Curcumin: Wikis

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Curcumin
Identifiers
CAS number 458-37-7 Yes check.svgY
PubChem 969516
ChemSpider 839564
SMILES
InChI
InChI key VFLDPWHFBUODDF-FCXRPNKRBF
Properties
Molecular formula C21H20O6
Molar mass 368.38 g/mol
Appearance Bright yellow-orange powder
Melting point

183 °C (361 °F) (361 K)

 Yes check.svgY (what is this?)  (verify)
Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa)
Infobox references
Curcumin Keto form
Curcumin Enol form

Curcumin is the principal curcuminoid of the popular Indian spice turmeric, which is a member of the ginger family (Zingiberaceae). The other two curcuminoids are desmethoxycurcumin and bis-desmethoxycurcumin. The curcuminoids are polyphenols and are responsible for the yellow color of turmeric. Curcumin can exist in at least two tautomeric forms, keto and enol. The enol form is more energetically stable in the solid phase and in solution.[1]

Curcumin can be used for boron quantification in the so-called curcumin method. It reacts with boric acid forming a red colored compound, known as rosocyanine.

Curcumin is brightly colored and may be used as a food coloring. As a food additive, its E number is E100 [2].

Contents

Chemistry

Curcumin incorporates several functional groups. The aromatic ring systems, which are polyphenols are connected by two α,β-unsaturated carbonyl groups. The two carbonyl groups form a diketone. The diketone form stable enols or are easily deprotonated and form enolates, while the α,β-unsaturated carbonyl is a good Michael acceptor and undergoes nucleophilic addition. The structure was first identified in 1910 by Kazimierz Kostanecki, J. Miłobędzka and Wiktor Lampe.

Curcumin is used as a reagent for Boron in EPA Method 212.3[3] Boron by Colorimetry.

Biosynthesis

The biosynthetic route of curcumin has proven to be very difficult for researchers to determine. In 1973 Roughly and Whiting proposed two mechanisms for curcumin biosynthesis. The first mechanism involved a chain extension reaction by cinnamic acid and 5 malonyl-CoA molecules that eventually arylized into a curcuminoid. The second mechanism involved two cinnamate units being coupled together by malonyl-CoA.16 Both mechanisms utilize cinnamic acid as their starting point, which is derived from the amino acid phenylalanine. This is noteworthy because plant biosyntheses employing cinnamic acid as a starting point are rare compared to the more common use of p-coumaric acid. .[4] Only a few identified compounds, such as anigorufone[5] and pinosylvin[6], use cinnamic acid as their start molecule. It wasn’t until 2008 in which an experimentally backed route was presented. This proposed biosynthetic route follows both the first and second mechanisms suggested by Roughley and Whiting. However, the labeling data supported the first mechanism model in which 5 malonyl-CoA molecules react with cinnamic acid to form curcumin.[4] However, the sequencing in which the functional groups, the alcohol and the methoxy, introduce themselves onto the curcuminoid seems to support more strongly the second proposed mechanism.[4] Therefore it was concluded that the second pathway proposed by Roughly and Whiting was correct.

Potential medical uses

Turmeric has been used historically as a component of Indian Ayurvedic medicine since 1900 BCE to treat a wide variety of ailments.[7] Research in the latter half of the 20th century has identified curcumin as responsible for most of the biological activity of turmeric.[7] In vitro and animal studies have suggested a wide range of potential therapeutic or preventive effects associated with curcumin. At present, these effects have not been confirmed in humans. However, as of 2008, numerous clinical trials in humans were underway, studying the effect of curcumin on numerous diseases including multiple myeloma, pancreatic cancer, myelodysplastic syndromes, colon cancer, psoriasis, and Alzheimer's disease.[8]

