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Curcumin

Curcumin is a polyphenol derived from the herbal remedy and dietary spice turmeric. It possesses diverse anti-inflammatory and anti-cancer properties following oral or topical administration. Apart from Curcumin’s potent antioxidant capacity at neutral and acidic pH, its mechanisms of action include inhibition of several cell signaling pathways at multiple levels, effects on cellular enzymes such as cyclooxygenase and glutathione S-transferases, immuno-modulation and effects on angiogenesis and cell–cell adhesion.

Curcumin’s ability to affect gene transcription and to induce apoptosis in preclinical models is likely to be of particular relevance to cancer chemoprevention and chemotherapy in patients. Although Curcumin’s low systemic bioavailability following oral dosing may limit access of sufficient concentrations for pharmacological effect in certain tissues, the attainment of biologically active levels in the gastrointestinal tract has been demonstrated in animals and humans. Sufficient data currently exist to advocate phase II clinical evaluation of oral Curcumin in patients with invasive malignancy or pre-invasive lesions of the gastrointestinal tract, particularly the colon and rectum.

Chemical properties of Curcumin

Curcumin is a bis-a,b-unsaturated b-diketone. As such, Curcumin exists in equilibrium with its enol tautomer. The bis-keto form predominates in acidic and neutral aqueous solutions and in the cell membrane. At pH 3–7, Curcumin acts as an extraordinarily potent H-atom donor. This is because, in the keto form of Curcumin, the heptadienone linkage between the two methoxyphenol rings contains a highly activated carbon atom, and the C–H carbon bonds on this carbon are very weak due to delocalization of the unpaired electron on the adjacent oxygens (Fig. 1). In contrast, above pH 8, the enolate form of the heptadienone chain predominates, and Curcumin acts mainly as an electron donor, a mechanism more typical for the scavenging activity of phenolic antioxidants. Curcumin is relatively insoluble in water, but dissolves in acetone, dimethylsulphoxide and ethanol.

Fig. 1. Tautomerism of curcumin under physiological conditions. Under acidic and neutral conditions, the bis-keto form (top) predominates, Whereas the enolate form is found above pH 8

Pharmacodynamics

In vitro, Curcumin has been shown to inhibit certain epigenetic enzymes (the histone deacetylases: HDAC1, HDAC3, and HDAC8) and transcriptional co-activator proteins (thep300 histone acetyltransferase). Curcumin also inhibits the arachidonate 5-lipoxygenase enzyme in vitro.

Pharmacokinetics

Daily consumption of Curcumin over a 3-month period of up to 12 grams was found to be safe in humans. In Phase I clinical trials, dietary Curcumin was shown to exhibit poor bioavailability, exhibited by rapid metabolism, low levels in plasma and tissues, and extensive rapid excretion, factors that make its’ in vivo activity poorly understood. Potential factors that limit the bioavailability of Curcumin include insolubility in water (more soluble in alkaline solutions) and non-absorption. Numerous approaches to increase Curcumin bioavailability are under research, including the use of absorption factors (such as piperine), liposomes, a structural analogue, or nanomaterial’s using specialized polymers.