ssmuБюллетень сибирской медициныBulletin of Siberian Medicine1682-03631819-3684Siberian State Medical University, the Ministry of Healthcare of the Russian Federation10.20538/1682-0363-2014-3-91-99ssmu-70Research ArticleОБЗОРЫ И ЛЕКЦИИREVIEW AND LECTURESМЕТАЛЛОТИОНЕИНЫ КАК СЕНСОРЫ И РЕГУЛЯТОРЫ ОБМЕНА МЕТАЛЛОВ В КЛЕТКАХMETALLOTHIONEINS AS SENSORS AND CONTROLS EXCHANGE OF METALS IN THE CELLSКутяковВ. А.KutyakovV. A.

Кутяков Виктор Андреевич

allasalmina@mail.ruСалминаА. Б.SalminaA. V.

Салмина Алла Борисовна, доктор медицинских наук, профессор

allasalmina@mail.ruКрасноярский государственный медицинский университет имени профессора В.Ф. Войно-Ясенецкого, КрасноярскРоссияV.F. Voino-Yasenetsky Krasnoyarsk State Medical University, KrasnoyarskRussian Federation2014280620141339199Copyright © Кутяков В.А., Салмина А.Б., 20142014Кутяков В.А., Салмина А.Б.Kutyakov V.A., Salmina A.V.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://bulletin.ssmu.ru/jour/article/view/70

В настоящем обзоре изложены основные сведения о классификации, структуре, индукции и деградации, функциях семейства белков – металлотионеинов (МТ), в том числе в центральной нервной системе в норме и при патологии. Установлено, что четыре основные изоформы металлотионеинов выполняют разные биологические роли, локализуются в различных тканях. Индукция МТ является универсальной реакцией на воздействие разнообразных стрессорных факторов. В течение последних лет представления о роли МТ в поддержании гомеостаза металлов в тканях в норме и при патологии претерпели существенные изменения. Отмечается полифункциональность металлотионеинов (транспорт ионов металлов, поддержание окислительно-восстановительных реакций, протекторная, сигнальная, модулирующая и регулирующая функции) и их влияние на такие базовые клеточные функции, как пролиферация, дифференцировка, программированная клеточная гибель. Кроме того, показана особая роль МТ в патогенезе сердечно-сосудистых, нейродегенеративных и опухолевых заболеваний. В настоящее время эти молекулы все чаще рассматриваются в качестве потенциальных мишеней для терапии широкого спектра заболеваний, а разработка подходов к направленной регуляции экспрессии МТ – одно из перспективных направлений фармакологии и токсикологии. Подчеркнута безопасность применени я металлотионеинов в качестве терапевтических средств.

The basic information on the classification, structure, induction and degradation, functions of the protein family – metallothionein (MT), including CNS in health and disease are presented in this review. It was found that four major isoforms of metallothionein perform different biological roles, are localized in dif- ferent tissues. Induction of MT is a universal reaction to the impact of a variety of stress factors. In recent years, understanding of the role of metallothioneins in metal homeostasis in the tissues in normal and pathological conditions have changed significantly. Notes polyfunctionality metallothioneins (transport of metal ions, maintaining redox reactions, tread, signal, modulated and regulatory functions) and their im- pact on basic cellular functions such as proliferation, differentiation, programmed cell death. Further- more, a special role is shown MT in the pathogenesis of cardiovascular, neurodegenerative and neoplastic disorders.Currently, these molecules are increasingly considered as potential targets for therapy of a wide range of diseases and the development of targeted approaches to the regulation of expression of MT – one of the promising areas of pharmacology and toxicology. Stressed the safety of metallothioneins as therapeutic agents.

