TPEN (N,N,N′,N′-tetrakis(2-pyridinylmethyl)-1,2-ethanediamine[1]) is an intracellular membrane-permeable ion chelator.[2] TPEN has a high affinity for many transition metals and should not be considered specific or selective for a particular ion. Chelators can be used in chelation therapy to remove toxic metals in the body. TPEN is a chelator that has a high affinity for zinc. For example, one study showed that TPEN is a stronger chelator compared to other chelators like pentetic acid (DTPA) when high levels of zinc are present (15 μM). When low levels of zinc were present however (0, 3, 6, 9 and 12 μM zinc), there was no significant difference.[2] TPEN is a hexadentate ligand which also forms complexes with other soft metal ions such as Cd2+.[3]
In addition to a heavy metal chelator, TPEN is also known to be an inducer of apoptosis.,[4] thus it may be toxic to cells. One study showed that depletion of zinc by TPEN induced apoptosis in liver cells of rats.[5] This may be because zinc is necessary for normal functioning of the body; for example, zinc acts as a cofactor for enzymes such as insulin-degrading enzyme. Zinc deficiency symptoms include growth and development problems, hair loss, diarrhea, loss of appetite, and more.[6]
One study showed that TPEN induces translocation of cytochrome c from the mitochondria to the cytosol in human peripheral blood T lymphocytes. This leads to the activation of caspases-3, -8, and -9. When these T lymphocytes were pretreated with caspase inhibitors, DNA fragmentation (an indicator of apoptosis) was prevented. This suggests that apoptosis that is triggered by zinc deficiency is dependent on caspase proteins.[7] Similar results were shown in rat and human thymocytes when TPEN was used.[8] TPEN is also shown to induce apoptosis in K562 cells,[9] and high doses (120 μM) of zinc result in microglial cell death.[10] One study examined the requirement for p53, a tumor suppressor protein, as an upstream transcription factor in TPEN-induced neuronal apoptosis, and found that depletion of intracellular zinc with TPEN induces apoptosis.[11] Additionally, the same study found that TPEN increased the expression of pro-apoptotic genes and led to the activation of caspase-11, a mammalian protease. These results suggest that the p53 tumor suppressor protein may play a role in regulating TPEN-induced neuronal apoptosis. Although these studies found that TPEN induces apoptosis, another study found that TPEN inhibits sodium dithionite and glucose deprivation (SDGD)-Induced neuronal death by modulating apoptosis.[12]
Hypoxiaedit
One study showed that after hypoxia, an increase in intracellular zinc induced an increase in reactive oxygen species via activation of NADPH oxidase.[13] Although reactive oxygen species are needed for some functions (such as secondary signaling), they are unstable and are commonly known to cause damage to DNA, lipids, and proteins when at high levels. During the study, the application of TPEN prevented a zinc-induced increase in reactive oxygen species. This may have implications for diseases that have hypoxic conditions, such as stroke. Additionally, another study showed that TPEN induced DNA damage in human colon cancer cells in a reactive oxygen species-dependent manner.[14] One implication may be that TPEN can be used as a form of treatment for hypoxic conditions and possibly be used to target specific cancers.
^ abCho, Young-Eun; Lomeda, Ria-Ann R.; Ryu, Sang-Hoon; Lee, Jong-Hwa; Beattie, John H.; Kwun, In-Sook (25 May 2007). "Cellular Zn depletion by metal ion chelators (TPEN, DTPA and chelex resin) and its application to osteoblastic MC3T3-E1 cells". Nutrition Research and Practice. 1 (1): 29–35. doi:10.4162/nrp.2007.1.1.29. PMC2882573. PMID 20535382.
^Takeshita, Kenji; Ishida, Masaru; Kondo, Misako; Nakano, Yoshio; Seida, Yoshimi (2004). "Recovery of Noble Metals by Hexadentate Ligand TPEN and Acidic Extractant D2EHPA". Asian Pacific Confederation of Chemical Engineering Congress Program and Abstracts. 2004: 238. doi:10.11491/apcche.2004.0.238.0.
