sibmedСибирский научный медицинский журналСибирский научный медицинский журнал2410-25122410-2520ИЦиГ СО РАН10.15372/SSMJ20190404sibmed-205Research ArticleМЕДИКО-БИОЛОГИЧЕСКИЕ НАУКИBIOMEDICINEЛИПОПРОТЕИНЫ КРОВИ КАК ПЛАТФОРМА ДЛЯ ТРАНСПОРТА ГИДРОФИЛЬНЫХ И ГИДРОФОБНЫХ СОЕДИНЕНИЙBLOOD LIPOPROTEINS AS A PLATFORM FOR TRANSPORT OF HYDROPHILIC AND HYDROPHOBIC COMPOUNDSПоляковЛ. М.PolyakovL. M.

д.м.н., проф.,

 630117, г. Новосибирск, ул. Тимакова, 2

doctor of medical sciences, professor

630117, Novosibirsk, Timakov str., 2

plm@niibch.ruКнязевР. А.KnyazevR. A.

к.б.н., 

 630117, г. Новосибирск, ул. Тимакова, 2

candidate of biological sciences

630117, Novosibirsk, Timakov str., 2

Knjazev_roman@mail.ruРябченкоА. В.RyabchenkoA. V.

к.б.н.,

 630117, г. Новосибирск, ул. Тимакова, 2

candidate of biological sciences

630117, Novosibirsk, Timakov str., 2

borrelia@mail.ruКотоваМ. В.KotovaM. V.

630117, г. Новосибирск, ул. Тимакова, 2

630117, Novosibirsk, Timakov str., 2

zerokiri@mail.ruТрифоноваН. В.TrifonovaN. V.

630117, г. Новосибирск, ул. Тимакова, 2

630117, Novosibirsk, Timakov str., 2

nataliya-tverdohleb@yandex.ruНИИ биохимии ФИЦ фундаментальной и трансляционной медициныРоссияInstitute of Biochemistry of Federal Research Center for Fundamental and Translational MedicineRussian Federation2019040920193943036Copyright © Поляков Л.М., Князев Р.А., Рябченко А.В., Котова М.В., Трифонова Н.В., 20192019Поляков Л.М., Князев Р.А., Рябченко А.В., Котова М.В., Трифонова Н.В.Polyakov L.M., Knyazev R.A., Ryabchenko A.V., Kotova M.V., Trifonova N.V.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://sibmed.elpub.ru/jour/article/view/205

В работе рассмотрены транспортные функции основных классов липопротеинов (ЛП) плазмы крови, не связанные с обменом липидов, входящих в их состав. Цель исследования – изучить способность различных  фракций ЛП плазмы крови (очень низкой (ЛПОНП), низкой (ЛПНП) и высокой плотности (ЛПВП)) взаимодействовать с гидрофильными и гидрофобными соединениями и показать роль ЛП как форм, способных транспортировать ксенобиотики в органы и ткани организма. Материал и методы. Исследования выполнены с использованием меченных тритием цитохалазина B, бензилпенициллина, бензантрацена, бензо(а)пирена, ультрацентрифугирования фракций ЛП плазмы крови, колоночной хроматографии; проведены опыты in vivo c внутривенным введением комплексов ЛП с меченым бензантраценом. Результаты. Методом ультрацентрифугирования показана способность различных классов ЛП образовывать комплексы с гидрофильными (цитохалазин B, бензилпенициллин) и гидрофобными (бензантрацен, бензо(а)пирен) соединениями. В плазме крови человека более 50 % радиоактивности гидрофильных соединений было представлено в составе фракций ЛПНП и ЛПВП, а в составе фракций ЛПОНП она была минимальной – 6,3 и 5,1 % соответственно. В инфранатанте присутствовала значительная часть цитохалазина B и бензилпенициллина – 43,6 и 40,9 % соответственно. Распределение в плазме крови для гидрофобных (бензантрацен, бензо(а)пирен) соединений было иным. Более 80 % радиоактивности было представлено в составе ЛП фракций, а в полярном белковом инфранатанте содержалось 16,1 % радиоактивности бензантрацена и 13,6 % бензо(а)пирена. В опытах in vivo с внутривенным введением крысам комплексов ЛП с меченным тритием бензантраценом показаны особенности поглощения липофильного ксенобиотика органами и тканями крыс. После введения 3Н-бензантрацена в составе ЛПОНП и ЛПНП наибольшая удельная радиоактивность была обнаружена в печени и надпочечниках. Вдвое меньшее поглощение меченого препарата наблюдали в семенниках и почках. Радиоактивность уменьшалась в ряду: легкие, жировая ткань, тимус, сердце и селезенка. Использование ЛПВП как платформы для 3Н-бензантрацена показало интенсивное накопление липофильного ксенобиотика в стероидпродуцирующих органах: надпочечниках и семенниках. Заключение. Полученные результаты позволяют считать реальной возможность использования ЛП плазмы крови в качестве платформ, способных транспортировать гидрофильные и гидрофобные соединения в клетки органов и тканей организма.