металлотионеинцентральная нервная системаметаллыmetallothioneincentral nervous systemmetallsReferencesDavis S.R., Cousins R. Metallothionein Expression in Animals: A Physiological Perspective on Function // J. J. Nutr. 2000. May. V. 130, № 5. P. 1085–1088.Davis S.R., Cousins R. Metallothionein Expression in Ani- mals: A Physiological Perspective on Function. J. J. Nutr., 2000, May, vol. 130, no. 5, pp. 1085–1088.Fujiwara Y., Satoh M. Protective Role of Metallothionein in Chemical and Radiation Carcinogenesis // Curr. Pharm. Biotechnology. 2013. Mar. V. 14, № 4. P. 394–399.Fujiwara Y., Satoh M. Protective Role of Metallothionein in Chemical and Radiation Carcinogenesis. Curr. Pharm. Biotechnology, 2013, Mar., vol. 14, no. 4, pp. 394–399.Krizkova S. et al. Metallothionein – a promising tool for cancer diagnostics // Bratisl. Med. J. – Bratisl. Lek. Listy. 2009. V. 110, № 2. P. 93–97.Krizkova S. et al. Metallothionein – a promising tool for cancer diagnostics. Bratisl. Med. J. – Bratisl. Lek. Listy, 2009, vol. 110, no. 2, pp. 93–97.Aschner M., West A.K. The role of MT in neurological di-sorders // Journal of Alzheimer’s Disease. 2005. Nov. V. 8, № 2. P. 139–145.Aschner M., West A.K. The role of MT in neurological dis- orders. Journal of Alzheimer’s Disease, 2005, Nov., vol. 8, no. 2, pp. 139–145.Громова О.А., Сотникова Н.Ю., Катаев С.И. и др. Протективная роль церебролизин-индуцированной экспрессии генов металлотионеина-1 и металлотионеина-2 при церебральной очаговой ишемии у крыс // Цитокины и воспаление. 2005. № 1, С. 40–45.Gromova O.A., Sotnikova N.Yu., Katayev S.I. et al. Protec- tive role of the tserebrolizin-induced expression of genes metallotionein-1 and metallotionein-2 at cerebral focal is- chemia at rats. Tsitokins and an inflammation, 2005, no. 1, pp. 40–45 (in Russian).Margoshes M., Vallee B.L. A cadmium protein from equine kidney cortex // J. Am. Chem. Soc. 1957. V. 79, № 17. P. 4813–4814.Margoshes M., Vallee B.L. A cadmium protein from equine kidney cortex. J. Am. Chem. Soc., 1957, vol. 79, no. 17, pp. 4813–4814.Blindauer C.A. Metallothioneins with unusual residues: histidines as modulators of zinc affinity and reactivity // J. Inorg. Biochem. 2000. Mar. V. 102, № 3. P. 507–521. doi: 10.1016/j.jinorgbio.2007.10.032. Epub. 2007. Nov. 28.Blindauer C.A. Metallothioneins with unusual residues: histidines as modulators of zinc affinity and reactivity. J. Inorg. Biochem., 2000, Mar., vol. 102, no. 3, pp. 507–521. doi: 10.1016/j.jinorgbio.2007.10.032. Epub . 2007. Nov. 28.Carpene E., Andreani G., Isani G. Metallothionein functions and structural characteristics // Journal of Trace Elements in Medicine and Biology. 2007. Dec. V. 21. Suppl. 1. P. 35–39.Carpene E., Andreani G., Isani G. Metallothionein functions and structural characteristics. Journal of Trace Elements in Medicine and Biologym., 2007. Dec., vol. 21, suppl. 1, pp. 35–39.Ryvolova M. et al. Analytical methods for metallothionein detection // Current Analytical Chemistry. 