Curcumin: A Potential Bioactive Agent

Abstract

Curcumin (diferuloylmethane), the main yellow bioactive component of turmeric has shown a wide spectrum of biological actions. Clinically, curcumin has already been used to reduce post-operative inflammation. Safety evaluation studies indicate that curcumin is well tolerated at a very high dose without any toxic effects. Moreover, curcumin have the potential for the development of modern medicine for the treatment of various diseases. This review paper serves to highlight the extensive work done to establish the biological and pharmacological actions, safety and stability aspects along with the structure and possible modifications in curcumin to enhance its bioeffectiveness.

Full text

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October – December 2011 RJPBCS Volume 2 Issue 4 Page No. 44
Research Journal of Pharmaceutical, Biological and Chemical
Sciences
REVIEW ARTICLE
Curcumin: A Potential Bioactive Agent
Deepak Prashar*, Khokra SL, Rahul Purohit, Shalini Sharma
Department of Pharmacy, Manav Bharti University, Solan (H.P.), India
ABSTRACT
Curcumin (diferuloylmethane), the main yellow bioactive component of turmeric has shown a wide
spectrum of biological actions. Clinically, curcumin has already been used to reduce post-operative inflammation.
Safety evaluation studies indicate that curcumin is well tolerated at a very high dose without any toxic effects.
Moreover, curcumin have the potential for the development of modern medicine for the treatment of various
diseases. This review paper serves to highlight the extensive work done to establish the biological and
pharmacological actions, safety and stability aspects along with the structure and possible modifications in
curcumin to enhance its bioeffectiveness.
Keywords: Curcumin, anticancer, bioavailability, anti-inflammation, antiviral
*Corresponding author
Email: prashardeepak99@yahoo.in

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INTRODUCTION
Curcumin is the active ingredient in the herbal remedy and dietary spice turmeric
(Curcuma longa Linn). Curcumin was identified to be responsible for most of the biological
effects of turmeric [1].This vibrant yellow spice, derived from the rhizome of the plant, has a
long history of use in traditional medicines of China and India [2]. Use of curcumin as a folk
remedy continues today. As part of the ancient Indian medical system, ayurveda, a poultice of
turmeric paste is used to treat common eye infections, and to dress wounds, treat bites, burns,
acne and various skin diseases [3]. In Northern India, women are given a tonic of fresh turmeric
paste with powder of dried ginger roots and honey in a glass of hot milk to drink twice daily
after childbirth. A poultice of turmeric is also applied to the perineum to aid in the healing of
any lacerations in the birth canal [4]. Powdered turmeric is taken with boiled milk to cure cough
and related respiratory ailments [3] and roasted turmeric is an ingredient used as an
antidysenteric for children [3]. This ancient remedy is also used to treat dental diseases,
digestive disorders such as dyspepsia and acidity, indigestion, flatulence, ulcers, as well to
alleviate the hallucinatory effects of hashish and other psychotropic drugs [5]. In food and
manufacturing, curcumin is currently used in perfumes and as a natural yellow coloring agent,
as well as an approved food additive to flavor various types of curries and mustards [5-6].
Recent emphasis on the use of natural and complementary medicines in Western medicine has
drawn the attention of the scientific community to this ancient remedy.
CHEMICAL COMPOSITION OF TURMERIC
Turmeric contains a number of phytoconstituents namely protein (6.3%), fat (5.1%),
minerals (3.5%), carbohydrates (69.4%) and moisture (13.1%). The essential oil (5.8%) obtained
by steam distillation of rhizomes has a-phellandrene (1%), sabinene (0.6%), cineol (1%), borneol
(0.5%), zingiberene (25%) and sesquiterpines (53%) [7]. Curcumin (diferuloylmethane) (3–4%) is
responsible for the yellow colour, and comprises curcumin I (94%), curcumin II (6%) and
curcumin III (0.3%) [8]. Demethoxy and bisdemethoxy derivatives of curcumin have also been
isolated. Curcumin was isolated in 1815 and its chemical structure was determined by Roughly
and Whiting [9] in 1973. It has a melting point at 176–177°C; forms a reddish-brown salt with
alkali and is soluble in ethanol, alkali, ketone, acetic acid and chloroform.
PHARMACOLOGICAL ACTION OF CURCUMIN
Effect on cardiovascular system (CVS)
Curcumin protects from damage caused by myocardial infarction [10] by decreasing the
severity of pathological changes. Curcumin improves Ca2+ transport from the cardiac muscle
sarcoplasmic reticulum, thereby raising the possibility of pharmacological interventions to
correct the defective Ca2+ homeostasis in the cardiac muscle [11]. Curcumin has significant
hypocholesteremic effect in hypercholesteremic rats [12]. Oral administration of curcumin