In vitro and animal studies have suggested that curcumin may have antitumor,[9][10] antioxidant, antiarthritic, anti-amyloid, anti-ischemic[11], and anti-inflammatory properties.[12] Anti-inflammatory properties may be due to inhibition of eicosanoid biosynthesis.[13] In addition it may be effective in treating malaria, prevention of cervical cancer, and may interfere with the replication of the HIV virus.[14] In HIV, it appears to act by interfering with P300/CREB-binding protein (CBP). It is also hepatoprotective.[15] A 2008 study at Michigan State University showed that low concentrations of curcumin interfere with Herpes simplex virus-1 (HSV-1) replication.[16] The same study showed that curcumin inhibited the recruitment of RNA polymerase II to viral DNA, thus inhibiting the transcription of the viral DNA.[16] This effect was shown to be independent of effect on histone acetyltransferase activities of p300/CBP.[16] A previous (1999) study performed at University of Cincinnati indicated that curcumin is significantly associated with protection from infection by HSV-2 in animal models of intravaginal infections.[17]

Curcumin acts as a free radical scavenger and antioxidant, inhibiting lipid peroxidation[18] and oxidative DNA damage. Curcuminoids induce glutathione S-transferase and are potent inhibitors of cytochrome P450.

A 2004 UCLA-Veterans Affairs study involving genetically altered mice suggests that curcumin might inhibit the accumulation of destructive beta-amyloid in the brains of Alzheimer's disease patients and also break up existing plaques associated with the disease.[19]

There is also circumstantial evidence that curcumin improves mental functions; a survey of 1010 Asian people who ate yellow curry and were between the ages of 60 and 93 showed that those who ate the sauce "once every six months" or more had higher MMSE results than those who did not.[20] From a scientific standpoint, though, this does not show whether the curry caused it, or people who had healthy habits also tended to eat the curry, or some completely different relationship.

Numerous studies have demonstrated that curcumin, amongst only a few other things such as high impact exercise, learning, bright light, and antidepressant usage, has a positive effect on neurogenesis in the hippocampus and concentrations of brain-derived neurotrophic factor (BDNF), reductions in both of which are associated with stress, depression, and anxiety.[21][22][23]

Curcumin has also been demonstrated to be a selective monoamine oxidase inhibitor (MAOI) of type MAO-A.

In 2009 an Iranian group demonstrated the combination effect of curcumin with 24 antibiotics against Staphylococcus aureus.It is showed that in the presence of sub-inhibitory concentration of curcumin the antibacterial activities of cefixime, cefotaxime, vancomycin and tetracycline have been increased against test strain. Increase in inhibition zone surface area for these antibiotics were 52.6% (cefixime), 24.9% (cephotaxime), 26.5% (vancomycin ), 24.4% (tetracycline). Also it is showed that curcumin has the antagonist effect on the antibacterial effect of Nalidixic acid against test strain.[24]

Although many pre-clinical studies suggest that curcumin may be useful for the prevention and treatment of several diseases, the effectiveness of curcumin has not yet been demonstrated in randomized, placebo-controlled, double-blind clinical trials.[25]

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Anticarcinogenic effects

Its potential anticancer effects stem from its ability to induce apoptosis in cancer cells without cytotoxic effects on healthy cells. Curcumin can interfere with the activity of the transcription factor NF-κB, which has been linked to a number of inflammatory diseases such as cancer.[26]

A 2009 study suggests that curcumin may inhibit mTOR complex I via a novel mechanism.[27]

Another 2009 study on curcumin effects on cancer states that curcumin "modulates growth of tumor cells through regulation of multiple cell signaling pathways including cell proliferation pathway (cyclin D1, c-myc), cell survival pathway (Bcl-2, Bcl-xL, cFLIP, XIAP, c-IAP1), caspase activation pathway (caspase-8, 3, 9), tumor suppressor pathway (p53, p21) death receptor pathway (DR4, DR5), mitochondrial pathways, and protein kinase pathway (JNK, Akt, and AMPK)".[28]

When 0.2% curcumin is added to diet given to rats or mice previously given a carcinogen, it significantly reduces colon carcinogenesis (Data from sixteen scientific articles reported in the Chemoprevention Database).

Bioavailability

Little curcumin, when eaten, is absorbed:[29] from 2 to 10 grams of curcumin eaten alone resulted in indetectable to very low serum levels.[30] Curcumin is unstable in the gut[citation needed], and the traces that pass through the GI tract rapidly degrade or are conjugated through glucuronidation.