The paper discusses the transport functions of the main classes of blood plasma lipoproteins (LP) that are not associated with the metabolism of lipids that make up their composition. The aim of the study was to study the ability of various plasma LP fractions (very low (VLDL), low (LDL) and high density (HDL)) to interact with certain hydrophilic and hydrophobic compounds and show the role of LP as transport forms of xenobiotics in the organs and tissues of the body. Material and methods. The studies were performed with tritium-labeled cytochalasin B, benzylpenicillin, benzanthracene, benzo(a)pyrene, ultracentrifugation of human plasma LP fractions, column chromatography; in vivo experiments with intravenous injection of LP complexes with tritium-labeled benzanthracene were conducted. Results. The ability of various classes of LP to form complexes with hydrophilic (cytochalasin B, benzylpenicillin) and hydrophobic (benzanthracene, benzo(a)pyrene) compounds is shown by the method of ultracentrifugation. More than 50 % of the radioactivity of hydrophilic compounds in human blood plasma was represented in the composition of the LDL and HDL fractions, and in the composition of the VLDL fractions it was minimal – 6.3 and 5.1 %, respectively. A significant part of cytochalasin and benzylpenicillin was also present in the protein infranatant – 43.6 and 40.9 %, respectively. The distribution in blood plasma for hydrophobic (benzanthracene, benzo(a)pyrene) compounds was different. More than 80 % of the radioactivity was represented in the composition of the LP fractions. The polar protein infranatant contained 16.1 % of the radioactivity of benzantracene and 13.6 % of benzo(a)pyrene. The features of the lipophilic xenobiotics uptake by organs and tissues were shown in vivo experiments with intravenous injection of complexes of LP with tritium-labeled benzanthracene to rats. The highest specific radioactivity was found in the liver and adrenal glands after the intravenous injection of 3H-benzanthracene in the composition of VLDL and LDL. Twice less uptake of the labeled drug was observed in the testis and kidneys. Radioactivity decreased in the series: lungs,adipose tissue, thymus, heart, and spleen. A feature of the use of HDL as a platform for 3H-enzanthracene is the intense accumulation of lipophilic xenobiotics in steroid-producing organs: the adrenal glands and testis. Conclusion. The results obtained allow us to consider the real possibility of using blood plasma PL as transport platforms for hydrophilic and hydrophobic compounds into the cells of organs and tissues.