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significantly decreases the lipid peroxides (33%), increased HDL cholesterol (29%), decreased
total serum cholesterol (11-12%) [13].
Effect on gastrointestinal system (GI)
Stomach: Turmeric powder has beneficial effect on the stomach. It increases mucin secretion in
rabbits and may thus act as gastroprotectant against irritants [14]. Controversy exists regarding
antiulcer activity of curcumin. Both antiulcer [15] and ulcerogenic [16-17] effects of curcumin
have been reported but detailed study is still required. Curcumin has been shown to protect the
stomach from ulcerogenic effects of phenylbutazone in guinea pigs at 50 mg/kg dose [18-19]. It
also protects from 5-hydroxytryptamine-induced ulceration at 20 mg/kg dose [18-19]. However,
small concentration of 0.5% curcumin failed to protect against histamine-induced ulcers [20].
Intestine: Curcumin has some pharmacological effects on the intestine also. Antispasmodic
activity of sodium curcuminate was observed in isolated guinea pig ileum [21]. Anti-flatulent
activity was also observed in both in vivo and in vitro experiments in rats [22]. Curcumin also
enhances intestinal lipase, sucrase and maltase activity [23].
Liver: Curcumin and its analogues have protective activity in cultured rat hepatocytes against
carbon tetrachloride (CCl4), D-galactosamine, peroxide and ionophore-induced toxicity [24].
Curcumin also protects against diethyl nitrosamine and 2-acetylaminofluorine-induced altered
hepatic foci development [25]. Increased level of bile was reported in dogs by both curcumin
[26].
Pancreas: Curcumin increases the activity of pancreatic lipase, amylase, trypsin and
chymotrypsin [27]. A synthetic derivative of p-tolylmethylcarbinol (an ingredient of C. longa) 1-
phenyl-1-hydroxy-n-pentane increases bicarbonate levels as well as plasma secretion [28].
Effect on nervous system
Curcumin and its complex with manganese offer protective action against vascular
dementia by exerting antioxidant activity [29-30]. Curcumin also reduces oxidized proteins in
amyloid pathology in Alzheimer transgenic mice [31]. It also decreases lipid peroxidation in rat
liver microsomes, erythrocyte membranes and brain homogenates [32].
BIOLOGICAL ACTION OF CURCUMIN
Turmeric plant extract (curcumin and other derivatives) have anti-inflammatory, anti-
arthritic, antioxidant, anti-microbial, anti-leishmanial, hepato protective, anti-cancer, anti-ulcer
and anti diabetic activity.