Incorporating turmeric into the western diet poses challenges. A majority of Americans equate the mild-flavored turmeric with spicy Indian food. Most recipes incorporating turmeric, such as curries, are too spicy for many Americans because they contain hot spices such as cayenne pepper. There have been several commercial products developed to provide an alternate route to curcumin. For example, curcumin supplements with piperine are readily available. But curcumin in a non-solubilized pill form can limit bioavailability. Other products, such as Nutmeric, provide curcumin in an oil-solubilized form similar to Indian curry preparations. Co-supplementation with 20 mg of piperine (extracted from black pepper) significantly increased the absorption of curcumin by 2000% in a study funded by a prominent manufacturer of piperine.[30] However, the increase in absorption only occurred during the first hour, after which the difference between the piperine curcumin and the regular curcumin was almost the same as far as absorption. Due to its effects on drug metabolism, piperine should be taken cautiously (if at all) by individuals taking other medications.

Some benefits of curcumin, such as the potential protection from colon cancer, may not require systemic absorption. Alternatively, dissolving curcumin in hot water or in warm oils prior to ingestion may possibly increase bioavailability; however, no published studies to date have documented this. Cooking with curcumin and oil may increase absorption, but peer-reviewed scientific literature has not documented this, while the literature has documented concerns regarding the heat stability of curcumin and its degradation in the gut.[citation needed]

In 2007, a polymeric nanoparticle-encapsulated formulation of curcumin ("nanocurcumin"[31]) has been synthesized which has the potential to bypass many of the shortcomings associated with free curcumin, such as poor solubility and poor systemic bioavailability. Nanocurcumin particles have a size of less than 100 nanometers on average, and demonstrate comparable to superior efficacy compared to free curcumin in human cancer cell line models.[31] However, actual in vivo absorption has not been demonstrated with this nanoparticle.

In July 2008, researchers from the aforementioned team in UCLA's Department of Neurology announced results on a form of "lipidated curcumin" that was noted to achieve more than 5 micromolar in the brain in vivo, 50 times that found in clinical studies.[32] Another method to increase the bioavailability of curcumin was filed in a patent in 2006[33] and involves a simple procedure creating a complex with soy phospholipids; the plasma concentration of curcumin using this method increased by 5-fold reaching 33.4 nanomolar in comparison to 6.5 nanomolar obtained with an equal molar quantity of unformulated curcumin administered as control.[34]

Potential risks and side-effects

Kawanishi et al. (2005) remarked that curcumin, like many antioxidants, can be a "double-edged sword" where in the test tube, anti-cancer and antioxidant effects may be seen in addition to pro-oxidant effects.[35] Carcinogenic effects are inferred from interference with the p53 tumor suppressor pathway, an important factor in human colon cancer.[36] Carcinogenic and LD50 tests in mice and rats, however, have failed to establish a relationship between tumorogenesis and administration of curcumin in turmeric oleoresin at >98% concentrations.[37] Other in vitro and in vivo studies suggest that curcumin may cause carcinogenic effects under specific conditions.[38][39]

In animal studies, hair loss (alopecia) and lowering of blood pressure have been reported.[40]

Clinical studies in humans with high doses (2–12 grams) of curcumin have shown few side effects, with some subjects reporting mild nausea or diarrhea.[41] More recently, curcumin was found to alter iron metabolism by chelating iron and suppressing the protein hepcidin, potentially causing iron deficiency in susceptible patients.[42] Further studies seem to be necessary to establish the benefit/risk profile of curcumin.[43]

There is no or little evidence to suggest that curcumin is either safe or unsafe for pregnant women. However, there is still some concern that medicinal use of products containing curcumin could stimulate the uterus, which may lead to a miscarriage, although there is not much evidence to support this claim. According to experiments done on rats and guinea-pigs, there is no obvious effect (neither positive, nor negative) on the pregnancy rate, number of live or dead embryos.[44]

