Reviewed: Nelson KM, Dahlin JL, Bisson J, Graham J, Pauli GF, Walters MA. The essential medicinal chemistry of curcumin [published online January 11, 2017]. J Med Chem. doi: 10.1021/acs.jmedchem.6b00975.

Curcumin is one of the major constituents of turmeric (Curcuma longa, Zingiberaceae), which has been used as a food, spice, and traditional medicine for thousands of years. Curcumin isolated from the plant’s rhizome has been studied as a therapeutic agent for many different conditions and diseases.

This review evaluated the medicinal chemistry of “curcumin” to determine if it is a suitable lead for the development of conventional pharmaceutical drugs. “Curcumin” is often used ambiguously in the scientific literature to refer to both the individual compound and mixtures of curcuminoids, which represent some of the alleged biologically active compounds in turmeric root and its extracts. Therefore, the authors of the review use “curcumin” interchangeably with “curcuminoids.” The authors also attempt to distinguish traditional botanical uses of chemically complex turmeric root/rhizome preparations from the more chemically focused and concentrated curcumin preparations, noting that the observed activity of the turmeric and curcumin-rich preparations cannot be explained solely by the putative activity of curcumin.

Although the review focuses on curcumin, the paper may also serve as a general guide on how to assess natural products (or, more specifically, pure compounds derived from chemically complex plant material) as potential candidates for pharmaceutical drug development. According to the authors, ideal conventional drug candidates are chemically stable and have high water solubility, potent and selective target activity, high bioavailability, broad tissue distribution, stable metabolism, and low toxicity. The review presents evidence that curcumin, as a single chemical entity or as a combination of related curcuminoids, does not exhibit these properties, although there does not seem to be any evidence that pure curcumin or collective curcuminoids are toxic at levels normally associated with their presence in orally consumed curcumin-rich dietary supplement preparations.

After analyzing the relevant scientific literature, the authors found high variability in reported “curcumin” purity and/or overall composition, in addition to a “widespread lack of characterization of ‘curcumin’ materials.” Despite most commercial “curcumin” ingredients and finished products containing multiple compounds (e.g., the curcuminoids curcumin, demethoxycurcumin, and bisdemethoxycurcumin), the specific composition was not always defined in the reviewed articles (and/or on the tested products’ labels). The authors note that this variability in commercial curcumin preparations is an obstacle to interpreting and reproducing experimental results.

According to the authors, curcumin exhibits all behaviors of pan-assay interference compounds (PAINS),1-9 which tend to give false positives in assay readouts. Assay interference may result from various properties or “behaviors” of PAINS, including covalent labeling of proteins, metal chelation, redox reactivity, aggregation, membrane disruption, fluorescence interference, or structural decomposition. Curcumin, which has a high number of reported bioactivities,10 has been shown to do all of the above. Thus, the authors caution that “any report of [curcumin] activity in an assay that does not either exclude or account for these potential modes of assay interference should be treated with caution.”

The review also discusses potential concerns regarding the stability of curcumin. The concentration of the compound reportedly decreases by 50% within 20 minutes at neutral pH, room temperature, and in an aqueous buffer solution. While curcumin is more stable in acidic environments (i.e., solutions with a pH of less than seven), curcumin becomes less water-soluble as the pH of its environment decreases.^11-13 The authors state that “Nearly all the manuscripts reviewed failed to consider the stability of [curcumin],” and that the “time frame for [assays] described in publications included in NAPRALERT allows for significant degradation of curcumin.”

In addition to stressing the importance of the initial characterization of the curcumin material, the authors note that it is imperative to identify amounts of degradation products present at the end of an experiment.¹⁴ “The polypharmacology of curcumin may in part, or even largely, be due to the sum of its degradation products. Instability of curcumin must be considered when interpreting bioassay results, if stability is not otherwise demonstrated. Curcumin stability can be improved with lipid encapsulation or nanoparticles, but these will have to be evaluated as new compounds with potential cytotoxicity.”

The authors also point out that “Curcumin also displays undesirable physicochemical properties relative to known drugs.” The main concern is that curcumin forms chemical aggregates (colloids) under many common bioassay conditions. Enzymes, which are often targeted in standard bioassays, can be inhibited by colloids.^15,16

Curcumin bioactivity was often observed at concentrations typically above the critical aggregation concentration threshold for curcumin. In addition, the authors found that “appropriate counterscreens for assay interference were frequently not performed, and target engagement was not confirmed nor was target selectivity.” Identifying the locations of cellular targets is important, “as curcumin has been shown to perturb cell membranes,” which can be “mistaken for specific binding to membrane-associated proteins.”⁷

The authors then discuss curcumin’s pharmacokinetic properties, which are described as “generally accepted … as poor.”^17,18 This review evaluated whether curcumin has suitable absorption, distribution, metabolism, excretion, and toxicology for a “drug lead.” In all clinical studies reviewed, the authors found no detection of curcumin in the serum of the majority of subjects tested. While distribution of curcumin in humans has been “sparingly studied,” rodent models suggest that curcumin has a high variability in distribution.^18-20 The authors state that this variability could be due to differences in material, extraction, preparation, detection methods, or lack of specificity in detection assays used.