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Anti-inflammatory agents
The water extracts of C. longa along with volatile oil, petroleum ether and alcohol shows
anti-inflammatory effects [33]. The natural analogues of curcumin, i.e. FHM and BHM, are also
potent anti-inflammatory agents. Curcumin is effective against carrageen induced oedema in
rats [33] and mice [34]. Curcumin offers anti-inflammatory effect through inhibition of NFkB
activation [35]. Curcumin has also been shown to reduce the TNF-a-induced expression of the
tissue factor gene in bovine aortic-endothelial cells by repressing activation of both AP-1 and
NFkB. The anti-inflammatory role of curcumin is also mediated through down regulation of
cyclooxygenase-2 and inducible nitric oxide synthetase through suppression of NFkB activation
[36].
Anti-cancer activity
Anti-cancer activity of curcuma is by inhibiting tumour cell proliferation, induction of
analysis, inhibition of transformation of normal cells to tumour cells and inhibition of invasion
of metastasis. A number of animal studies have shown that curcumin has a dose-dependent
chemopreventive effect in colon, duodenal, stomach, esophageal and oral carcinogenesis [37].
Colon carcinoma is prevented by curcumin through arrest of cell-cycle progression independent
of inhibition of prostaglandin synthesis [38]. Curcumin was an effective cytotoxic agent against
the mouse bladder tumor line MBT-2 and the UMUC human bladder tumor cell line, and
effectively inhibited implantation and growth of bladder tumor cells in C3H mice [39]. Curcumin
inhibits cancer development in rat stomach initiated by Nmethyl- N-nitro-N-nitrosoguanisine
(MNNG) [40] and reduces the incidence and/or multiplicity of esophageal tumors and
preneoplastic lesions in rats with N-nitrosomethylbenzylamine-induced esophageal
carcinogenesis [41].
Anti-coagulant activity
By inhibiting collagen and adrenaline-induced platelet aggregation Curcumin shows
anticoagulant activity both in vitro as well as in vivo in rat thoracic aorta [42].
Anti-fibrotic effect
Curcumin suppresses bleomycin-induced pulmonary fibrosis in rats [43]. It also
suppresses bleomycin-induced alveolar macrophage-production of TNF-a, superoxide and nitric
oxide. Thus curcumin acts as a potent anti-fibrotic agent. Oral administration of curcumin at
300 mg/kg dose inhibits bleomycin-induced pulmonary fibrosis by increase in total cell counts
and biomarkers of inflammatory responses.

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Anti-mutagenic activity
Curcumin has shown the reduction in the number of aberrant cells in
cyclophosphamide-induced chromosomal aberration with the dose of 100 and 200 mg/kg body
wt in Wistar rats [44]. Curcumin exerts both pro- mutagenic and anti-mutagenic effects.
Curcumin has also been shown to be non-protective against hexavalent chromium-induced
DNA strand break. In fact, the total effect of chromium and curcumin is additive in causing DNA
breaks in human lymphocytes and gastric mucosal cells [45].
Anti-fertility activity
100% anti-fertility effect has been observed with aqueous extracts of turmeric rhizomes
in rats on oral administration [46]. Curcumin inhibits 5a-reductase, which converts testosterone
to 5a-dihydrotestosterone, thereby inhibiting the growth of flank organs in hamster [47]. Ability
of curcumin to inhibit human sperm motility has developed the potential for its application in
the development of novel intra-vaginal contraceptive [48].
Anti-bacterial activity
Growth of several bacteria like Streptococcus, Staphylococcus and Lactobacillus [22]
could be suppressed by curcumin. The aqueous extract of turmeric rhizomes has reported the
antibacterial effects [49]. In vitro growth of Helicobacter pylori can also be prevented by the use
of curcumin [50].
Anti-diabetic effect
Curcumin decreases advanced glycation end products induced complications in diabetes
mellitus [51]. At very low doses, curcumin prevents galactose-induced cataract formation [52].
Curcumin decrease blood sugar level in alloxan-induced diabetes in rat [53]. Curcumin also
reduces oxidative stress in diabetic induced rats having increased NADPH/NADP ratio as well as
increased activity of oxidative enzymes [54].
Anti-protozoan activity
In vitro curcumin has anti-Leishmania activity [55]. Several synthetic derivatives of
curcumin have anti- Leishmania. amazonensis effect [56]. Anti-Plasmodium falciparum and anti-
Leishmania major effects of curcumin have also been reported [57].
Anti-viral effect
Curcumin acts as an efficient inhibitor of Epstein-Barr virus (EBV) key activator Bam H
fragment z left frame 1 (BZLF1) protein transcription in Raji DR-LUC cells [58]. EBV inducers such
as 12-0-tetradecanoylphorbol-13-acetate, sodium butyrate and transforming growth factor-