^Nakatani, T.; Tawaramoto, M.; Opare Kennedy, D.; Kojima, A.; Matsui-Yuasa, I. (15 March 2000). "Apoptosis induced by chelation of intracellular zinc is associated with depletion of cellular reduced glutathione level in rat hepatocytes". Chemico-Biological Interactions. 125 (3): 151–163. Bibcode:2000CBI...125..151N. doi:10.1016/s0009-2797(99)00166-0. PMID 10731516.
^"Zinc Evidence - Mayo Clinic". www.mayoclinic.org.
^Kolenko, V. M.; Uzzo, R. G.; Dulin, N.; Hauzman, E.; Bukowski, R.; Finke, J. H. (1 December 2001). "Mechanism of apoptosis induced by zinc deficiency in peripheral blood T lymphocytes". Apoptosis. 6 (6): 419–429. doi:10.1023/A:1012497926537. PMID 11595831. S2CID 20515580.
^MJ, McCabe Jr.; SA, Jiang; S, Orrenius (1 July 1993). "Chelation of intracellular zinc triggers apoptosis in mature thymocytes". Laboratory Investigation. 69 (1): 101–10. PMID 8331893.
^Rojas-Valencia, Luisa; Velez-Pardo, Carlos; Jimenez-Del-Rio, Marlene (1 June 2017). "Metal chelator TPEN selectively induces apoptosis in K562 cells through reactive oxygen species signaling mechanism: implications for chronic myeloid leukemia". BioMetals. 30 (3): 405–421. doi:10.1007/s10534-017-0015-0. PMID 28409295. S2CID 3762482.
^Ra, Hana; Kim, Hyun-Lim; Lee, Han-Woong; Kim, Yang-Hee (6 May 2009). "Essential role of p53 in TPEN-induced neuronal apoptosis". FEBS Letters. 583 (9): 1516–1520. doi:10.1016/j.febslet.2009.04.008. PMID 19364507. S2CID 42686881.
^Zhang, Feng; Ma, Xue-Ling; Wang, Yu-Xiang; He, Cong-Cong; Tian, Kun; Wang, Hong-Gang; An, Di; Heng, Bin; Xie, Lai-Hua; Liu, Yan-Qiang (1 March 2017). "TPEN, a Specific Zn(2+) Chelator, Inhibits Sodium Dithionite and Glucose Deprivation (SDGD)-Induced Neuronal Death by Modulating Apoptosis, Glutamate Signaling, and Voltage-Gated K(+) and Na(+) Channels". Cellular and Molecular Neurobiology. 37 (2): 235–250. doi:10.1007/s10571-016-0364-1. PMID 26983717. S2CID 7930010.
^Slepchenko, Kira G; Lu, Qiping; Li, Yang V (25 April 2016). "Zinc wave during the treatment of hypoxia is required for initial reactive oxygen species activation in mitochondria". International Journal of Physiology, Pathophysiology and Pharmacology. 8 (1): 44–51. PMC4859878. PMID 27186322.
^Rahal, Omar Nasser; Fatfat, Maamoun; Hankache, Carla; Osman, Bassam; Khalife, Hala; Machaca, Khaled; Muhtasib, Hala-Gali (1 November 2016). "Chk1 and DNA-PK mediate TPEN-induced DNA damage in a ROS dependent manner in human colon cancer cells". Cancer Biology & Therapy. 17 (11): 1139–1148. doi:10.1080/15384047.2016.1235658. PMC5137490. PMID 27690730.
