Reviewed: Nelson KM, Dahlin JL, Bisson J, Graham J,
Pauli GF, Walters MA. The essential medicinal chemistry of curcumin. J Med Chem. January 11, 2017. doi: 10.1021/acs.jmedchem.6b00975.
Turmeric
(Curcuma longa, Zingiberaceae), the
source of curcumin, has been used as a food, spice, and traditional medicine
for thousands of years. The curcumin isolated from the rhizome has been researched
as a therapeutic agent for many different conditions and diseases.
This
review evaluated the medicinal chemistry of curcumin — a name used by the
authors for both the individual curcuminoid compound and mixtures of curcuminoids
(some of the biologically active compounds in turmeric root and its extracts) —
to determine if it is a suitable lead for the development of conventional
pharmaceutical drugs. 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 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 does not exhibit these
properties.
After
analyzing the relevant scientific literature, the authors reported high
variability in curcumin purity, in addition to a “widespread lack of
characterization of ‘curcumin’ materials.” Despite most commercial “curcumin” ingredients
and finished products’ containing multiple compounds (i.e., the curcuminoids curcumin,
demethoxycurcumin, and bisdemethoxycurcumin), the specific composition was not
always defined (presumably in the products’ labels and/or in the reviewed
articles). Therefore, the review uses “curcumin” interchangeably with “curcuminoids,”
noting that 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 has been shown to do all of the above, which
leads the authors to 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.”
Researchers
have reported that curcumin has a high rate of bioactivity.10 Of
particular concern is curcumin’s stability, which 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 7), curcumin shifts to a much less soluble form as the
pH of its environment decreases.12,13 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.”
The
authors stress the importance of the initial characterization of the curcumin material,
but they note that it is also 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.”
“Curcumin
also displays undesirable physicochemical properties relative to known drugs,”
the authors added. 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.
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,” leading to “membrane perturbation
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.”15,16 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 curcurmin has a high variability in distribution.16-18
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 against many cancer
cells lines, but it has been reported as toxic against normal human cells in only
a few studies.19, 20
The
authors caution those who seek to improve the pharmacokinetics of curcumin, as
they could increase these potential cytotoxic effects.19 The hypothesis
as to why there is such a high observed tolerance in humans and low rate of
adverse events in the vast amount of curcumin literature is that it is all “likely
due to … poor absorption and low bioavailability.” However, the authors also
mention it is possible that the benefits of curcumin on human health could be
due to effects on the gut microbiome,15 making absorption moot
(although curcumin’s lack of efficacy at high doses in clinical trials does not
bode well for this hypothesis).
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.” This review intends to help ensure that researchers
and readers are assessing the medicinal chemistry of bioactivity assays before
moving forward with further research. The authors remain skeptical that oral
curcumin (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. The review concludes that
curcumin does not possess the properties required for a reliable conventional
drug candidate. While isolated curcumin may not be a viable conventional therapeutic,
according to this review, natural products require a holistic approach be
considered, as well. As the authors explain, “there is increasing evidence that
[chemically complex traditional medicine] agents cannot be described with reductionist
pharmacology models.”21
This article was covered fairly extensively in the
mainstream media in the US with the misleading message that turmeric and/or
curcumin-standardized turmeric extracts have been found to be ineffective.
—Alexis Collins, MA, MS
ABC Comments
The different uses of curcumin as a conventional
drug and as a dietary supplement must be distinguished. Caution must be taken
when interpreting in vitro data using this pure compound or group of
curcuminoids, and extrapolating the observed effects into activities in humans.
Curcumin has produced positive results in many of these tests, and some of
these results are likely due to assay
interferences, as detailed by the authors, rather than actual bioactivity of
curcumin. 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. The use of
curcuminoids, turmeric extracts, or powdered turmeric as a dietary s upplement,
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 have shown positive results with curcumin in the area of
osteoarthritis, for example, have been published. Therefore, the authors’
statement that “curcumin [which includes
curcuminoid mixtures consisting of curcumin, demethoxycurcumin and
bisdemethoxycurcumin at various concentrations according to the authors] has
never been shown to be conclusively effective in a randomized,
placebo-controlled clinical trial for any indication” is inaccurate.
In addition, the use of curcumin (or turmeric) preparations
on a regular basis may have some disease-preventing effects. It takes substantial
effort to prove a preventive effect scientifically, since extensive long-term
investigations are necessary, but the available data suggest that curcumin
might be beneficial for the prevention of certain inflammatory diseases, and
possibly others.
Finally, the authors raise an interesting point,
which is the potential that curcumin provides health benefits through
interactions with the gut metabolome. As 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
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