Zinc protoporphyrin (ZPP) refers to coordination complexes of zinc and

protoporphyrin IX Protoporphyrin IX is an organic compound, classified as a porphyrin, that plays an important role in living organisms as a precursor to other critical compounds like heme (hemoglobin) and chlorophyll. It is a deeply colored solid that is not sol ...

. It is a red-purple solid that is soluble in water. The complex and related species are found in

red blood cell Red blood cells (RBCs), also referred to as red cells, red blood corpuscles (in humans or other animals not having nucleus in red blood cells), haematids, erythroid cells or erythrocytes (from Greek ''erythros'' for "red" and ''kytos'' for "holl ...

s when

heme Heme, or haem (pronounced / hi:m/ ), is a precursor to hemoglobin, which is necessary to bind oxygen in the bloodstream. Heme is biosynthesized in both the bone marrow and the liver. In biochemical terms, heme is a coordination complex "consisti ...

production is inhibited by

lead Lead is a chemical element with the symbol Pb (from the Latin ) and atomic number 82. It is a heavy metal that is denser than most common materials. Lead is soft and malleable, and also has a relatively low melting point. When freshly cu ...

and/or by lack of

iron Iron () is a chemical element with symbol Fe (from la, ferrum) and atomic number 26. It is a metal that belongs to the first transition series and group 8 of the periodic table. It is, by mass, the most common element on Earth, right in f ...

Clinical utility

Measurement of zinc protoporphyrin in red cells has been used for screening for

lead poisoning Lead poisoning, also known as plumbism and saturnism, is a type of metal poisoning caused by lead in the body. The brain is the most sensitive. Symptoms may include abdominal pain, constipation, headaches, irritability, memory problems, inferti ...

. and for

iron deficiency Iron deficiency, or sideropenia, is the state in which a body lacks enough iron to supply its needs. Iron is present in all cells in the human body and has several vital functions, such as carrying oxygen to the tissues from the lungs as a key ...

. Zinc protoporphyrin levels can be elevated as the result of a number of conditions, for instance: *

sickle cell anemia Sickle cell disease (SCD) is a group of blood disorders typically inherited from a person's parents. The most common type is known as sickle cell anaemia. It results in an abnormality in the oxygen-carrying protein haemoglobin found in red blo ...

sideroblastic anemia Sideroblastic anemia, or sideroachrestic anemia, is a form of anemia in which the bone marrow produces ringed sideroblasts rather than healthy red blood cells (erythrocytes). In sideroblastic anemia, the body has iron available but cannot incorpora ...

anemia of chronic disease Anemia of chronic disease (ACD) or anemia of chronic inflammation is a form of anemia seen in chronic infection, chronic immune activation, and malignancy. These conditions all produce elevation of interleukin-6, which stimulates hepcidin product ...

vanadium Vanadium is a chemical element with the symbol V and atomic number 23. It is a hard, silvery-grey, malleable transition metal. The elemental metal is rarely found in nature, but once isolated artificially, the formation of an oxide layer ( pas ...

exposure *

erythropoietic protoporphyria Erythropoietic protoporphyria (or commonly called EPP) is a form of porphyria, which varies in severity and can be very painful. It arises from a deficiency in the enzyme ferrochelatase, leading to abnormally high levels of protoporphyrin in the ...

*Diverse types of cancer 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. ZnPP is finding a new use as a drug in combined cancer therapies.

History

Porphyrin complexes of zinc have been known since the 1930s. In 1974 ZPP was identified as a major non-heme porphyrin formed in red cells as the result of lead poisoning or iron deficiency., 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. The early literature is sometimes confusing, and results are hard to compare without detailed examination of the measurement methods and the conversion factors used to report the results.Some reports, for instance, measured the ZPP/Heme molar ratio (μmole ZPP per mole of heme), but reported this as the weight concentration (μg of EP per deciliter of packed red cells, or μg of EP per g hemoglobin at an ''assumed'' hematocrit of 35), and sometimes without easy access to the assumptions used in the conversion. Reports may refer to free erythrocyte protoporphyrin (FEP) or erythrocyte protoporphyrin (EP or EPP). ZPP is also abbreviated ZP and ZnPP. Current practice is tending to measure and report the molar ratio of ZPP to heme (μmole/mole).

