Липиды: гепатопротекторы, точки приложения, фармакологические эффекты
Липиды: гепатопротекторы, точки приложения, фармакологические эффекты
Плотникова Е.Ю., Сухих А.С. Липиды: гепатопротекторы, точки приложения, фармакологические эффекты. Consilium Medicum. Гастроэнтерология (Прил.). 2016; 1: 5–11.
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Plotnikova E.Yu., Sukhikh A.S. Lipids: hepatoprotectors, the point of application, the pharmacological effects. Consilium Medicum. Gastroenterology (Suppl.). 2016; 1: 5–11.
Липиды: гепатопротекторы, точки приложения, фармакологические эффекты
Плотникова Е.Ю., Сухих А.С. Липиды: гепатопротекторы, точки приложения, фармакологические эффекты. Consilium Medicum. Гастроэнтерология (Прил.). 2016; 1: 5–11.
________________________________________________
Plotnikova E.Yu., Sukhikh A.S. Lipids: hepatoprotectors, the point of application, the pharmacological effects. Consilium Medicum. Gastroenterology (Suppl.). 2016; 1: 5–11.
Липиды разных классов существенно отличаются по структуре и функциям, особое внимание в статье уделено двум группам липидов – фосфолипидам (ФЛ) и урсодезоксихолевой кислоте (УДХК). ФЛ – большой класс липидов, получивших свое название из-за остатка фосфорной кислоты, придающего им свойства амфифильности. Благодаря этому свойству ФЛ формируют бислойную структуру мембран, в которую погружены белки. УДХК является одной из желчных кислот организма человека. Она отличается от других желчных кислот, составляющих общий пул у человека, она не омыляется в тонкой кишке и устойчива к окислению. В статье дано определение двум основным гепатопротекторам-липидам – ФЛ и УДХК. Подробно рассмотрены их фармакокинетика и фармакодинамика с учетом физиологических аспектов. Определено их место в клинической практике.
Ключевые слова: фосфолипиды, урсодезоксихолевая кислота, заболевания печени и желчных путей.
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Lipids of different classes differ substantially in structure and function, special attention is paid to two groups of lipids – phospholipids and ursodeoxycholic acid. Phospholipids – a large class of lipids named for the remainder of the phosphoric acid, which imparts to them properties of amphiphiles, due to this property of phospholipids form a bilayer structure of membranes, in which proteins are immersed. Ursodeoxycholic acid is one of the bile acids in the human body. It differs from the other bile acids that constitute a common pool in humans, it is not saponified in the small intestine and is resistant to oxidation. In article definition of the two main liver-lipids – phospholipids and ursodeoxycholic acid. They considered in detail the pharmacokinetics and pharmacodynamics taking into account physiological aspects. Determine their place in clinical practice.
Key words: phospholipids, ursodeoxycholic acid, liver diseases and biliary tract.
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9. Leventis A, Grinstein S. The distribution and function of phosphatidylserine in cellular membranes. Annu Rev Biophys 2010; 39: 407–27.
10. Fruhwirth GO, Loidl A, Hermetter A. Oxidized phospholipids: from molecular properties to disease. Biochim Biophys Acta 2007; 1772: 718–36.
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13. Maciel E, Da Silva RN, Simões C et al. Structural characterization of oxidized glycerophosphatidylserine: evidence of polar head oxidation. J Am Soc Mass Spectrom 2011; 22: 1804–14.
14. Küllenberg D, Taylor LA, Schneider M, Massing U. Health effects of dietary phospholipids. Lipids Health Dis 2012; 11: 3.
15. Gundermann KJ, Kuenker A, Kuntz E, Drozdzik M. Activity of essential phospholipids (EPL) from soybean in liver diseases. Pharmacol Rep 2011; 63 (3): 643–59.
16. Cunnane SC. Problems with essential fatty acids: time for a new paradigm? Progr Lipid Res 2003; 42 (Issue 6): 544–68.
17. Brown JM, Hazen SL. Meta-Organismal Nutrient Metabolism as a Basis of Cardiovascular Disease. Curr Opin Lipidol 2014; 25 (1): 48–53.
18. Trøseid M, Ueland T, Hov JR et al. Microbiota-dependent metabolite trimethylamine-N-oxide is associated with disease severity and survival of patients with chronic heart failure. J Intern Med 2015; 277 (6): 717–26.