2011. July. V. 7, № 3. P. 243–261.Ryvolova M. et al. Analytical methods for metallothionein detection. Current Analytical Chemistry, 2011, July, vol. 7, no. 3, pp. 243–261.Hozumi I. et al. Metallothionein-3 is expressed in the brain and various peripheral organs of the rat // J. Neurosci. Lett. 2008. Jun. V. 438, № 1. P. 54–58. doi: 10.1016/j.neulet.2008.04.047. Epub. 2008. Apr. 18.Hozumi I. et al. Metallothionein-3 is expressed in the brain and various peripheral organs of the rat. J. Neurosci. Lett., 2008, Jun, vol. 438, no. 1, pp. 54–58. doi: 10.1016/j.neulet.2008.04.047. Epub. 2008. Apr. 18.Skutkova H. et al. Structure, Polymorphisms and Electrochemistry of Mammalian Metallothioneins – A Review // Int. J. Electrochem. Sci. 2012. Dec. V. 7, № 12. P. 12415–12431.Skutkova H., et al. Structure, Polymorphisms and Electrochem- istry of Mammalian Metallothioneins – A Review. Int. J. Electrochem. Sci., 2012, Dec., vol. 7, no. 12, pp. 12415–12431.Пыхтеева Е.Г. Металлотионеин: биологические функции. Роль металлотионеина в транспорте металлов в организме // Актуальные проблемы транспортной медицины. 2009. № 4 (18). С. 44–58.Pykhteeva E.G. Metallothionein: biological functions. Role of Metallothionein in transport of metals in an organism. Actual problems of transport medicine, 2009, no. 4 (18), pp. 44–58 (in Russian).Пыхтеева Е.Г., Шафран Л.М., Большой Д.В., Шитко Е.С. Роль металлотионеинов в обеспечении гомеостаза цинка при беременности // Актуальные проблемы транспортной медицины. 2011. № 4 (26). С. 96–102.Pykhteeva E.G., Schafran L.M., Bolshoy D.V., Shitko E.S. Role of metallothioneins in providing a homeostasis of zinc at pregnancy. Actual problems of transport medicine, 2011, no. 4 (26), pp. 96–102 (in Russian).Николаев А.Я. Биологическая химия. 3-е изд., перераб. и доп. М.: Мед. информ. агентство, 2004. С. 144–145.Nikolaev A.Ya. Biological chemistry. 3-rd ed. Res. and additional. Moscow, Medical inform. agency Publ., 2004, pp. 144–145 (in Russian).Cousins R.J. Absorption, transport, and hepatic metabolism of copper and zinc: special reference to metallothionein and ceruloplasmin // Physiol. Rev. 1985. V. 65, № 2. P. 238–309.Cousins R.J. Absorption, transport, and hepatic metabolism of copper and zinc: special reference to metallothionein and ceruloplasmin. Physiol. Rev., 1985, vol. 65, no. 2, pp. 238–309.Шафран Л.М., Пыхтеева Е.Г., Большой Д.В. Токсикология металлов в решении задач охраны здоровья населения и окружающей среды // Причерноморський екологічний бюлетень. 2003. № 1 (7). С. 93–100.Schafran L.M., Pykhteeva E.G., Bolshoy D.V. Toxicology of metals in the solution of problems of public health care and environment. Prichernomorsky Ekologichny Bulletin, 2003, no. 1 (7), pp. 93–100 (in Russian).Egli D. et al. The four members of the Drosophila metallothionein family exhibit distinct yet overlapping roles in heavy metals homeostasis and detoxification // Genes Cell. 2006. Jun. V. 11, № 6. P. 647–658.Egli D. et al. The four members of the Drosophila metallothionein family exhibit distinct yet overlapping roles in heavy metals homeostasis and detoxification. Genes Cell., 2006, Jun., vol. 11, no. 6, pp. 647–658.Formigari A., Irato P., Santon A. Zinc, antioxidant systems and metallothionein in metal mediated-apoptosis: biochemical and cytochemical aspects // Comp. Biochem. Physiol. C: Toxicol. Pharmacol. 