Curcumin

Curcumin
IUPAC name (1E,6E)-1,7-bis (4-hydroxy- 3-methoxyphenyl) -1,6- heptadiene-3,5-dione
Other names curcumin diferuloylmethane C.I. 75300 Natural Yellow 3
Identifiers
CAS number	458-37-7 Y
PubChem	969516
ChemSpider	839564 Y
UNII	IT942ZTH98 Y
ChEBI	CHEBI:3962 Y
ChEMBL	CHEMBL116438 N
Jmol-3D images	Image 1
SMILES O=C(\C=C\c1ccc(O)c(OC)c1)CC(=O)\C=C\c2cc(OC)c(O)cc2
InChI InChI=1S/C21H20O6/c1-26-20-11-14(5-9-18(20)24)3-7-16(22)13-17(23)8-4-15-6-10-19(25)21(12-15)27-2/h3-12,24-25H,13H2,1-2H3/b7-3+,8-4+ Y Key: VFLDPWHFBUODDF-FCXRPNKRSA-N Y InChI=1/C21H20O6/c1-26-20-11-14(5-9-18(20)24)3-7-16(22)13-17(23)8-4-15-6-10-19(25)21(12-15)27-2/h3-12,24-25H,13H2,1-2H3/b7-3+,8-4+ Key: VFLDPWHFBUODDF-FCXRPNKRBF
Properties
Molecular formula	C21H20O6
Molar mass	368.38 g/mol
Appearance	Bright yellow-orange powder
Melting point	183 °C (361 °F) (456.15 K)
N (verify) (what is: Y/N?) Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa)
Infobox references

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 natural phenols and are responsible for the yellow color of turmeric. Curcumin can exist in several tautomeric forms, including a 1,3-diketo form and two equivalent enol forms. The enol form is more energetically stable in the solid phase and in solution.^[1]

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

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

Curcumin Keto form

Curcumin Enol form

Curcumin

Chemistry

Curcumin incorporates several functional groups. The aromatic ring systems, which are polyphenols are connected by two α,β-unsaturated carbonyl groups. The diketones 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 J. Miłobędzka, Stanisław Kostanecki and Wiktor Lampe.^[3]

Curcumin is used as a reagent for boron in EPA Method 212.3.^[4]

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. Both mechanisms use 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.^[5] Only a few identified compounds, such as anigorufone^[6] and pinosylvin,^[7] use cinnamic acid as their start molecule. An experimentally backed route was not presented until 2008. 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.^[5] 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.^[5] Therefore, it was concluded the second pathway proposed by Roughly and Whiting was correct.

Demonstrated medical uses

A daily dose of 2 grams of Curcuma domestica extract was found to provide pain relief that was equivalent to ibuprofen for the relief of pain associated with osteoarthritis of the knee.^[8] An extensive survey of the literature shows a number of other potential uses and that daily doses over a 3 month period of up to 12 grams proved safe.^[9] Commercial capsules of curcumin contain piperine, a compound found in pepper which aids absorption of curcumin into the blood stream. However, as curcuma is known to inhibit blood clotting, it should be avoided for a two week period prior to major surgery and not used in conjunction with blood thinners such as warfarin and Plavix. It is also known to aggravate gallstone problems.^[10]

Potential medical uses

Turmeric has been used historically as a component of Indian Ayurvedic medicine since 1900 BC to treat a wide variety of ailments.^[11] Research in the latter half of the 20th century has identified curcumin as responsible for most of the biological activity of turmeric.^[11] 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 various diseases, including multiple myeloma, pancreatic cancer, myelodysplastic syndromes, colon cancer, psoriasis, and Alzheimer's disease.^[12]