19. Nagatomo Y, Tang WH. Intersections Between Microbiome and Heart Failure: Revisiting the Gut Hypothesis. J Card Fail 2015; 21 (12): 973–80.
20. Wang Z, Wilson Tang WH, Jennifer A et al. Prognostic value of choline and betaine depends on intestinal microbiota-generated metabolite trimethylamine-N-oxide. First published online: 4 February 2014. http://dx.doi.org/10.1093/eurheartj/ehu002
21. Lagacea TA, Ridgwayb ND. The role of phospholipids in the biological activity and structure of the endoplasmic reticulum. Biochimica et Biophysica Acta (BBA). Mol Cell Res 2013; 1833 (Issue 11): 2499–510.
22. Wang Z, Klipfell E, Bennett BJ et al. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature 2011; 472 (7341): 57–63.
23. Lazaridis KN, Gores JG, Lindor KD. Ursodeoxycholic acid mechanisms of action and clinical use in hepatobiliary disorders. J Hepatol 2001; 35: 134–46.
24. Hofmann AF. Pharmacology of ursodeoxycholic acid, an enterohepatic drug. Scand J Gastroenterol 1994; 29 (Suppl. 204): 1–15.
25. Paumgartner G. Ursodeoxycholic acid in cholestasis liver disease: mechanisms of action and therapeutic use revisited. Hepatol 2002; 36: 525–31.
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27. Rubin RA, Kowalski TE, Khandelwal M, Malet PF. Ursodiol for hepatobiliary disorders. Ann Intern Med 1994; 121: 207–18.
28. O’Hara SP, Tabibian JH, Splinter PL et al. The dynamic biliary epithelia: Molecules, pathways, and disease. J Hepatology 2013; 58: 575–82.
29. Gamboa A, Tian Ch, Massaad J et al. The Therapeutic Role of Ursodeoxycholic Acid in Digestive Diseases. AGH 2011; 000: (000).
30. Kotb MA. Molecular Mechanisms of Ursodeoxycholic Acid Toxicity & Side Effects: Ursodeoxycholic Acid Freezes Regeneration & Induces Hibernation Mode. Int J Mol Sci 2012; 13: 8882–14.
31. Харченко Н.В. К обсуждению статьи «Молекулярные механизмы токсичности и побочных эффектов урсодезоксихолевой кислоты: замедление регенерации и индукция состояния клеточного покоя». Здоров'я України 21 сторіччя. 2015; 9. / Kharchenko N.V. K obsuzhdeniiu stat'i «Molekuliarnye mekhanizmy toksichnosti i pobochnykh effektov ursodezoksikholevoi kisloty: zamedlenie regeneratsii i induktsiia sostoianiia kletochnogo pokoia». Zdorov'ia Ukraїni 21 storіchchia. 2015; 9. [in Russian]
32. Heuman DM. Quantitative estimation of the hydrophilic-hydrophobic balance of mixed bile salt solutions. J Lipid Res 1989; 30: 719–30.
33. Faubion WA, Guicciardi ME, Miyoshi H et al. Toxic bile salts induce rodent hepatocyte apoptosis via direct activation of Fas. J Clin Invest 1999; 103: 137–45.
34. Castro RE, Amaral JD, Solá S et al. Differential regulation of cyclin D1 and cell death by bile acids in primary rat hepatocytes. Am J Physiol Gastrointest Liver Physiol 2007; 293: 327–34.
35. Rodrigues CMP, Fan G, Wong PY et al. Ursodeoxycholic acid may inhibit deoxycholic acid-induced apoptosis by modulating mitochondrial transmembrane potential and reactive oxygen species production. Mol Med 1998; 4: 165–78.
36. Amaral JD, Castro RE, Solá S et al. p53 is a key molecular target of ursodeoxycholic acid in regulating apoptosis. J Biol Chem 2007; 282: 34250–9.
37. Rodrigues CM, Fan G, Ma X et al. A novel role for ursodeoxycholic acid in inhibiting apoptosis by modulating mitochondrial membrane perturbation. J Clin Invest 1998; 101: 2790–9.