January 01, 1970
tpen, tetrakis, pyridinylmethyl, ethanediamine, intracellular, membrane, permeable, chelator, high, affinity, many, transition, metals, should, considered, specific, selective, particular, chelators, used, chelation, therapy, remove, toxic, metals, body, chela. TPEN N N N N tetrakis 2 pyridinylmethyl 1 2 ethanediamine 1 is an intracellular membrane permeable ion chelator 2 TPEN has a high affinity for many transition metals and should not be considered specific or selective for a particular ion Chelators can be used in chelation therapy to remove toxic metals in the body TPEN is a chelator that has a high affinity for zinc For example one study showed that TPEN is a stronger chelator compared to other chelators like pentetic acid DTPA when high levels of zinc are present 15 mM When low levels of zinc were present however 0 3 6 9 and 12 mM zinc there was no significant difference 2 TPEN is a hexadentate ligand which also forms complexes with other soft metal ions such as Cd2 3 TPEN Names Preferred IUPAC name N1 N1 N2 N2 Tetrakis pyridin 2 yl methyl ethane 1 2 diamine Identifiers CAS Number 16858 02 9 Y 3D model JSmol Interactive image ChEBI CHEBI 88217 ChEMBL ChEMBL1472575 ChemSpider 5318 ECHA InfoCard 100 110 079 EC Number 605 520 7 PubChem CID 5519 UNII R9PTU1U29I Y CompTox Dashboard EPA DTXSID50168583 InChI InChI 1S C26H28N6 c1 5 13 27 23 9 1 19 31 20 24 10 2 6 14 28 24 17 18 32 21 25 11 3 7 15 29 25 22 26 12 4 8 16 30 26 h1 16H 17 22H2Key CVRXLMUYFMERMJ UHFFFAOYSA N SMILES c1ccc nc1 CN CCN Cc1ccccn1 Cc1ccccn1 Cc1ccccn1 Properties Chemical formula C 26H 28N 6 Molar mass 424 552 g mol 1 Appearance Crystalline solid 1 Except where otherwise noted data are given for materials in their standard state at 25 C 77 F 100 kPa Infobox referencesToxicity editIn addition to a heavy metal chelator TPEN is also known to be an inducer of apoptosis 4 thus it may be toxic to cells One study showed that depletion of zinc by TPEN induced apoptosis in liver cells of rats 5 This may be because zinc is necessary for normal functioning of the body for example zinc acts as a cofactor for enzymes such as insulin degrading enzyme Zinc deficiency symptoms include growth and development problems hair loss diarrhea loss of appetite and more 6 One study showed that TPEN induces translocation of cytochrome c from the mitochondria to the cytosol in human peripheral blood T lymphocytes This leads to the activation of caspases 3 8 and 9 When these T lymphocytes were pretreated with caspase inhibitors DNA fragmentation an indicator of apoptosis was prevented This suggests that apoptosis that is triggered by zinc deficiency is dependent on caspase proteins 7 Similar results were shown in rat and human thymocytes when TPEN was used 8 TPEN is also shown to induce apoptosis in K562 cells 9 and high doses 120 mM of zinc result in microglial cell death 10 One study examined the requirement for p53 a tumor suppressor protein as an upstream transcription factor in TPEN induced neuronal apoptosis and found that depletion of intracellular zinc with TPEN induces apoptosis 11 Additionally the same study found that TPEN increased the expression of pro apoptotic genes and led to the activation of caspase 11 a mammalian protease These results suggest that the p53 tumor suppressor protein may play a role in regulating TPEN induced neuronal apoptosis Although these studies found that TPEN induces apoptosis another study found that TPEN inhibits sodium dithionite and glucose deprivation SDGD Induced neuronal death by modulating apoptosis 12 Hypoxia editOne study showed that after hypoxia an increase in intracellular zinc induced an increase in reactive oxygen species via activation of NADPH oxidase 13 Although reactive oxygen species are needed for some functions such as secondary signaling they are unstable and are commonly known to cause damage to DNA lipids and proteins when at high levels