References

Notes
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  4. ^ a b c d Kita, T.; Imai, S.; Sawada, H.; Kumagai, H.; Seto, H. The biosynthetic pathway of curcuminoid in turmeric (Curcuma longa) as revealed by 13C-labeled precursors. Bioscience, Biotechnology, and Biochemistry 2008, 72, 1789-1798.
  5. ^ Schmitt, B.; Holscher, D.; Schneider, B. Variability of phenylpropanoid precursors in the biosynthesis of phenylphenalenones in Anigozanthos preissii. Phytochemistry 2000, 53, 331-337.
  6. ^ Gehlert, R.; Schoeppner, A.; Kindl, H. Stilbene synthase from seedlings of Pinus sylvestris: purification and induction in response to fungal infection. Molecular Plant-Microbe Interactions 1990, 3, 444-449.
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  15. ^ Marotta, F.; et al. (October 2003). "Hepatoprotective effect of a curcumin/absinthium compound in experimental severe liver injury". Chinese Journal of Digestive Diseases (Blackwell Publishing) 4 (3): 122–7. doi:10.1046/j.1443-9573.2003.00133.x. 
  16. ^ a b c Kutluay SB, Doroghazi J, Roemer ME, Triezenberg SJ (January 2008). "Curcumin inhibits herpes simplex virus immediate-early gene expression by a mechanism independent of p300/CBP histone acetyltransferase activity". Virology 373: 239. doi:10.1016/j.virol.2007.11.028. PMID 18191976. 
  17. ^ Bourne KZ, Bourne N, Reising SF, Stanberry LR (1999 July). "Plant products as topical microbicide candidates: assessment of in vitro and in vivo activity against herpes simplex virus type 2". Antiviral research 42 (3): 219–26. doi:10.1016/S0166-3542(99)00020-0. PMID 10443534. 
  18. ^ <Shukla PK, Khanna VK, Khan MY, Srimal RC.Protective effect of curcumin against lead neurotoxicity in rat.Hum Exp Toxicol. 2003 Dec;22(12):653-8.PMID: 14992327>
  19. ^ Yang, F; Lim GP; Begum AN; Ubeda OJ; Simmons MR; Ambegaokar SS; Chen PP; Kayed R; Glabe CG; Frautschy SA; Cole GM (February 2005). "Curcumin inhibits formation of amyloid beta oligomers and fibrils, binds plaques, and reduces amyloid in vivo". Journal of Biological Chemistry (American Society for Biochemistry and Molecular Biology) 280 (7): 5892–901. doi:10.1074/jbc.M404751200. PMID 15590663. 
  20. ^ Ng TP; Chiam PC; Lee T; Chua HC; Lim L; Kua EH (November 2006). "Curry consumption and cognitive function in the elderly". American Journal of Epidemiology (Oxford University Press) 164 (9): 898_906. doi:10.1093/aje/kwj267. PMID 16870699. 
  21. ^ Xu Y, Ku B, Cui L, Li X, Barish PA, Foster TC, Ogle WO. (August 2007). "Curcumin reverses impaired hippocampal neurogenesis and increases serotonin receptor 1A mRNA and brain-derived neurotrophic factor expression in chronically stressed rats". Brain Res 1162: 9. doi:10.1016/j.brainres.2007.05.071. PMID 17617388. 
  22. ^ Wu A, Ying Z, Gomez-Pinilla F. (February 2006). "Dietary curcumin counteracts the outcome of traumatic brain injury on oxidative stress, synaptic plasticity, and cognition". Experimental Neurology 197: 309. doi:10.1016/j.expneurol.2005.09.004. PMID 16364299. 
  23. ^ Bala K, Tripathy BC, Sharma D. (April 2006). "Neuroprotective and anti-ageing effects of curcumin in aged rat brain regions". Biogerontology 7: 81. doi:10.1007/s10522-006-6495-x. PMID 16802111. 
  24. ^ Kamyar Mollazadeh Moghaddam, Mehrdad Iranshahi, Mahsa Chitsazian Yazdi, Ahmad Reza Shahverdi (August 2009). "The combination effect of curcumin with different antibiotics against Staphylococcus aureus". IJGP 3(2):141-143.doi:10.4103/0973-8258.54906
  25. ^ Mancuso C, Barone E (2009). "Curcumin in clinical practice: myth or reality?". Trends Pharmacol Sci. 30 (7): 333–4. PMID 19523696. 