38. Лаврик И.Н. Регуляция апоптоза, индуцируемого через CD95/FAS и другие «рецепторы смерти». Молекулярная биология. 2011; 45 (1): 173–9. / Lavrik I.N. Reguliatsiia apoptoza, indutsiruemogo cherez CD95/FAS i drugie «retseptory smerti». Molekuliarnaia biologiia. 2011; 45 (1): 173–9. [in Russian]
39. Rodrigues CM.P, Solá S, Sharpe JC et al. Tauroursodeoxycholic acid prevents Bax-induced membrane perturbation and cytochrome C release inisolated mitochondria. Biochemistry 2003; 42: 3070–80.
40. Azzaroli F, Mehal W, Soroka CJ et al. Ursodeoxycholic acid diminishes Fas-ligand-induced apoptosis in mouse hepatocytes. Hepatology 2002; 36: 49–54.
41. Park IH, Kim MK, Kim SU. Ursodeoxycholic acid prevents apoptosis of mouse sensory neurons induced by cisplatin by reducing P53 accumulation. Biochem Biophys Res Commun 2008; 77: 1025–30.
42. Amaral JD, Castro RE, Solá S et al. Ursodeoxycholic acid modulates the ubiquitin-proteasome degradation pathway of p53. Biochem Biophysi Res Commun 2010; 400: 649–54.
43. Azzaroli F, Mehal W, Soroka CJ et al. Ursodeoxycholic acid diminishes Fas-ligand-induced apoptosis in mouse hepatocytes. Hepatology 2002; 36: 49–54.
44. Solá S, Castro RE, Kren BT et al. Modulation of nuclear steroid receptors by ursodeoxycholic acid inhibits TGF-b1-induced E2F-1/p53-mediated apoptosis of rat hepatocytes. Biochemistry 2004; 43: 8429–38.
45. Solá S, Ma X, Castro RE et al. Ursodeoxycholic acid modulates E2F-1 and p53 expression through a caspase-independent mechanism in transforming growth factor beta1-induced apoptosis of rat hepatocytes. J Biol Chem 2003; 278: 48831–8.
46. Mello-Vieira J, Sousa T, Coutinho A et al. Cytotoxic bile acids, but not cytoprotective species, inhibit the ordering effect of cholesterol in model membranes at physiologically active concentrations. Biochimica et Biophysica Acta 2013; 1828: 2152–63.
47. Zhou Y, Doyen R, Lichtenberger LM. The role of membrane cholesterol in determining bile acid cytotoxicity and cytoprotection of ursodeoxycholic acid. Biochimica et Biophysica Acta 2009; 1788: 507–13.
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________________________________________________
1. Tiukavkina N.A., Baukov Iu.I., Zurabian S.E. Bioorganicheskaia khimiia: uchebnik. M., 2010. [in Russian]
2. Normy fiziologicheskikh potrebnostei v energii i pishchevykh veshchestvakh dlia razlichnykh grupp naseleniia Rossiiskoi Federatsii. Metodicheskie rekomendatsii MR 2.3.1.2432. M., 2008. [in Russian]
3. Fisher AE, Naughton DP. Iron supplements: the quick fix with long-term consequences. J Nutrition 2004; 3 (2).
4. Lagacea TA., Ridgwayb ND. The role of phospholipids in the biological activity and structure of the endoplasmic reticulum. Biochimica et Biophysica Acta (BBA). Mol Cell Res2013; 1833 (Issue 11): 2499–510.
5. Biokhimiia. Uchebnik dlia vuzov. Pod red. E.S.Severina. 2003. [in Russian]
6. Skurikhin I.M., Tutel'ian V.A. Tablitsy khimicheskogo sostava i kaloriinosti rossiiskikh produktov pitaniia: spravochnik. M.: DeLi print, 2007. [in Russian]
7. Kvetnaia A.S., Zhelezova L.I. Stimuliruiushchee vliianie fosfotidilkholina (letsitina) na patogennye svoistva. Uchenye zapiski SPbGMU im. akad. I.P.Pavlova. 2014; XXI (1): 48–51. [in Russian]
8. Takasuga S, Sasaki T. Phosphatidylinositol-3.5-bisphosphate: metabolism and physiological functions. J Biochem 2013; 154 (3): 211–8.
9. Leventis A, Grinstein S. The distribution and function of phosphatidylserine in cellular membranes. Annu Rev Biophys 2010; 39: 407–27.
10. Fruhwirth GO, Loidl A, Hermetter A. Oxidized phospholipids: from molecular properties to disease. Biochim Biophys Acta 2007; 1772: 718–36.