During the study the application of TPEN prevented a zinc induced increase in reactive oxygen species This may have implications for diseases that have hypoxic conditions such as stroke Additionally another study showed that TPEN induced DNA damage in human colon cancer cells in a reactive oxygen species dependent manner 14 One implication may be that TPEN can be used as a form of treatment for hypoxic conditions and possibly be used to target specific cancers References edit a b TPEN CAS 16858 02 9 www caymanchem com a b Cho Young Eun Lomeda Ria Ann R Ryu Sang Hoon Lee Jong Hwa Beattie John H Kwun In Sook 25 May 2007 Cellular Zn depletion by metal ion chelators TPEN DTPA and chelex resin and its application to osteoblastic MC3T3 E1 cells Nutrition Research and Practice 1 1 29 35 doi 10 4162 nrp 2007 1 1 29 PMC 2882573 PMID 20535382 Takeshita Kenji Ishida Masaru Kondo Misako Nakano Yoshio Seida Yoshimi 2004 Recovery of Noble Metals by Hexadentate Ligand TPEN and Acidic Extractant D2EHPA Asian Pacific Confederation of Chemical Engineering Congress Program and Abstracts 2004 238 doi 10 11491 apcche 2004 0 238 0 TPEN CAS 16858 02 9 www scbt com Nakatani T Tawaramoto M Opare Kennedy D Kojima A Matsui Yuasa I 15 March 2000 Apoptosis induced by chelation of intracellular zinc is associated with depletion of cellular reduced glutathione level in rat hepatocytes Chemico Biological Interactions 125 3 151 163 Bibcode 2000CBI 125 151N doi 10 1016 s0009 2797 99 00166 0 PMID 10731516 Zinc Evidence Mayo Clinic www mayoclinic org Kolenko V M Uzzo R G Dulin N Hauzman E Bukowski R Finke J H 1 December 2001 Mechanism of apoptosis induced by zinc deficiency in peripheral blood T lymphocytes Apoptosis 6 6 419 429 doi 10 1023 A 1012497926537 PMID 11595831 S2CID 20515580 MJ McCabe Jr SA Jiang S Orrenius 1 July 1993 Chelation of intracellular zinc triggers apoptosis in mature thymocytes Laboratory Investigation 69 1 101 10 PMID 8331893 Rojas Valencia Luisa Velez Pardo Carlos Jimenez Del Rio Marlene 1 June 2017 Metal chelator TPEN selectively induces apoptosis in K562 cells through reactive oxygen species signaling mechanism implications for chronic myeloid leukemia BioMetals 30 3 405 421 doi 10 1007 s10534 017 0015 0 PMID 28409295 S2CID 3762482 Higashi Youichirou Aratake Takaaki Shimizu Shogo Shimizu Takahiro Nakamura Kumiko Tsuda Masayuki Yawata Toshio Ueba Tetuya Saito Motoaki 27 February 2017 Influence of extracellular zinc on M1 microglial activation Scientific Reports 7 43778 Bibcode 2017NatSR 743778H doi 10 1038 srep43778 PMC 5327400 PMID 28240322 Ra Hana Kim Hyun Lim Lee Han Woong Kim Yang Hee 6 May 2009 Essential role of p53 in TPEN induced neuronal apoptosis FEBS Letters 583 9 1516 1520 doi 10 1016 j febslet 2009 04 008 PMID 19364507 S2CID 42686881 Zhang Feng Ma Xue Ling Wang Yu Xiang He Cong Cong Tian Kun Wang Hong Gang An Di Heng Bin Xie Lai Hua Liu Yan Qiang 1 March 2017 TPEN a Specific Zn 2 Chelator Inhibits Sodium Dithionite and Glucose Deprivation SDGD Induced Neuronal Death by Modulating Apoptosis Glutamate Signaling and Voltage Gated K and Na Channels Cellular and Molecular Neurobiology 37 2 235 250 doi 10 1007 s10571 016 0364 1 PMID 26983717 S2CID 7930010 Slepchenko Kira G Lu Qiping Li Yang V 25 April 2016 Zinc wave during the treatment of hypoxia is required for initial reactive oxygen species activation in mitochondria International Journal of Physiology Pathophysiology and Pharmacology 8 1 44 51 PMC 4859878 PMID 27186322 Rahal Omar Nasser Fatfat Maamoun Hankache Carla Osman Bassam Khalife Hala Machaca Khaled Muhtasib Hala Gali 1 November 2016 Chk1 and DNA PK mediate TPEN induced DNA damage in a ROS dependent manner in human colon cancer cells Cancer Biology amp Therapy 17 11 1139 1148 doi 10 1080 15384047 2016 1235658 PMC 5137490 PMID 27690730 Retrieved from https en wikipedia org w index php title TPEN amp oldid 1210826912, wikipedia, wiki, book, books, library,