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Cyclosporine A transfer between high- and lowdensity lipoproteins: independent from lipid transfer protein I-facilitated transfer of lipoprotein-coated phospholipids because of high affinity of cyclosporine a for the protein component of lipoproteins. J. Pharm. Sci. 2001; 90 (9): 1308–1317.Kwong M., Sivak O., Kwong E.H., Wasan K.M. Cyclosporine A transfer between high- and lowdensity lipoproteins: independent from lipid transfer protein I-facilitated transfer of lipoprotein-coated phospholipids because of high affinity of cyclosporine a for the protein component of lipoproteins. J. Pharm. Sci. 2001; 90 (9): 1308–1317.Kwong M., Sivak O., Kwong E.H., Wasan K.M. Cyclosporine A transfer between high- and lowdensity lipoproteins: independent from lipid transfer protein I-facilitated transfer of lipoprotein-coated phospholipids because of high affinity of cyclosporine a for the protein component of lipoproteins. J. Pharm. Sci. 2001; 90 (9): 1308–1317.Kwong M., Sivak O., Kwong E.H., Wasan K.M. Cyclosporine A transfer between high- and lowdensity lipoproteins: independent from lipid transfer protein I-facilitated transfer of lipoprotein-coated phospholipids because of high affinity of cyclosporine a for the protein component of lipoproteins. J. Pharm. Sci. 2001; 90 (9): 1308–1317.Masquelier M., Tirzitis G., Peterson C.O., Palsson M., Amolins A., Plotniece M., Plotniece A., Makarova N., Vitols S.G. Plasma stability and cytotoxicity of lipophilic daunorubicin derivatives incorporated into low density lipoproteins. Eur. J. Med. Chem. 2000; 35 (4): 429–438.Masquelier M., Tirzitis G., Peterson C.O., Palsson M., Amolins A., Plotniece M., Plotniece A., Makarova N., Vitols S.G. Plasma stability and cytotoxicity of lipophilic daunorubicin derivatives incorporated into low density lipoproteins. Eur. J. Med. Chem. 2000; 35 (4): 429–438.Masquelier M., Tirzitis G., Peterson C.O., Palsson M., Amolins A., Plotniece M., Plotniece A., Makarova N., Vitols S.G. Plasma stability and cytotoxicity of lipophilic daunorubicin derivatives incorporated into low density lipoproteins. Eur. J. Med. Chem. 2000; 35 (4): 429–438.Masquelier M., Tirzitis G., Peterson C.O., Palsson M., Amolins A., Plotniece M., Plotniece A., Makarova N., Vitols S.G. Plasma stability and cytotoxicity of lipophilic daunorubicin derivatives incorporated into low density lipoproteins. Eur. J. Med. Chem. 2000; 35 (4): 429–438.Mo Z.C., Ren K., Liu X., Tang Z.L., Yi G.H. A high-density lipoprotein-mediated drug delivery system. Adv. Drug Deliv. Rev. 2016; 106 (Pt. A): 132–147.Mo Z.C., Ren K., Liu X., Tang Z.L., Yi G.H. A high-density lipoprotein-mediated drug delivery system. Adv. Drug Deliv. Rev. 2016; 106 (Pt. A): 132–147.Mo Z.C., Ren K., Liu X., Tang Z.L., Yi G.H. A high-density lipoprotein-mediated drug delivery system. Adv. Drug Deliv. Rev. 2016; 106 (Pt. A): 132–147.Mo Z.C., Ren K., Liu X., Tang Z.L., Yi G.H. A high-density lipoprotein-mediated drug delivery system. Adv. Drug Deliv. Rev. 2016; 106 (Pt. A): 132–147.Polyakov L.M., Chasovskikh M.I., Panin L.E. Binding and transport of benzo[a]pyrene by blood plasma lipoproteins: the possible role of apolipoprotein B in this process. Bioconjug. Chem. 1996; 7 (4): 396–400.Polyakov L.M., Chasovskikh M.I., Panin L.E. Binding and transport of benzo[a]pyrene by blood plasma lipoproteins: the possible role of apolipoprotein B in this process. Bioconjug. Chem. 1996; 7 (4): 396–400.Polyakov L.M., Chasovskikh M.I., Panin L.E. Binding and transport of benzo[a]pyrene by blood plasma lipoproteins: the possible role of apolipoprotein B in this process. Bioconjug. Chem. 1996; 7 (4): 396–400.Polyakov L.M., Chasovskikh M.I., Panin L.E. Binding and transport of benzo[a]pyrene by blood plasma lipoproteins: the possible role of apolipoprotein B in this process. Bioconjug. Chem. 1996; 7 (4): 396–400.Sabnis N., Lacko A.G. Drug delivery via lipoprotein-based carriers: answering the challenges in systemic therapeutic. Ther. Deliv. 