Принята к публикации. Проблемы репродукции, 2010.
3. Leonhardt SA, Boonyaratanakornkit V, Edwards DP. Progesterone receptor transcription and non-transcription signaling mechanisms. Steroids 2003; 68 (10–13): 761–70.
4. Torshin IYu. Bioinformatics in the post-genomic era: physiology and medicine. NY: Nova Biomedical Books, 2007; 35–67.
5. Torshin IYu. Bioinformatics in the post-genomic era: sensing the change from molecular genetics to personalized medicine. In series: «Bioinformatics in the Post-
Genomic Era». NY: Nova Biomedical Books, 2009.
6. Krieg AJ, Krieg SA, Ahn BS, Shapiro DJ. Interplay between estrogen response element sequence and ligands controls in vivo binding of estrogen receptor to regulated genes. J Biol Chem 2004; 279 (6): 5025–34.
7. Jegga AG, Chen J, Gowrisankar S et al. GenomeTrafac: a whole genome resource for the detection of transcription factor binding site clusters associated with conventional and microRNA encoding genes conserved between mouse and human gene orthologs. Nucleic Acids Res 2007; 35.
8. Stepanova M, Lin F, Lin VC. Establishing a statistic model for recognition of steroid hormone response elements. Comput Biol Chem 2006; 30 (5): 339–47.
9. Stormo GD. DNA binding sites: representation and discovery. Bioinformatics 2000; 16 (1): 16–23.
10. Initial sequencing and analysis of the human genome Intl Human Genome Sequencing Consortium Nature 2001; 409: 860–920.
11. Kalinka J, Szekeres-Bartho J. The impact of dydrogesterone supplementation on hormonal profile and progesterone induced blocking factor concentrations in women with threatened abortion. AJRI 2005; 53: 1–6.
12. Raudrant D, Rabe T. Progestogens with antiandrogenic properties. Drugs 2003; 63 (5): 463–92.
13. Yiou R, Lefaucheur JP, Atala A. The regeneration process of the striated urethral sphincter involves activation of intrinsic satellite cells. Anat Embryol (Berl) 2003; 206 (6): 429–35.
14. Biason-Lauber A, Konrad D. WNT4 and sex development. Sex Dev 2008; 2 (4–5): 210–8.
15. Miyagawa S, Satoh Y, Haraguchi R et al. Genetic interactions of the androgen and Wnt/beta-catenin pathways for the masculinization of external genitalia. Mol Endocrinol 2009; 23 (6): 871–80.
16. Dumaual CM, Sandusky GE, Crowell PL, Randall SK. Cellular localization of PRL-1 and PRL-2 gene expression in normal adult human tissues. J Histochem Cytochem 2006; 54 (12): 1401–12.
17. Dhanasekaran SM, Dash A, Yu J et al. Molecular profiling of human prostate tissues: insights into gene expression patterns of prostate development during puberty. FASEBJ 2005; 19 (2): 243–5.
18. Nimkarn S, New MI. Prenatal diagnosis and treatment of congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Mol Cell Endocrinol 2009; 300 (1–2): 192–6.
19. Pusalkar M, Meherji P, Gokral J et al. CYP11A1 and CYP17 promoter polymorphisms associate with hyperandrogenemia in polycystic ovary syndrome. Fertil Steril 2009; 92 (2): 653–9.
20. Goto M, Piper Hanley K, Marcos J et al. In humans, early cortisol biosynthesis provides a mechanism to safeguard female sexual development. J Clin Invest 2006; 116 (4): 953–60.
21. Dahlman-Wright K, Cavailles V, Fuqua SA et al. International Union of Pharmacology. LXIV. Estrogen receptors. Pharmacol Rev 2006; 58 (4): 773–81.
22. Sarkar PS, Paul S, Han J, Reddy S. Six5 is required for spermatogenic cell survival and spermiogenesis. Hum Mol Genet 2004; 13 (14): 1421–31.
23. Sato A, Khadka DK, Liu W et al. Profilin is an effector for Daam1 in non-canonical Wnt signaling and is required for vertebrate gastrulation. Development 2006; 133 (21): 4219–31.
2. Сухих Г.Т., Торшин И.Ю., Громова О.А. Молекулярные механизмы дидрогестерона (Дюфастона). Часть 1: исследование селективности взаимодействия дидрогестерона с прогестероновыми рецепторами методами молекулярной механики. Принята к публикации. Проблемы репродукции, 2010.
3. Leonhardt SA, Boonyaratanakornkit V, Edwards DP. Progesterone receptor transcription and non-transcription signaling mechanisms. Steroids 2003; 68 (10–13): 761–70.