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beta increase the level of BZLF1 m-RNA at 12–48 h after treatment in these cells, which is
effectively blocked by curcumin [58]. Therefore, curcumin has been shown to have antiviral
activity. More importantly, curcumin also shows anti-HIV (human immunodeficiency virus)
activity by inhibiting the HIV-1 integrase needed for viral replication [59-60]. It also inhibits UV
light-induced HIV gene expression [61]. Thus curcumin and its analogues may have the
potential for novel drug development against HIV.
BIOAVAILABILITY ASPECTS OF CURCUMIN
Curcumin has got poor bioavailability but is remarkably well tolerated and does not
appear to be toxic to animals [62] or humans [63] even at high doses. Curcumin has also been
measured in human tissue, i.e. in the liver and portal blood of 12 patients undergoing resection
of hepatic metastases of colorectal cancer. They administer dose of 450 – 3600 mg curcumin
daily for 1 week prior to surgery [64]. Low nano-molar levels of curcumin and its metabolites,
curcumin glucuronide and curcumin sulfate, were detected in portal serum of all 3 patients who
received 3600 mg of curcumin. Metabolic reduction products of curcumin (hexahydrocurcumin
and hexahydrocurcuminol) were found in the liver of 1 patient. Therefore, the researchers
concluded that the bioavailability of curcumin is poor in tissues remote from the
gastrointestinal tract, including the liver.
An independent dose-escalation study on 15 patients with advanced colorectal cancer
was conducted in the United Kingdom [65]. Patients consumed a single daily dose of 440 – 2200
mg curcuma extract, equivalent to 36 –180 mg curcumin, for up to 4 months. The treatment
was well tolerated and there was no dose-limiting toxicity. Lao et al. studies also gave a similar
result in healthy human volunteers consuming a single dose of curcumin ranging from 500 to
12,000 mg [66]. No dose-limiting toxicities were observed, and low levels of curcumin were only
detected in the serum receiving the highest doses of curcumin (10,000 or 12,000 mg/day).
Interestingly, curcumin was only detected in 2 of these 6 patients, perhaps indicating the
existence of genetic modifiers of curcumin metabolism.
STABILITY ASPECTS OF CURCUMIN
The stability of curcumin toward chemical degradation by alkali has been investigated
by several laboratories with varying results, possibly due to differences in the media used [67-
70]. Tonnesen et al. [68] identified degradation products including ferulic acid and
feruloylmethane, and studied kinetics of degradation in a MeOH/aqueous buffer medium (1:9),
with phosphate buffer (pH 6 – 9) or carbonate buffer (pH 9 – 10). The rate behavior was
complex showing several peaks and valleys in the 7 – 10 pH regimes, showing second order rate
kinetics in curcumin. Wang et al. [69] found that curcumin decomposed 90% within 30 min in
0.1 M phosphate buffer at pH 7.2 at 378C, and tentatively identified the decomposition product
trans-6-(4_-hydroxy-3_-methoxyphenyl)-2,4-dioxo-5-hexenal, from which they identified
vanillin as a final product along with ferulic acid and feruloylmethane.

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STRUCTURAL ASPECTS OF CURCUMIN
Curcumin is a lipophilic molecule and rapidly permeates cell membranes [71]. Curcumin
was found to affect the structure and function of cellular membranes and mimic typical events
occurring during apoptosis; however, the cellular response to curcumin contrasted with typical
apoptotic cell death because loss of membrane integrity was immediate, partly reversible, and
cells could recover in a relatively short time [71]. To overcome its limited water solubility, a
number of new approaches have been explored to deliver curcumin effectively, such as
liposome encapsulation [72-73]. Arezzini et al. [74] has sought to improve solubility by
modifying the structure by covalent linking of a sugar to curcumin and have studied its potential
as an agent for treatment of iron-overload disease. Metal ion complexation of curcumin, those
with the cations [VO] 2+ [75,76], Mn2+ [77,78], Fe2+/3+ [79-82] and Cu2+ [83-85] have findings of
particular biological interest.
CONCLUSION
On the basis of various literatures survey, curcumin was considered to be an effective
bioactive agent. The low water solubility and poor bioavailability of curcumin can be overcome
by various structural modifications. Stability aspect shows better effect and less toxicity offering
better pharmacodynamic characteristics. A lot of work has been done and a lot to do in this
field.
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