In vitro and animal studies have proven that curcumin has antitumor,^[13][14][15] antioxidant, antiarthritic, antiamyloid, anti-ischemic,^[16] and anti-inflammatory properties.^[17] Anti-inflammatory properties may be due to inhibition of eicosanoid biosynthesis.^[18] In addition it may be effective in treating malaria, prevention of cervical cancer, and may interfere with the replication of the human immunodeficiency virus (HIV).^[19] In HIV, it appears to act by interfering with P300/CREB-binding protein (CBP). It is also hepatoprotective.^[20] A 2008 study at Michigan State University showed low concentrations of curcumin interfere with Herpes simplex virus-1 (HSV-1) replication.^[21] The same study showed curcumin inhibited the recruitment of RNA polymerase II to viral DNA, thus inhibiting its transcription.^[21] This effect was shown to be independent of effect on histone acetyltransferase activities of p300/CBP.^[21] A previous (1999) study performed at University of Cincinnati indicated curcumin is significantly associated with protection from infection by HSV-2 in animal models of intravaginal infections.^[22]

Curcumin acts as a free radical scavenger and antioxidant, inhibiting lipid peroxidation^[23] and oxidative DNA damage. Curcuminoids induce glutathione S-transferase and are potent inhibitors of cytochrome P450.

The Siegel Life Project funded an initial study on curcumin for Alzheimer's in 1997-1998 through the UCLA Center on Aging. UCLA/VA researchers Drs. Cole and Frautschy presented potent anti-Alzheimer's effects in 1997 and 2000 at the Society for Neuroscience.^[24][25] These data were then published in 2001, demonstrating that curcumin was particularly effective in reducing neurodegeneration, oxidative damage, diffuse plaque deposition, aberrant inflammation and impaired inflammatory clearance following beta-amyloid infusion, which was published in 2001.^[26] This led to testing in a transgenic animal model where it was shown to dramatically diminish plaque burden and overall inflammation, but also increase plaque associated inflammatory cells suggesting clearance.^[27] In 2004 this UCLA/Veterans group demonstrated that the effect was in part to the highly specific binding effects to beta-amyloid, whereby it could break apart amyloid aggregates in vitro, bind to plaques in vivo, and because of its fluorescent properties, it could be determined that plaques of transgenic mice ingesting curcumin fluoresced green, demonstrating brain penetration.^[28] A Harvard group showed that 7 days of tail vein injections of curcumin shrunk plaque size and reduced dystrophic neurites.^[29] The UCLA group also showed curcumin synerigizing with fish oil working to protect against cognitive deficits in another transgenic model.^[30] However humans show much more glucuronidation than rodents, and glucuronidated curcumin does not pass the blood brain barrier (See section on curcumin formulations). Free curcumin but not glucuronidated curcumin readily passes through the barrier. But extensive glucuronidation in humans is the major barrier to translation in neurodegenerative diseases. Human intestinal cells glucuronidate more than rodent intestine (Ireson) ^[31]

There is also circumstantial evidence curcumin improves mental functions; a survey of 1010 Asian people who ate yellow curry and were between the ages of 60 and 93 showed those who ate the sauce "once every six months" or more had higher MMSE results than those who did not.^[32] 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 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.^[33][34][35] Curcumin has also been demonstrated to be a selective monoamine oxidase inhibitor (MAOI) of type MAO-A. Fluorescent imaging in a mouse model of Alzheimer's disease showed that curcumin crosses the blood-brain barrier.^[36] Several studies have demonstrated that unlike glucuronidated curcumin, free curcumin, which is lipophilic, readily passes the blood brain barrier^[37][38]

In 2009, an Iranian group demonstrated the combination effect of curcumin with 24 antibiotics against Staphylococcus aureus. In that study, in the presence of a subinhibitory concentration of curcumin, the antibacterial activities of cefixime, cefotaxime, vancomycin and tetracycline were increased against test strain. The increase in inhibition zone surface area for these antibiotics were 52.6% (cefixime), 24.9% (cephotaxime), 26.5% (vancomycin ) and 24.4% (tetracycline). Also it showed curcumin has an antagonist effect on the antibacterial effect of nalidixic acid against the test strain.^[39]

Although many preclinical studies suggest 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.^[40]

