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Zinc protoporphyrin

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Zinc protoporphyrin
Names
Other names
Zinc protoporphyrin IX
Identifiers
ChEBI
ECHA InfoCard 100.035.853 Edit this at Wikidata
KEGG
MeSH zinc+protoporphyrin
UNII
Properties
C34H32N4O4Zn
Molar mass 626.032 g/mol
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Zinc protoporphyrin (ZPP) refers to coordination complexes of zinc and protoporphyrin IX. It is a red-purple solid that is soluble in water. The complex and related species are found in red blood cells when heme production is inhibited by lead and/or by lack of iron.[1]

Clinical utility

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Measurement of zinc protoporphyrin in red cells has been used for screening for lead poisoning.[2][3] and for iron deficiency.[4][1][5]

Zinc protoporphyrin levels can be elevated as the result of a number of conditions, for instance:[2]

The virtue of elevated ZPP testing as a screen is that all of these conditions can be considered worth discovering.

The fluorescent properties of ZPP in intact red cells allows the ZPP/heme molar ratio to be measured quickly, at low cost, and in a small sample volume.[7]

ZnPP is finding a new use as a drug in combined cancer therapies.

History

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Porphyrin complexes of zinc have been known since the 1930s.[1] In 1974 ZPP was identified as a major non-heme porphyrin formed in red cells as the result of lead poisoning or iron deficiency.,[8] It was already known at this time that non-heme protoporphyrin IX levels were elevated in these conditions, but prior investigators had used acidic extraction methods in their assays that converted ZPP to unbound Protoporphyrin IX.[9] The early literature on quantifying zinc-PP levels may be unreliable.[1][4]

For cancer therapy

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ZnPP has been investigated for cancer therapies.[10][11][12]

ZnPP is a competitive inhibitor of heme oxygenase.[12] Heme oxygenase is a cytoprotective enzyme that copes with oxidative stress on a cell and shows higher expression in cancerous tissues.[13] ZnPP suppression of heme oxygenase reduces cell viability of cancer cells and increases cytotoxicity in cancer cells.[13] ZnPP works in combination with anticancer drugs to increase cytotoxicity.[14] ZnPP inhibits tumor growth especially solid tumors.[14] Tumors from brain cancer, colon cancer, prostate cancer, renal cell cancer, oral squamous cell cancer, and leukemia all show a susceptibility to ZnPP due to increase expression of heme oxygenase.[14] The inhibition of heme oxygenase leads to an increase of reactive oxidative species in the cell which sensitizes the cells to chemotherapeutic agents.[10] Increased reactive oxidative species can cause apoptosis in cancer cells and reduce drug resistance when exposed to ZnPP due to loss of the heme oxygenase coping mechanism.[14] The combination of these two therapies is highly effective in treating cancer in experiments thus far, and is a possible new method for overcoming drug resistance. The reduced coping ability of tissues treated with ZnPP also increases radiosensitivity.[15] Cells treated with ZnPP and radiation as opposed to simply one of the two are less viable and more likely to stay in G1 phase of the cell cycle, rather than progress to the G2 phase.[15] ZnPP and radiation combination therapy shows more apoptosis than the same amount of radiation displaying that ZnPP puts stress on cancerous tissue.[15] ZnPP have been injected in a number of trials on solid tumors, but can be utilized more broadly when effectively delivered to cancer cells and not healthy cells.[10] A targeted delivery system is needed to fully exploit the uses of ZnPP as a therapeutic agent and heme oxygenase inhibitor due to the potential side effects of free ZnPP on healthy tissue.[10] Reducing the anti-oxidant capability of healthy cells can reduce effects that would have been favorable.[10] However ZnPP have been encapsulated in nanoparticles with specialized coating for drug delivery inside the body.[10] ZnPP did not show any reduce inhibitory potential on heme oxygenase when loaded into nanoparticles.[10] Similarly ZnPP loaded into nanoparticles has a higher cytotoxicity than free ZnPP after two days due to a more favorable release rate as well as better biodistribution and internalization.[10] The possible negative effects on major organs were not seen and blood distribution is more desirable in ZnPP loaded nanoparticles than free ZnPP.[10] The specific inhibition of heme oxygenase using nanoparticles with encapsulated ZnPP reduces side effects and is likely the future method of administering ZnPP treatment.[10]

Structural chemistry

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Zinc porphyrins are always five- or six-coordinate. Because the axial ligands are labile, these complexes are often depicted with planar structures. Planar zinc(II) complexes are unknown.