11. Bochkov VN, Oskolkova OV. Birukov KG et al. Generation and biological activities of oxidized phospholipids. J Antioxid Redox Signal 2010; 12 (8): 1009–59.
12. Liu J, Li W, Chen R et al. Circulating biologically active oxidized phospholipids show on-going and increased oxidative stress in older male mice. Redox Biology 2013; p. 110–4.
13. Maciel E, Da Silva RN, Simões C et al. Structural characterization of oxidized glycerophosphatidylserine: evidence of polar head oxidation. J Am Soc Mass Spectrom 2011; 22: 1804–14.
14. Küllenberg D, Taylor LA, Schneider M, Massing U. Health effects of dietary phospholipids. Lipids Health Dis 2012; 11: 3.
15. Gundermann KJ, Kuenker A, Kuntz E, Drozdzik M. Activity of essential phospholipids (EPL) from soybean in liver diseases. Pharmacol Rep 2011; 63 (3): 643–59.
16. Cunnane SC. Problems with essential fatty acids: time for a new paradigm? Progr Lipid Res 2003; 42 (Issue 6): 544–68.
17. Brown JM, Hazen SL. Meta-Organismal Nutrient Metabolism as a Basis of Cardiovascular Disease. Curr Opin Lipidol 2014; 25 (1): 48–53.
18. Trøseid M, Ueland T, Hov JR et al. Microbiota-dependent metabolite trimethylamine-N-oxide is associated with disease severity and survival of patients with chronic heart failure. J Intern Med 2015; 277 (6): 717–26.
19. Nagatomo Y, Tang WH. Intersections Between Microbiome and Heart Failure: Revisiting the Gut Hypothesis. J Card Fail 2015; 21 (12): 973–80.
20. Wang Z, Wilson Tang WH, Jennifer A et al. Prognostic value of choline and betaine depends on intestinal microbiota-generated metabolite trimethylamine-N-oxide. First published online: 4 February 2014. http://dx.doi.org/10.1093/eurheartj/ehu002
21. Lagacea TA, Ridgwayb ND. The role of phospholipids in the biological activity and structure of the endoplasmic reticulum. Biochimica et Biophysica Acta (BBA). Mol Cell Res 2013; 1833 (Issue 11): 2499–510.
22. Wang Z, Klipfell E, Bennett BJ et al. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature 2011; 472 (7341): 57–63.
23. Lazaridis KN, Gores JG, Lindor KD. Ursodeoxycholic acid mechanisms of action and clinical use in hepatobiliary disorders. J Hepatol 2001; 35: 134–46.
24. Hofmann AF. Pharmacology of ursodeoxycholic acid, an enterohepatic drug. Scand J Gastroenterol 1994; 29 (Suppl. 204): 1–15.
25. Paumgartner G. Ursodeoxycholic acid in cholestasis liver disease: mechanisms of action and therapeutic use revisited. Hepatol 2002; 36: 525–31.
26. Dolzhenko M.N., Shupika P.L. Novye aspekty primeneniia ursodezoksikholevoi kisloty: vzgliad kardiologa. Zdorov'e Ukrainy. 2008; 15–16: 56–8. [in Russian]
27. Rubin RA, Kowalski TE, Khandelwal M, Malet PF. Ursodiol for hepatobiliary disorders. Ann Intern Med 1994; 121: 207–18.
28. O’Hara SP, Tabibian JH, Splinter PL et al. The dynamic biliary epithelia: Molecules, pathways, and disease. J Hepatology 2013; 58: 575–82.
29. Gamboa A, Tian Ch, Massaad J et al. The Therapeutic Role of Ursodeoxycholic Acid in Digestive Diseases. AGH 2011; 000: (000).
30. Kotb MA. Molecular Mechanisms of Ursodeoxycholic Acid Toxicity & Side Effects: Ursodeoxycholic Acid Freezes Regeneration & Induces Hibernation Mode. Int J Mol Sci 2012; 13: 8882–14.
31. Kharchenko N.V. K obsuzhdeniiu stat'i «Molekuliarnye mekhanizmy toksichnosti i pobochnykh effektov ursodezoksikholevoi kisloty: zamedlenie regeneratsii i induktsiia sostoianiia kletochnogo pokoia». Zdorov'ia Ukraїni 21 storіchchia. 2015; 9. [in Russian]
32. Heuman DM. Quantitative estimation of the hydrophilic-hydrophobic balance of mixed bile salt solutions. J Lipid Res 1989; 30: 719–30.