  26. ^ Aggarwal BB, Shishodia S. Suppression of the nuclear factor-kappaB activation pathway by spice-derived phytochemicals: reasoning for seasoning. Ann N Y Acad Sci. 2004 Dec;1030:434-41. PMID 15659827.
  27. ^ Beevers CS, Chen L, Liu L, Luo Y, Webster NJ, Huang S (February 2009). "Curcumin disrupts the Mammalian target of rapamycin-raptor complex". Cancer Res. 69 (3): 1000–8. doi:10.1158/0008-5472.CAN-08-2367. PMID 19176385. 
  28. ^ Ravindran, J.; Prasad, S.; Aggarwal, B. (Jul 2009). "Curcumin and Cancer Cells: How Many Ways Can Curry Kill Tumor Cells Selectively?". The AAPS journal 11 (3): 495. doi:10.1208/s12248-009-9128-x. PMID 19590964.  edit
  29. ^ Anand P, Kunnumakkara AB, Newman RA, Aggarwal BB (2007). "Bioavailability of curcumin: problems and promises". Molecular pharmaceutics 4 (6): 807–18. doi:10.1021/mp700113r. PMID 17999464. 
  30. ^ a b Shoba G; Joy D; Joseph T; Majeed M; Rajendran R; Srinivas PS (May 1998). "Influence of piperine on the pharmacokinetics of curcumin in animals and human volunteers". Planta Med 64 (4): 353–6. doi:10.1055/s-2006-957450. PMID 9619120. 
  31. ^ a b Bisht, Savita; et al. (2007). "Polymeric nanoparticle-encapsulated curcumin ("nanocurcumin"): a novel strategy for human cancer therapy". Journal of Nanobiotechnology (BioMed Central) 5 (3): 3. doi:10.1186/1477-3155-5-3. PMID 17439648. 
  32. ^ Begum AN, Jones MR, Lim GP, Morihara T, Kim P, Heath DD, Rock CL, Pruitt MA, Yang F, Hudspeth B, Hu S, Faull KF, Teter B, Cole GM, Frautschy SA. (July 2008). "Curcumin structure-function, bioavailability, and efficacy in models of neuroinflammation and Alzheimer's disease.". J Pharmacol Exp Ther 326: 196. doi:10.1124/jpet.108.137455. PMID 18417733. 
  33. ^ European patent EP20060004820
  34. ^ Marczylo TH, Verschoyle RD, Cooke DN, Morazzoni P, Steward WP, Gescher AJ (2007). "Comparison of systemic availability of curcumin with that of curcumin formulated with phosphatidylcholine". Cancer Chemother Pharmacol 60 (2): 171–7. doi:10.1007/s00280-006-0355-x. 
  35. ^ Kawanishi, S; Oikawa, S; Murata, M; (2005). "Evaluation for safety of antioxidant chemopreventive agents". Antioxidants & Redox Signaling 7 (11-12): 1728–39. doi:10.1089/ars.2005.7.1728. PMID 16356133. 
  36. ^ Moos PJ; Edes K; Mullally JE; Fitzpatrick FA (2004). "Curcumin impairs tumor suppressor p53 function in colon cancer cells". Carcinogenesis 25 (9): 1611–7. doi:10.1093/carcin/bgh163. PMID 15090465. 
  37. ^ Lois Swirsky Gold. Turmeric (>98% curcurmin). Carcinogenic Potency Database Project. Last updated 3 Apr 2006. Last accessed 4 Jan 2007. [1]
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  39. ^ López-Lázaro M (2008). "Anticancer and carcinogenic properties of curcumin: considerations for its clinical development as a cancer chemopreventive and chemotherapeutic agent.". Mol Nutr Food Res. 52 (Suppl 1): S103–S27. PMID 18496811. 
  40. ^ National Institutes of Health
  41. ^ Hsu CH, Cheng AL (2007). "Clinical studies with curcumin". Adv. Exp. Med. Biol. 595: 471–80. doi:10.1007/978-0-387-46401-5_21. PMID 17569225. 
  42. ^ Jiao Y, Wilkinson J, Di X, et al. (January 2009). "Curcumin, a cancer chemopreventive and chemotherapeutic agent, is a biologically active iron chelator". Blood 113 (2): 462–9. doi:10.1182/blood-2008-05-155952. PMID 18815282. 
  43. ^ Burgos-Moron E, Calderón-Montaño JM, Salvador J, Robles A, López-Lázaro M. (2009). "The dark side of curcumin.". Int J Cancer.. PMID 19830693. 
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