4. Torshin IYu. Bioinformatics in the post-genomic era: physiology and medicine. NY: Nova Biomedical Books, 2007; 35–67.
5. Torshin IYu. Bioinformatics in the post-genomic era: sensing the change from molecular genetics to personalized medicine. In series: «Bioinformatics in the Post-
Genomic Era». NY: Nova Biomedical Books, 2009.
6. Krieg AJ, Krieg SA, Ahn BS, Shapiro DJ. Interplay between estrogen response element sequence and ligands controls in vivo binding of estrogen receptor to regulated genes. J Biol Chem 2004; 279 (6): 5025–34.
7. Jegga AG, Chen J, Gowrisankar S et al. GenomeTrafac: a whole genome resource for the detection of transcription factor binding site clusters associated with conventional and microRNA encoding genes conserved between mouse and human gene orthologs. Nucleic Acids Res 2007; 35.
8. Stepanova M, Lin F, Lin VC. Establishing a statistic model for recognition of steroid hormone response elements. Comput Biol Chem 2006; 30 (5): 339–47.
9. Stormo GD. DNA binding sites: representation and discovery. Bioinformatics 2000; 16 (1): 16–23.
10. Initial sequencing and analysis of the human genome Intl Human Genome Sequencing Consortium Nature 2001; 409: 860–920.
11. Kalinka J, Szekeres-Bartho J. The impact of dydrogesterone supplementation on hormonal profile and progesterone induced blocking factor concentrations in women with threatened abortion. AJRI 2005; 53: 1–6.
12. Raudrant D, Rabe T. Progestogens with antiandrogenic properties. Drugs 2003; 63 (5): 463–92.
13. Yiou R, Lefaucheur JP, Atala A. The regeneration process of the striated urethral sphincter involves activation of intrinsic satellite cells. Anat Embryol (Berl) 2003; 206 (6): 429–35.
14. Biason-Lauber A, Konrad D. WNT4 and sex development. Sex Dev 2008; 2 (4–5): 210–8.
15. Miyagawa S, Satoh Y, Haraguchi R et al. Genetic interactions of the androgen and Wnt/beta-catenin pathways for the masculinization of external genitalia. Mol Endocrinol 2009; 23 (6): 871–80.
16. Dumaual CM, Sandusky GE, Crowell PL, Randall SK. Cellular localization of PRL-1 and PRL-2 gene expression in normal adult human tissues. J Histochem Cytochem 2006; 54 (12): 1401–12.
17. Dhanasekaran SM, Dash A, Yu J et al. Molecular profiling of human prostate tissues: insights into gene expression patterns of prostate development during puberty. FASEBJ 2005; 19 (2): 243–5.
18. Nimkarn S, New MI. Prenatal diagnosis and treatment of congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Mol Cell Endocrinol 2009; 300 (1–2): 192–6.
19. Pusalkar M, Meherji P, Gokral J et al. CYP11A1 and CYP17 promoter polymorphisms associate with hyperandrogenemia in polycystic ovary syndrome. Fertil Steril 2009; 92 (2): 653–9.
20. Goto M, Piper Hanley K, Marcos J et al. In humans, early cortisol biosynthesis provides a mechanism to safeguard female sexual development. J Clin Invest 2006; 116 (4): 953–60.
21. Dahlman-Wright K, Cavailles V, Fuqua SA et al. International Union of Pharmacology. LXIV. Estrogen receptors. Pharmacol Rev 2006; 58 (4): 773–81.
22. Sarkar PS, Paul S, Han J, Reddy S. Six5 is required for spermatogenic cell survival and spermiogenesis. Hum Mol Genet 2004; 13 (14): 1421–31.
23. Sato A, Khadka DK, Liu W et al. Profilin is an effector for Daam1 in non-canonical Wnt signaling and is required for vertebrate gastrulation. Development 2006; 133 (21): 4219–31.
________________________________________________
2. Сухих Г.Т., Торшин И.Ю., Громова О.А. Молекулярные механизмы дидрогестерона (Дюфастона). Часть 1: исследование селективности взаимодействия дидрогестерона с прогестероновыми рецепторами методами молекулярной механики. Принята к публикации. Проблемы репродукции, 2010.
3. Leonhardt SA, Boonyaratanakornkit V, Edwards DP. Progesterone receptor transcription and non-transcription signaling mechanisms. Steroids 2003; 68 (10–13): 761–70.
