TPEN

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]

TPEN
Names
IUPAC name
N,N,N′,N′-Tetrakis(2-pyridinylmethyl)-1,2-ethanediamine
Identifiers
3D model (JSmol)
ECHA InfoCard 100.110.079
UNII
Properties
C26H28N6
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 references

Toxicity

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]

Hypoxia

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.

References
  1. "TPEN (CAS 16858-02-9)". www.caymanchem.com.
  2. 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.
  3. 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.
  4. "TPEN - CAS 16858-02-9". www.scbt.com.
  5. 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. doi:10.1016/s0009-2797(99)00166-0. PMID 10731516.
  6. "Zinc Evidence - Mayo Clinic". www.mayoclinic.org.
  7. 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.
  8. Jr, McCabe MJ; SA, Jiang; S, Orrenius (1 July 1993). "Chelation of intracellular zinc triggers apoptosis in mature thymocytes". Laboratory Investigation. 69 (1): 101–10. PMID 8331893.
  9. 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.
  10. 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.
  11. 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.
  12. 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.
  13. 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.
  14. 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. PMC 5137490. PMID 27690730.
This article is issued from Wikipedia. The text is licensed under Creative Commons - Attribution - Sharealike. Additional terms may apply for the media files.