For cancer therapy

ZnPP has been investigated for cancer therapies.Kongpetch, S., Kukongviriyapan, V., Prawan, A., Senggunprai, L., Kukongviriyapan, U., & Buranrat, B. Crucial role of heme oxygenase-1 on the sensitivity of cholangiocarcinoma cells to chemotherapeutic agents. ''PLoS. One'' 2012'', 7''(4)Rouhani, H., Sepehri, N., Montazeri, H., Khoshayand, M. R., Ghahremani, M. H., Ostad, S. N., Dinarvand, R. Zinc protoporphyrin polymeric

nanoparticle A nanoparticle or ultrafine particle is usually defined as a particle of matter that is between 1 and 100 nanometres (nm) in diameter. The term is sometimes used for larger particles, up to 500 nm, or fibers and tubes that are less than 1 ...

s: Potent heme oxygenase inhibitor for cancer therapy. ''Pharm. Res.'' 2014'', 31'' (8), 2124-39.Wang, S., Hannafon, B. N., Lind, S. E., & Ding, W. Zinc protoporphyrin suppresses beta]-catenin protein expression in human cancer cells: The potential involvement of lysosome-mediated degradation. ''PLoS. One'' 2015'', 10''(5) ZnPP is a competitive inhibitor of heme oxygenase. Heme oxygenase is a cytoprotective enzyme that copes with oxidative stress on a cell and shows higher expression in cancerous tissues.Kang, K. A., Maeng, Y. H., Zhang, R., Yang, Y. R., Piao, M. J., Kim, K. C., Hyun, J. W.. Involvement of heme oxygenase-1 in korean colon cancer. ''Tumor Biol.'' 2012'', 33''(4), 1031-8 ZnPP suppression of heme oxygenase reduces cell viability of cancer cells and increases cytotoxicity in cancer cells. ZnPP works in combination with anticancer drugs to increase cytotoxicity.Yin, H., Fang, J., Liao, L., Maeda, H., & Su, Q. Upregulation of heme oxygenase-1 in colorectal cancer patients with increased circulation carbon monoxide levels, potentially affects chemotherapeutic sensitivity. ''BMC Cancer'' 2014'', 14'', 436. ZnPP inhibits tumor growth especially solid tumors. 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. The inhibition of heme oxygenase leads to an increase of reactive oxidative species in the cell which sensitizes the cells to chemotherapeutic agents. 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. 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.Zhang, W., Qiao, T., & Zha, L. Inhibition of heme oxygenase-1 enhances the radiosensitivity in human nonsmall cell lung cancer A549 cells. ''Cancer Biother. Radiopharm.'' 2011'', 26''(5), 639-45. 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. ZnPP and radiation combination therapy shows more apoptosis than the same amount of radiation displaying that ZnPP puts stress on cancerous tissue. 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. 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. Reducing the anti-oxidant capability of healthy cells can reduce effects that would have been favorable. However ZnPP have been encapsulated in nanoparticles with specialized coating for drug delivery inside the body. ZnPP did not show any reduce inhibitory potential on heme oxygenase when loaded into nanoparticles. 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. The possible negative effects on major organs were not seen and blood distribution is more desirable in ZnPP loaded nanoparticles than free ZnPP. The specific inhibition of heme oxygenase using nanoparticles with encapsulated ZnPP reduces side effects and is likely the future method of administering ZnPP treatment.

Structural chemistry

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

{{DEFAULTSORT:Zinc Protoporphyrin Porphyrins Blood cells