2007. Nov. V. 146, № 4. P. 443–459.Formigari A., Irato P., Santon A. Zinc, antioxidant systems and metallothionein in metal mediated-apoptosis: biochemi- cal and cytochemical aspects. Comp. Biochem. Physiol. C: Toxicol. Pharmacol., 2007, Nov., vol. 146, no. 4, pp. 443–459.Yamasaki S. et al. Zinc is a novel intracellular second messenger // J. Cell. Biol. 2007. May. V. 177, № 4. P. 637–645.Yamasaki S. et al. Zinc is a novel intracellular second mes- senger. J. Cell. Biol., 2007, May, vol. 177, no. 4, pp. 637–645.Kimura T., Itoh N. Function of metallothionein in gene expression and signal transduction: Newly found protective role of metallothionein // Journal of Healthy Science. 2008. V. 54, № 3. P. 251–260. doi: 10.1248/jhs.54.251.Kimura T., Itoh N. Function of metallothionein in gene ex- pression and signal transduction: Newly found protective role of metallothionein. Journal of Healthy Science, 2008, vol. 54, no. 3, pp. 251–260. doi: 10.1248/jhs.54.251.West A.K. et al. Metallothionein in the central nervous system: Roles in protection, regeneration and cognition // Neurotoxicology. 2008. May. V. 29, № 3. P. 489–503. doi: 10.1016/j.neuro.2007.12.006. Epub. 2008. Jan. 19.West A.K. et al. Metallothionein in the central nervous system: Roles in protection, regeneration and cognition. Neurotoxicology, 2008, May, vol. 29, no. 3, pp. 489–503. doi: 10.1016/j.neuro.2007.12.006. Epub. 2008. Jan. 19.Dufault R. et al. A macroepigenetic approach to identify factors responsible for the autism epidemic in the United States // Clin. Epigenetics. 2012. Apr. V. 4, № 1. doi: 10.1186/1868-7083-4-6.Dufault R. et al. A macroepigenetic approach to identify fac- tors responsible for the autism epidemic in the United States. Clin. Epigenetics, 2012, Apr., vol. 4, no. 1. doi: 10.1186/1868-7083-4-6.Kim Jong-Heon et al. Amyloid neurotoxicity is attenuated by metallothionein: dual mechanisms at work // J. Neurochem. 2012. V. 121, № 5. P. 751–762.Kim Jong-Heon et al. Amyloid neurotoxicity is attenuated by metallothionein: dual mechanisms at work. J. Neurochem., 2012, vol. 121, no. 5, pp. 751–762.Uchida Y. et al. The growth inhibitory factor that is deficient in the Alzheimer’s disease brain is a 68 amino acid metallothionein-like protein // Neuron. 1991. Aug. V. 7, № 2. P. 337–347.Uchida Y. et al. The growth inhibitory factor that is deficient in the Alzheimer’s disease brain is a 68 amino acid metallothionein-like protein. Neuron., 1991, Aug., vol. 7, no. 2, pp. 337–347.Uchida Y. Growth-inhibitory factor, metallothionein-like protein, and neurodegenerative diseases // Biol. Signals. 1994. Jul-Aug. V. 36, № 4. P. 211–215.Uchida Y. Growth-inhibitory factor, metallothionein-like protein, and neurodegenerative diseases. Biol. Signals, 1994, Jul–Aug., vol. 36, no. 4, pp. 211–215.Ruttkay-Nedecky B. et al. The Role of Metallothionein in Oxidative Stress // Int. J. Mol. Sci. 2013. V. 14, № 3. P. 6044–6066. doi: 10.3390/ijms14036044.Ruttkay-Nedecky B. et al. The Role of Metallothionein in Oxidative Stress. Int. J. Mol. Sci., 2013. vol. 14, no. 3, рр. 6044–6066. doi: 10.3390/ijms14036044.Sharma S. et al. Biomarkers in Parkinson’s disease (recent update) // Neurochem. Int. 2013. Sep. V. 63, № 3. P. 201–229. doi.org/10.1016/ j.neuint.2013.06.005.Kazanbaev R.T., Prohorenkov V.I., Yakovleva T.A., Vasilieva E.Yu. Immunological mechanisms in development of the allergic dermatoses. Siberian Medical Review, 2013, no. 4, pp. 9–13 (in Russian).