2012; 3 (5): 599–608.Sabnis N., Lacko A.G. Drug delivery via lipoprotein-based carriers: answering the challenges in systemic therapeutic. Ther. Deliv. 2012; 3 (5): 599–608.Sabnis N., Lacko A.G. Drug delivery via lipoprotein-based carriers: answering the challenges in systemic therapeutic. Ther. Deliv. 2012; 3 (5): 599–608.Sabnis N., Lacko A.G. Drug delivery via lipoprotein-based carriers: answering the challenges in systemic therapeutic. Ther. Deliv. 2012; 3 (5): 599–608.Soine P.J., Blanke R.V., Guzelian P.S., Schwartz C.C. Preferential binding of chlordecone to the protein and high density lipoprotein fractions of plasma from humans and other species. J. Toxicol. Environ. Health. 1982; 9 (1): 107–118.Soine P.J., Blanke R.V., Guzelian P.S., Schwartz C.C. Preferential binding of chlordecone to the protein and high density lipoprotein fractions of plasma from humans and other species. J. Toxicol. Environ. Health. 1982; 9 (1): 107–118.Soine P.J., Blanke R.V., Guzelian P.S., Schwartz C.C. Preferential binding of chlordecone to the protein and high density lipoprotein fractions of plasma from humans and other species. J. Toxicol. Environ. Health. 1982; 9 (1): 107–118.Soine P.J., Blanke R.V., Guzelian P.S., Schwartz C.C. Preferential binding of chlordecone to the protein and high density lipoprotein fractions of plasma from humans and other species. J. Toxicol. Environ. Health. 1982; 9 (1): 107–118.Van’t Hooft F.M., van Tol A. The sites of degradation of rat high-density-lipoprotein apolipoprotein E specifically labelled with O-(4-diazo-3-[125I] iodobenzoyl)sucrose. Biochem. J. 1985; 226 (3): 715–721.Van’t Hooft F.M., van Tol A. The sites of degradation of rat high-density-lipoprotein apolipoprotein E specifically labelled with O-(4-diazo-3-[125I] iodobenzoyl)sucrose. Biochem. J. 1985; 226 (3): 715–721.Van’t Hooft F.M., van Tol A. The sites of degradation of rat high-density-lipoprotein apolipoprotein E specifically labelled with O-(4-diazo-3-[125I] iodobenzoyl)sucrose. Biochem. J. 1985; 226 (3): 715–721.Van’t Hooft F.M., van Tol A. The sites of degradation of rat high-density-lipoprotein apolipoprotein E specifically labelled with O-(4-diazo-3-[125I] iodobenzoyl)sucrose. Biochem. J. 1985; 226 (3): 715–721.Yang H., Fogo A.B., Kon V. Kidneys: key modulators of high-density lipoprotein levels and function. Curr. Opin. Nephrol. Hypertens. 2016; 25 (3): 174–179.Yang H., Fogo A.B., Kon V. Kidneys: key modulators of high-density lipoprotein levels and function. Curr. Opin. Nephrol. Hypertens. 2016; 25 (3): 174–179.Yang H., Fogo A.B., Kon V. Kidneys: key modulators of high-density lipoprotein levels and function. Curr. Opin. Nephrol. Hypertens. 2016; 25 (3): 174–179.Yang H., Fogo A.B., Kon V. Kidneys: key modulators of high-density lipoprotein levels and function. Curr. Opin. Nephrol. Hypertens. 2016; 25 (3): 174–179.Yuan Y., Wen J., Tang J., Kan Q., Ackermann R., Olsen K., Schwendeman A. Synthetic high-density lipoproteins for delivery of 10-hydroxycamptothecin. Int. J. Nanomedicine. 2016; 11: 6229–6238.Yuan Y., Wen J., Tang J., Kan Q., Ackermann R., Olsen K., Schwendeman A. Synthetic high-density lipoproteins for delivery of 10-hydroxycamptothecin. Int. J. Nanomedicine. 2016; 11: 6229–6238.Yuan Y., Wen J., Tang J., Kan Q., Ackermann R., Olsen K., Schwendeman A. Synthetic high-density lipoproteins for delivery of 10-hydroxycamptothecin. Int. J. Nanomedicine. 2016; 11: 6229–6238.Yuan Y., Wen J., Tang J., Kan Q., Ackermann R., Olsen K., Schwendeman A. Synthetic high-density lipoproteins for delivery of 10-hydroxycamptothecin. Int. J. Nanomedicine. 2016; 11: 6229–6238.

The authors declare that there are no conflicts of interest present.