Extensive research has examined curcumin metabolism in human liver microsomes and has shown a high potential for modification by both first and second phase metabolism. Regarding excretion, rodent studies show that the majority of curcumin is excreted in the feces, while small amounts may be absorbed and excreted unchanged, or not absorbed at all and passed directly to feces. Metabolized curcumin is excreted in urine as glucuronide and sulfate conjugates.

Regarding its toxicology, curcumin has been shown to interact with human enzymes (e.g., cytochrome P450s and glutathione S-transferase) that have been implicated in the occurrence of adverse events or interactions with conventional pharmaceutical drugs. Curcumin has been reported as toxic to many cancer cells lines, but it has been reported as toxic to normal human cells in only a few studies.^21,22 The authors caution those who seek to improve the pharmacokinetics of curcumin, as they could increase these potential cytotoxic effects.²¹  They hypothesize that curcumin’s high observed tolerance in humans and low rate of reported adverse events is “likely due to [its] … poor absorption and low bioavailability.” However, the authors also mention that curcumin’s reported human health benefits could potentially be due to its effects on the gut microbiome,¹⁷ which would make absorption moot. As they explain, “it may be possible for curcumin to have an effect on human health without being absorbed. Emerging research suggests that it could affect the gut microbiota, which has been linked to several chronic diseases.”

One common theme the authors found disturbing is that “published bioactivity data of curcumin are typically not evaluated critically before [they are] used to justify further research.” Therefore, they urge researchers to assess the medicinal chemistry of bioactivity assays before moving forward with further research.

The authors remain skeptical that oral curcumin supplementation (as a single compound) has any effect on human health, and their review of clinical trials does not support further investigation into curcumin as a conventional pharmaceutical therapeutic agent.

Overall, the review concludes that curcumin does not possess the properties required for a reliable conventional drug candidate. However, while isolated curcumin may not be a viable conventional therapeutic according to this review, the authors acknowledge that natural products require a holistic approach. As they explain: “there is increasing evidence that [chemically complex traditional medicine] agents cannot be described with reductionist pharmacology models.”²³

This article was covered fairly extensively in the mainstream media in the United States with the misleading message that turmeric and/or turmeric extracts standardized to curcumin have been found to be ineffective. Major national publications featured headlines such as “Turmeric May Not Be a Miracle Spice After All” (TIME, January 12, 2017), “Everybody Needs To Stop With This Turmeric Molecule” (Forbes, January 18, 2017), and “Turmeric May Be Tasty, But It’s Not a Cure-All” (Smithsonian Magazine, January 13, 2017).^24-26

—Alexis Collins, MA, MS

ABC Comments

The different uses of “curcumin” as a conventional drug and as a primary ingredient in curcumin-rich dietary supplements must be distinguished. In addition, caution must be taken when interpreting in vitro data based on this pure compound, a group of curcuminoids, or their mixtures with other constituents, and extrapolating the observed effects into activities in humans. Curcumin has produced positive results in many of these in vitro tests, and some of these results are likely due to assay interferences, as detailed by the authors, rather than actual bioactivity. Based on the available data, the usefulness of curcumin as a conventional drug (e.g., to treat cancer or Alzheimer’s disease) is limited.

However, this does not mean that turmeric and products made from turmeric do not have beneficial bioactivities — a point also highlighted by the authors. The use of certain “curcumin” ingredients (e.g., turmeric extracts or powdered turmeric rhizome) as a dietary supplement, in particular to address inflammatory conditions, has merit and warrants further investigation. The limitations in bioavailability and stability of curcumin are well-known and can be addressed to some extent by improving the formulations, as has been done with some commercial turmeric extracts. Clinical studies that reported positive results with “curcumin” in the area of osteoarthritis, for example, have been published. Therefore, the authors’ statement that “curcumin … has never been shown to be conclusively effective in a randomized, placebo-controlled clinical trial for any indication” may be based on very strict requirements for substantiating conclusive efficacy.

In addition, the use of turmeric preparations on a regular basis may have some disease-preventing effects. Demonstrating a preventive effect scientifically is particularly challenging, since extensive long-term investigations on relatively large test populations are needed. However, the available data, although incomplete, may suggest that turmeric can be beneficial for the prevention of certain inflammatory diseases, and possibly other diseases as well.

Finally, the authors raise an interesting point about curcumin’s health benefits potentially stemming from its interactions with the gut metabolome. They note: “As an alternative approach, it may be possible for curcumin to have an effect on human health without being absorbed. Emerging research suggests that it could affect the gut microbiota, which has been linked to several chronic diseases.”