33. Faubion WA, Guicciardi ME, Miyoshi H et al. Toxic bile salts induce rodent hepatocyte apoptosis via direct activation of Fas. J Clin Invest 1999; 103: 137–45.
34. Castro RE, Amaral JD, Solá S et al. Differential regulation of cyclin D1 and cell death by bile acids in primary rat hepatocytes. Am J Physiol Gastrointest Liver Physiol 2007; 293: 327–34.
35. Rodrigues CMP, Fan G, Wong PY et al. Ursodeoxycholic acid may inhibit deoxycholic acid-induced apoptosis by modulating mitochondrial transmembrane potential and reactive oxygen species production. Mol Med 1998; 4: 165–78.
36. Amaral JD, Castro RE, Solá S et al. p53 is a key molecular target of ursodeoxycholic acid in regulating apoptosis. J Biol Chem 2007; 282: 34250–9.
37. Rodrigues CM, Fan G, Ma X et al. A novel role for ursodeoxycholic acid in inhibiting apoptosis by modulating mitochondrial membrane perturbation. J Clin Invest 1998; 101: 2790–9.
38. Lavrik I.N. Reguliatsiia apoptoza, indutsiruemogo cherez CD95/FAS i drugie «retseptory smerti». Molekuliarnaia biologiia. 2011; 45 (1): 173–9. [in Russian]
39. Rodrigues CM.P, Solá S, Sharpe JC et al. Tauroursodeoxycholic acid prevents Bax-induced membrane perturbation and cytochrome C release inisolated mitochondria. Biochemistry 2003; 42: 3070–80.
40. Azzaroli F, Mehal W, Soroka CJ et al. Ursodeoxycholic acid diminishes Fas-ligand-induced apoptosis in mouse hepatocytes. Hepatology 2002; 36: 49–54.
41. Park IH, Kim MK, Kim SU. Ursodeoxycholic acid prevents apoptosis of mouse sensory neurons induced by cisplatin by reducing P53 accumulation. Biochem Biophys Res Commun 2008; 77: 1025–30.
42. Amaral JD, Castro RE, Solá S et al. Ursodeoxycholic acid modulates the ubiquitin-proteasome degradation pathway of p53. Biochem Biophysi Res Commun 2010; 400: 649–54.
43. Azzaroli F, Mehal W, Soroka CJ et al. Ursodeoxycholic acid diminishes Fas-ligand-induced apoptosis in mouse hepatocytes. Hepatology 2002; 36: 49–54.
44. Solá S, Castro RE, Kren BT et al. Modulation of nuclear steroid receptors by ursodeoxycholic acid inhibits TGF-b1-induced E2F-1/p53-mediated apoptosis of rat hepatocytes. Biochemistry 2004; 43: 8429–38.
45. Solá S, Ma X, Castro RE et al. Ursodeoxycholic acid modulates E2F-1 and p53 expression through a caspase-independent mechanism in transforming growth factor beta1-induced apoptosis of rat hepatocytes. J Biol Chem 2003; 278: 48831–8.
46. Mello-Vieira J, Sousa T, Coutinho A et al. Cytotoxic bile acids, but not cytoprotective species, inhibit the ordering effect of cholesterol in model membranes at physiologically active concentrations. Biochimica et Biophysica Acta 2013; 1828: 2152–63.
47. Zhou Y, Doyen R, Lichtenberger LM. The role of membrane cholesterol in determining bile acid cytotoxicity and cytoprotection of ursodeoxycholic acid. Biochimica et Biophysica Acta 2009; 1788: 507–13.
48. Plotnikova E.Iu., Sukhikh A.S. Ursodezoksikholevaia kislota vchera i segodnia. Terapevt. 2012; 7: 23–33. [in Russian]
Авторы
Е.Ю.Плотникова*, А.С.Сухих
ГБОУ ВПО Кемеровская государственная медицинская академия Минздрава России. 650029, Россия, Кемерово, ул. Ворошилова, д. 22а
*eka-pl@rambler.ru
________________________________________________
E.Yu.Plotnikova*, A.S.Sukhikh
Kemerovo State Medical Academy of the Ministry of Health of the Russian Federation. 650029, Russian Federation, Kemerovo, ul. Voroshilova, d. 22a
*eka-pl@rambler.ru