References

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  1. ^ a b c d Labbé RF, Vreman HJ, Stevenson DK (December 1999). "Zinc protoporphyrin: A metabolite with a mission". Clinical Chemistry. 45 (12): 2060–2072. doi:10.1093/clinchem/45.12.2060. PMID 10585337.
  2. ^ a b Martin CJ, Werntz CL, Ducatman AM (December 2004). "The interpretation of zinc protoporphyrin changes in lead intoxication: a case report and review of the literature". Occupational Medicine. 54 (8): 587–591. doi:10.1093/occmed/kqh123. PMID 15576877.
  3. ^ Verschoor M, Herber R, Zielhuis R, Wibowo A (1987). "Zinc protoporphyrin as an indicator of lead exposure: precision of zinc protoporphyrin measurements". International Archives of Occupational and Environmental Health. 59 (6): 613–621. Bibcode:1987IAOEH..59..613V. doi:10.1007/BF00377923. PMID 3679557. S2CID 7583183.
  4. ^ a b Crowell R, Ferris AM, Wood RJ, Joyce P, Slivka H (July 2006). "Comparative effectiveness of zinc protoporphyrin and hemoglobin concentrations in identifying iron deficiency in a group of low-income, preschool-aged children: practical implications of recent illness". Pediatrics. 118 (1): 224–232. doi:10.1542/peds.2006-0156. PMID 16818569. S2CID 8050501.
  5. ^ Mei, Z; Flores-Ayala, RC; Grummer-Strawn, LM; Brittenham, GM (31 May 2017). "Is Erythrocyte Protoporphyrin a Better Single Screening Test for Iron Deficiency Compared to Hemoglobin or Mean Cell Volume in Children and Women?". Nutrients. 9 (6): 557. doi:10.3390/nu9060557. PMC 5490536. PMID 28561801.
  6. ^ Casanova-González MJ, Trapero-Marugán M, Jones EA, Moreno-Otero R (September 2010). "Liver disease and erythropoietic protoporphyria: a concise review". World Journal of Gastroenterology. 16 (36): 4526–31. doi:10.3748/wjg.v16.i36.4526. PMC 2945483. PMID 20857522.
  7. ^ Blumberg WE, Eisinger J, Lamola AA, Zuckerman DM (February 1977). "The hematofluorometer". Clinical Chemistry. 23 (2 PT. 1): 270–274. doi:10.1093/clinchem/23.2.270. PMID 832391.
  8. ^ Lamola AA, Yamane T (December 1974). "Zinc protoporphyrin in the erythrocytes of patients with lead intoxication and iron deficiency anemia". Science. 186 (4167): 936–938. Bibcode:1974Sci...186..936L. doi:10.1126/science.186.4167.936. PMID 4469690. S2CID 24011145.
  9. ^ Piomelli S (June 1973). "A micromethod for free erythrocyte porphyrins: the FEP test". The Journal of Laboratory and Clinical Medicine. 81 (6): 932–940. PMID 4710372.
  10. ^ a b c d e f g h i j Kongpetch S, Kukongviriyapan V, Prawan A, Senggunprai L, Kukongviriyapan U, Buranrat B (2012-04-13). Sim RB (ed.). "Crucial role of heme oxygenase-1 on the sensitivity of cholangiocarcinoma cells to chemotherapeutic agents". PLOS ONE. 7 (4): e34994. Bibcode:2012PLoSO...734994K. doi:10.1371/journal.pone.0034994. PMC 3325916. PMID 22514698.
  11. ^ Rouhani H, Sepehri N, Montazeri H, Khoshayand MR, Ghahremani MH, Ostad SN, et al. (August 2014). "Zinc protoporphyrin polymeric nanoparticles: potent heme oxygenase inhibitor for cancer therapy". Pharmaceutical Research. 31 (8): 2124–2139. doi:10.1007/s11095-014-1313-7. PMID 24558012. S2CID 254885235.
  12. ^ a b Wang S, Hannafon BN, Lind SE, Ding WQ (2015-05-22). Tan M (ed.). "Zinc Protoporphyrin Suppresses β-Catenin Protein Expression in Human Cancer Cells: The Potential Involvement of Lysosome-Mediated Degradation". PLOS ONE. 10 (5): e0127413. Bibcode:2015PLoSO..1027413W. doi:10.1371/journal.pone.0127413. PMC 4441374. PMID 26000787.
  13. ^ a b Kang KA, Maeng YH, Zhang R, Yang YR, Piao MJ, Kim KC, et al. (August 2012). "Involvement of heme oxygenase-1 in Korean colon cancer". Tumour Biology. 33 (4): 1031–1038. doi:10.1007/s13277-012-0336-0. PMID 22302482. S2CID 18067203.
  14. ^ a b c d Yin H, Fang J, Liao L, Maeda H, Su Q (June 2014). "Upregulation of heme oxygenase-1 in colorectal cancer patients with increased circulation carbon monoxide levels, potentially affects chemotherapeutic sensitivity". BMC Cancer. 14 (1): 436. doi:10.1186/1471-2407-14-436. PMC 4075569. PMID 24927633.
  15. ^ a b c Zhang W, Qiao T, Zha L (October 2011). "Inhibition of heme oxygenase-1 enhances the radiosensitivity in human nonsmall cell lung cancer a549 cells". Cancer Biotherapy & Radiopharmaceuticals. 26 (5): 639–645. doi:10.1089/cbr.2010.0939. PMID 21950555.
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