4. Torshin IYu. Bioinformatics in the post-genomic era: physiology and medicine. NY: Nova Biomedical Books, 2007; 35–67.
5. Torshin IYu. Bioinformatics in the post-genomic era: sensing the change from molecular genetics to personalized medicine. In series: «Bioinformatics in the Post-
Genomic Era». NY: Nova Biomedical Books, 2009.
6. Krieg AJ, Krieg SA, Ahn BS, Shapiro DJ. Interplay between estrogen response element sequence and ligands controls in vivo binding of estrogen receptor to regulated genes. J Biol Chem 2004; 279 (6): 5025–34.
7. Jegga AG, Chen J, Gowrisankar S et al. GenomeTrafac: a whole genome resource for the detection of transcription factor binding site clusters associated with conventional and microRNA encoding genes conserved between mouse and human gene orthologs. Nucleic Acids Res 2007; 35.
8. Stepanova M, Lin F, Lin VC. Establishing a statistic model for recognition of steroid hormone response elements. Comput Biol Chem 2006; 30 (5): 339–47.
9. Stormo GD. DNA binding sites: representation and discovery. Bioinformatics 2000; 16 (1): 16–23.
10. Initial sequencing and analysis of the human genome Intl Human Genome Sequencing Consortium Nature 2001; 409: 860–920.
11. Kalinka J, Szekeres-Bartho J. The impact of dydrogesterone supplementation on hormonal profile and progesterone induced blocking factor concentrations in women with threatened abortion. AJRI 2005; 53: 1–6.
12. Raudrant D, Rabe T. Progestogens with antiandrogenic properties. Drugs 2003; 63 (5): 463–92.
13. Yiou R, Lefaucheur JP, Atala A. The regeneration process of the striated urethral sphincter involves activation of intrinsic satellite cells. Anat Embryol (Berl) 2003; 206 (6): 429–35.
14. Biason-Lauber A, Konrad D. WNT4 and sex development. Sex Dev 2008; 2 (4–5): 210–8.
15. Miyagawa S, Satoh Y, Haraguchi R et al. Genetic interactions of the androgen and Wnt/beta-catenin pathways for the masculinization of external genitalia. Mol Endocrinol 2009; 23 (6): 871–80.
16. Dumaual CM, Sandusky GE, Crowell PL, Randall SK. Cellular localization of PRL-1 and PRL-2 gene expression in normal adult human tissues. J Histochem Cytochem 2006; 54 (12): 1401–12.
17. Dhanasekaran SM, Dash A, Yu J et al. Molecular profiling of human prostate tissues: insights into gene expression patterns of prostate development during puberty. FASEBJ 2005; 19 (2): 243–5.
18. Nimkarn S, New MI. Prenatal diagnosis and treatment of congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Mol Cell Endocrinol 2009; 300 (1–2): 192–6.
19. Pusalkar M, Meherji P, Gokral J et al. CYP11A1 and CYP17 promoter polymorphisms associate with hyperandrogenemia in polycystic ovary syndrome. Fertil Steril 2009; 92 (2): 653–9.
20. Goto M, Piper Hanley K, Marcos J et al. In humans, early cortisol biosynthesis provides a mechanism to safeguard female sexual development. J Clin Invest 2006; 116 (4): 953–60.
21. Dahlman-Wright K, Cavailles V, Fuqua SA et al. International Union of Pharmacology. LXIV. Estrogen receptors. Pharmacol Rev 2006; 58 (4): 773–81.
22. Sarkar PS, Paul S, Han J, Reddy S. Six5 is required for spermatogenic cell survival and spermiogenesis. Hum Mol Genet 2004; 13 (14): 1421–31.
23. Sato A, Khadka DK, Liu W et al. Profilin is an effector for Daam1 in non-canonical Wnt signaling and is required for vertebrate gastrulation. Development 2006; 133 (21): 4219–31.
Авторы
И.Ю.Торшин2, 3, О.А.Громова2,3, Г.Т.Сухих1, С.А.Галицкая3, И.С.Юргель3
1. ФГУ Научный центр акушерства, гинекологии и перинатологии им. В.И.Кулакова, Москва;
2. Вычислительный центр им. А.А.Дородницына РАН;
3. ГОУ ВПО «Ивановская государственная медицинская академия Росздрава»
1. ФГУ Научный центр акушерства, гинекологии и перинатологии им. В.И.Кулакова, Москва;
2. Вычислительный центр им. А.А.Дородницына РАН;
3. ГОУ ВПО «Ивановская государственная медицинская академия Росздрава»
Цель портала OmniDoctor – предоставление профессиональной информации врачам, провизорам и фармацевтам.