Казанбаев Р.Т., Прохоренков В.И., Яковлева Т.А., Васильева Е.Ю. Иммунологические механизмы развития аллергических дерматозов // Сиб. мед. обозрение. 2013. № 4. С. 9–13.Sharma S. et al. Biomarkers in Parkinson’s disease (recent update). Neurochem. Int., 2013, Sep., vol. 63, no. 3, pp. 201–229. doi.org/10.1016/ j.neuint.2013.06.005.Sears M.E. Chelation: Harnessing and enhancing heavy metal detoxification – a review // The Scientific World Journal. V. 2013, Article ID 219840. 13 p. doi.org/10.1155/2013/219840.Sears M.E. Chelation: Harnessing and enhancing heavy met- al detoxification – a review. The Scientific World Journal, vol. 2013, Article ID 219840, 13 p. doi.org/10. 1155/2013/219840.Inoue K., Takano H. Metallothionein as a Therapeutic Molecular Target against Human Diseases // Curr. Pharm. Biotechnology. 2013. Mar. V. 14, № 4. P. 391–393.Inoue K., Takano H. Metallothionein as a Therapeutic Mo- lecular Target against Human Diseases. Curr. Pharm. Bio- technology, 2013, Mar., vol. 14, no. 4, pp. 391–393.Hidalgo J. et al. Roles of the metallothionein family of proteins in the central nervous system // Brain Research Bulletin. 2001. May. V. 55, № 2. P. 133–145.Hidalgo J. et al. Roles of the metallothionein family of pro- teins in the central nervous system. Brain Research Bulletin, 2001, May, vol. 55, no. 2, pp. 133–145.Ito Y., Tanaka H., Hara H. The Potential Roles of Metallothionein as a Therapeutic Target for Cerebral Ischemia and Retinal Diseases // Curr. Pharm. Biotechnology. 2013. Mar. V. 14, № 4. P. 400–407.Ito Y., Tanaka H., Hara H. The Potential Roles of Metallothionein as a Therapeutic Target for Cerebral Ische- mia and Retinal Diseases. Curr. Pharm. Biotechnology, 2013, Mar., vol. 14, no. 4, pp. 400–407.Tsuruma K. et al. Metallothionein-III Deficiency Exacerbates Light-Induced Retinal Degeneration // IOVS. 2012. Nov. V. 53, № 12. P. 7896–7903. doi: 10.1167/iovs.12-10165.Tsuruma K. et al. Metallothionein-III Deficiency Exacerbates Light-Induced Retinal Degeneration. IOVS, 2012, Nov., vol. 53, no. 12, pp. 7896–7903. doi: 10.1167/iovs.12-10165.You Ho Jin et al. Protective effect of metallothionein-III on DNA damage in response to reactive oxygen species // Biochimica et Biophysica Acta (BBA) – General Subjects. 2002. Oct. V. 1573, № 1. P. 33–38.You Ho Jin et al. Protective effect of metallothionein-III on DNA damage in response to reactive oxygen species. Biochimica et Biophysica Acta (BBA) – General Subjects, 2002, Oct., vol. 1573, no. 1, pp. 33–38.Manso Y. et al. Characterization of the role of metallothionein-3 in an animal model of Alzheimer's disease // Cell. Mol. Life Sci. 2012. Nov. V. 69. P. 3683–3700. doi: 10.1007/s00018-012-1047-9. Epub. 2012. Jun. 22.Manso Y. et al. Characterization of the role of metallothionein-3 in an animal model of Alzheimer's disease. Cell. Mol. Life Sci., 2012, Nov., vol. 69, pp. 3683–3700. doi: 10.1007/s00018-012-1047-9. Epub. 2012. Jun. 22.Nagamine T. Significance of Metallothionein Expression in Liver Disease // Curr. Pharm. Biotechnology. 