In 2008 scientists at the Salk Institute (Drs. Dave Schubert and Pam Maher) performed high throughput screening, identifying a curcumin pyrazole derivative, which improved memory,^[41] is broadly neuroprotective,^[42] stimulates BDNF in vitro and in vivo. This group showed in collaboration with UCLA that it was protective in brain trauma ^[43] and in collaboration with Cedars Sinai/UCSD groups that it was protective in stroke.^[44]

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.^[45]

A 2009 study suggested curcumin may inhibit mTOR complex I via a novel mechanism.^[46]

Another 2009 study on curcumin effects on cancer states it "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)".^[47]

A 2010 study in malignant brain tumors showed curcumin effectively inhibits tumor cell proliferation, as well as migration and invasion, and these effects may be mediated through interference with the STAT3 signaling pathway.^[48]

When 0.2% curcumin is added to diet given to rats or mice previously given a carcinogen, it significantly reduces colon carcinogenesis.^[49]

Curcumin has recently been shown to have phyto-estrogenic activity that might contribute to activity against breast cancer.^[50] In the murine model of breast cancer metastasis, curcumin inhibits the formation of lung metastases ^[51] probably through the NF-kappa-B dependent regulation of protumorigenic inflammatory cytokines.^[52]

Curcumin might be potentially useful in some kidney diseases by preventing renal inflammation.^[53]

Bioavailability

There have been several commercial products developed to provide an alternative route to curcumin. Several trials with unformulated curcumin show extensive glucuronidation and sulfation and typically undetectable levels of free curcumin.^[54][55] For example, trials show that ingestion from 2 to 10 grams of unformulated curcumin lead to undetectable or very low serum levels of free curcumin.^[56] For neurodegenerative diseases, it is important that curcumin is absorbed predominantly as 'free" as opposed to glucuronidated, since glucuronidated curcumin does not penetrate the blood brain barrier, while free curcumin is readily brain penetrant.^[37]

The first formulation to improve bioavailability was curcumin supplements with piperine ("bioperine", manufactured by Sabinsa Corp, New Jersey) and distributed by several companies. Co-supplementation with 20 mg of piperine (extracted from black pepper) significantly increased the absorption of curcumin by 2000% in a study funded by the manufacturer of piperine.^[56] However, the increase in absorption in plasma 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. It is important to recognize that rapid clearance from plasma after acute administration does not necessarily represent levels in tissues such as adispose, breast or brain.^[37] Glucuronidation inhibitors should be taken cautiously (if at all) by individuals taking other medications, but whether the doses of piperine used can dramatically alter pharmacokinetics of other drugs is unclear.

The second major commercial innovation of curcumin bioavailability was made in 2006, when UC Regents and the Veterans Administration filed a provisional patent, which led to Longvida Optimized Curcumin. In July 2008, the inventors described a new form of "lipidated curcumin" from Verdure Sciences as "Longvida" that was noted to achieve more than 5 micromolar in the brain in vivo.^[37] Pharmacokinetics of Longvida in humans shows superior absorption of free curcumin.^[57] Extensive toxicity studies have been performed showing Longvida to have an excellent safety profile.^[58] as was found in the NIH cancer toxicity studies with tumeric oleoresin leading it to be placed on the FDA's GRAS (generally recognized as safe) list.^[59]

Another method to increase the bioavailability of curcumin was later developed as Meriva, patent pending since 2006^[60] and involves a simple procedure creating a complex with soy phospholipids. However, there was no plasma concentration of free curcumin found in humans. In animals, free curcumin reaching 33.4 nanomolar while in humans, none was detected.^[61]

Another curcumin proprietary formulation was introduced in 2008 (BCM-95®, Biocurcumax, Arjuna) mixed with turmeric oils, was shown in human cross-over bioavailability comparison tests to have 8 times the bioavailability and greater blood retention time than standard 95% and up to 5 times more than curcumin combined with lecithin and piperine.^[62] This same formula was also shown to remain above 200 ng/g for 12 hours in a human clinical study. Plain curcumin remained above 200 ng/g for less than 2 hours. Two hours after ingestion, BCM-95 levels of free curcumin were 10-fold over that of plain curcumin.^[63] However these data were in contrast to a six-month placebo-controlled, double-blind clinical trial for Alzheimer's disease, individuals in the BCM-95 groups even doses as high as 4 g failed to yield any significant free curcumin in the plasma. Interestingly there was a non-significant increase in serum amyloid beta with the high dose, which may relate to some effect on amyloid clearance from the brain. ”.^[64]