—Stefan Gafner, PhD

References

1. Fang J, Lu J, Holmgren A. Thioredoxin reductase is irreversibly modified by curcumin: a novel molecular mechanism for its anticancer activity. J Biol Chem. 2005;280(26):25384-253890.
2. Jurrmann N, Birgelius-Flohe R, Boel GF. Curcumin blocks interleukin-1 (IL-1) signaling by inhibiting the recruitment of the IL-1 receptor-associated kinase IRAK in murine thymoma EL-4 cells. J Nutr. 2005;135(8):1859-1864.
3. Jung Y, Xu W, Kim H, Ha N, Neckers L. Curcumin-induced degradation of ErbB2: A role for the E3 ubiquitin ligase CHIP and the Michael reaction acceptor activity of curcumin. Biochim Biophys Acta. 2007;1773(3):383-390.
4. Chin D, Huebbe P, Frank J, Rimbach G, Pallauf K. Curcumin may impair iron status when fed to mice for six months. Redox Biol. 2014;2:563-569.
5. Schneider C, Gordon ON, Edwards RL, Luis PB. Degradation of curcumin: From mechanism to biological implications. J Agric Food Chem. 2015;63(35):7606-7614.
6. Duan D, Doak AK, Nedyalkova L, Soichet BK. Colloidal aggregation and the in vitro activity of traditional Chinese medicines. ACS Chem Biol. 2015;10(4):978-988.
7. Ingolfsson HI, Takur P, Herold KF, et al. Phytochemicals perturb membranes and promiscuously alter protein function. ACS Chem Biol. 2014; 9(8):1788-1798.
8. Priyadarsini KI. Photophysics, photochemistry, and photo-biology of curcumin: Studies from organic solutions, bio-mimetics and living cells. J Photochem Photobiol, C. 2009;10:81-95.
9. Esatbeyoglu T, Ulbrich K, Rehberg C, Rohn S, Rimbach G. Thermal stability, antioxidant, and anti-inflammatory activity of curcumin and its degradation product 4-vinyl guaiacol. Food Funct. 2015;6(3):887-893.
10. Bisson J, McAlpine JB, Friesen JB, Chen SN, Graham J, Pauli GF. Can invalid bioactives undermine natural product-based drug discovery? J Med Chem. 2016;59(5):1671-1690.
11. Griesser M, Pistis V, Suzuki T, Tejera N, Pratt DA, Schneider C. Autoxidative and cyclooxygenase-2 catalyzed transformation of the dietary chemopreventive agent curcumin. J Biol Chem. 2011;286(2):1114-1124.
12. Wang YJ, Pan MH, Chen AL, et al. Stability of curcumin in buffer solutions and characterization of its degradation products. J Pharm Biomed Anal. 1997;15(12):1867-1876.
13. Jagannathan R, Abraham PM, Poddar P. Temperature-dependent spectroscopic evidences of curcumin in aqueous medium: A mechanistic study of its solubility and stability. J Phys Chem B. 2012;116(5):14533-14540.
14. Simmler C, Hajirahimkhan A, Lankin DC, et al. Dynamic residual complexity of the isoliquiritigenin-liquiritigenin interconversion during bioassay. J Agric Food Chem. 2013;61(9):2146-2157.
15. McGovern SL, Helfand BT, Feng B, Shoichet BK. A specific mechanism of nonspecific inhibition. J Med Chem. 2003;46:4265-4272.
16. Shoichet BK. Virtual screening of chemical libraries. Nature. 2004;432:862-865.
17. Chin D, Huebbe P, Pallauf K, Rimach G. Neuroprotective properties of curcumin in Alzheimer’s disease – merits and limitations. Curr Med Chem. 2013;20(32):3955-3985.
18. Siviero A, Gallo E, Maggini V, et al. Curcumin, a golden spice with a low bioavailability. Journal of Herbal Medicine. 2015;5:57-50.
19. Heger M, van Golen RF, Broekgaarden M, Michel MC. The molecular basis for the pharmacokinetics and pharmacodynamics of curcumin and its metabolites in relation to cancers. Pharmacol Rev. 2014;66(1):222-307.
20. Suresh D, Srinivasan K. Tissue distribution and elimination of capsaicin, piperine, and curcumin following oral intake in rats. Indian J Med Res. 2010;131:682-691.
21. Glaser J, Holzgrabe U. Focus on PAINS: False friends in the quest for selective anti-protozoal lead structures from nature? MedChemComm. 2016;7:214-223.
22. Kuttan R, Bhanumathy P, Nirmala K, George MC. Potential anticancer activity of turmeric (Curcuma longa). Cancer Lett (NY, NY, US). 1985;29:197-202.
23. Wagner H. Synergy research: Approaching a new generation of phytopharmaceuticals. Fitoterapia 2011;82(1):34-37.
24. MacMillan M. Turmeric may not be a miracle spice after all. January 12, 2017. TIME. Available at: http://time.com/4633558/turmeric-curcumin-inflammation-spice. Accessed April 17, 2017.
25. Lemonick S. Everybody needs to stop with this turmeric molecule. January 19, 2017. Forbes. Available at: www.forbes.com/sites/samlemonick/2017/01/19/everybody-needs-to-quit-it-with-this-turmeric-molecule. Accessed April 17, 2017.
26. Lewis D. Turmeric may be tasty, but it’s not a cure-all. January 13, 2017. Smithsonian Magazine. Available at: www.smithsonianmag.com/smart-news/turmeric-may-taste-good-its-not-cure-all-180961786/. Accessed April 17, 2017.