2013. Mar. V. 14, № 4. P. 420–426.Nagamine T. Significance of Metallothionein Expression in Liver Disease. Curr. Pharm. Biotechnology, 2013, Mar., vol. 14, no. 4, pp. 420–426.Sato M. et al. Obesity and Metallothionein // Curr. Pharm. Biotechnology. 2013. Mar. V. 14, № 4. P. 432–440.Sato M. et al. Obesity and Metallothionein. Curr. Pharm. Biotechnology, 2013, Mar., vol. 14, no. 4, pp. 432–440.Takahashi S. Molecular functions of metallothionein and its role in hematological malignancies // Journal of Hematology & Oncology. 2012. 5:41. doi: 10.1186/1756-8722-5-41.Takahashi S. Molecular functions of metallothionein and its role in hematological malignancies. Journal of Hematology & Oncology, 2012, 5:41. doi: 10.1186/1756-8722-5-41.Penkowa M. Metallothioneins are multipurpose neuroprotectants during brain pathology // FEBS Journal. 2006. May. V. 273, № 9. P. 1857–1870.Penkowa M. Metallothioneins are multipurpose neuroprotectants during brain pathology. FEBS Journal, 2006, May., vol. 273, no. 9, pp. 1857–1870.Swindell W.R. Metallothionein and the Biology of Aging // Ageing Res. Rev. 2011. Jan. V. 10, № 1. P. 132–145. doi: 10.1016/j.arr.2010.09.007. Epub. 2010. Oct. 8.Swindell W.R. Metallothionein and the Biology of Aging. Ageing Res. Rev., 2011, Jan., vol. 10, no. 1, pp. 132–145. doi: 10.1016/j.arr.2010.09.007. Epub. 2010. Oct. 8.Liang L. et al. Activation of the Complete Mouse Metallothionein Gene Locus in the Maternal Deciduum // Molecular reproduction and development. 1996. Jan. V. 43, № 1. P. 25–37.Liang L. et al. Activation of the Complete Mouse Metallothionein Gene Locus in the Maternal Deciduum. Mo- lecular reproduction and development, 1996, Jan., vol. 43, no. 1, pp. 25–37.Meloni G. et al. Organization and Assembly of Metal-Thiolate Clusters in Epithelium-specific Metallothionein-4 // The Journal of Biological Chemistry. 2006. May. V. 281, № 21. P. 14588–14595. Epub. 2006. Mar. 23.Meloni G. et al. Organization and Assembly of Metal- Thiolate Clusters in Epithelium-specific Metallothionein-4. The Journal of Biological Chemistry, 2006, May, vol. 281, no. 21, pp. 14588–14595. Epub. 2006. Mar. 23.Nuño-Ayala M. et al. Cystathionine – synthase deficiency causes infertility by impairing decidualization and gene expression networks in uterus implantation sites // Physiol Genomics. 2012. Jul. V. 44, № 14. P. 702–716. doi: 10.1152/physiolgenomics.00189.2010. Epub. 2012. May 22.Nuño-Ayala M. et al. Cystathionine – synthase deficiency causes infertility by impairing decidualization and gene expression networks in uterus implantation sites. Physiol Ge- nomics, 2012, Jul., vol. 44, no. 14, pp. 702–716. doi: 10.1152/physiolgenomics.00189.2010. Epub. 2012. May 22.Quaife Carol J. et al. Induction of a New Metallothionein Isoform (MT-IV) Occurs during Differentiation of Stratified Squamous Epithelia // Biochemistry. 1994. Jun. V. 33, № 23. P. 7250–7259.Quaife Carol J. et al. Induction of a New Metallothionein Isoform (MT-IV) Occurs during Differentiation of Stratified Squamous Epithelia. Biochemistry, 1994, Jun., vol. 33, no. 23, pp. 7250–7259.

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