There are other formulations for curcumin in the pipeline, that have not yet become commercial. In 2007, a polymeric nanoparticle-encapsulated formulation of curcumin ("nanocurcumin"^[65]). 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.^[65] However, actual in vivo absorption (injected or oral) should be tested with this nanoparticle.

In 2010, a food-grade polymer micellar encapsulation system was shown to increase curcumin's water solubility and in vitro anti-cancer activity. It was found that hydrophobically modified starch, usually used to encapsulate flavors, was able to form polymer micelles. Using a simple high-speed homogenization method, it can load curcumin into its hydrophobic core, and thus solubilize curcumin. Cell culture experiments revealed an enhanced anti-cancer activity on HepG2 cell line. However, more in vivo studies are needed to further prove its efficacy in the aspect of bioavailability.^[66]

Populations ingesting high amounts of curcumin in foods may have reduced risk for some diseases (Parkinson's), which may be due to an effect of cooking or dissolution in oil. Some benefits of curcumin, such as the potential protection from colon cancer, may not require systemic absorption. Alternatively, dissolving curcumin in warm oils prior to ingestion increases bioavailability; however, other than abstracts presented at Society for Neuroscience in 2009 "Efficacy of curcumin formulations in relation to systemic availability in the brain and different blood compartments in neuroinflammatory and AD models. Society for Neuroscience, Oct 18. 2009, #211.7, Chicago Ill 36:2009", no manuscripts to date have documented this. The poor stability in aqueous solution as opposed to high stability in lipid solutions argues that cooking with curcumin and oil may increase absorption. Curcumin is not stable in water because it is prone to hydrolysis, that convert it to vanillin and ferulic acid.^[67] In addition to curries, one can purchase food products containing turmeric (~5% curcumin) such as Nutmeric,^[68] which provide turmeric in an oil-solubilized form similar to Indian curry preparations. The amount of curcumin in such foods compares readily to the typical Indian diet. . Bioavailability of curcumin can be increased by preparing matrix tablet for colon targeted using natural polymer.

Potential risks and side effects

Extensive in vivo toxicity studies have been performed with turmeric Oleoresin (85% curcumin) which led to it being placed on the FDA's GRAS (generally recognized as safe) list [54]. Kawanishi et al. (2005) remarked that curcumin, like many antioxidants, can be a "double-edged sword" where, in the test tube, anticancer and antioxidant effects may be seen in addition to pro-oxidant effects.^[69] Carcinogenic effects are inferred from interference with the p53 tumor suppressor pathway, an important factor in human colon cancer.^[70] Carcinogenic and LD₅₀ tests in mice and rats, however, have failed to establish a clear relationship between tumorogenesis and administration of curcumin in turmeric oleoresin at >98% concentrations.^[71] Other in vitro and in vivo studies suggest that curcumin may cause carcinogenic effects under specific conditions.^[72][73]

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.^[74] More recently, curcumin was found to alter iron metabolism by chelating iron and suppressing the protein hepcidin, potentially causing iron deficiency in susceptible patients.^[75] Further studies seem to be necessary to establish the benefit/risk profile of curcumin.^[76]

There is no or little evidence to suggest curcumin is either safe or unsafe for pregnant women. However, there is still some concern 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 or number of live or dead embryos.^[77] Curcumin has embryotoxic and teratogenic effects on zebrafishes (Danio rerio) embryos.^[78]

References

Notes

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External links

• Turmeric and curcumin, from Memorial Sloan-Kettering Cancer Center
• Turmeric and curcumin, from M.D. Anderson Cancer Center
• Turmeric, from the University of Maryland Medical Center