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To the Editor:

Wilson disease (WD) is characterized by copper overload in the liver and basal ganglia and is caused by mutations in the gene encoding protein ATP7B. We read with great interest the article by van den Berghe et al.1 in which they report the beneficial effect of curcumin, the active component of turmeric, in partially restoring protein expression of most ATP7B mutants. Here we propose that, in addition to the ability to enhance the protein expression of ATP7B mutants, several other important properties, such as the antioxidant activity, copper-chelating activity, and superoxide dismutase (SOD) activity of Cu(II)-curcumin complexes, in combination with its pharmacological safety make the natural product curcumin an attractive potential multifunctional agent for the treatment of WD.

First, curcumin is an ideal antioxidant and an effective scavenger of reactive oxygen species (ROS) and reactive nitrogen species (RNS).2, 3 It can also inhibit lipid peroxidation and increase glutathione availability.4 As oxidative stress and lipid peroxidation play central roles in the pathogenesis of WD and patients with WD have relevant glutathione depression, curcumin is expected to have beneficial effects by suppressing oxidative stress, preventing lipid peroxidation, and increasing glutathione levels. The antioxidant activity of curcumin has been implicated in its various pharmacological effects.

Second, curcumin can act as a copper-chelating agent.5-8 The unique structure of curcumin makes it form complexes of types 1:1 and 1:2 with copper with relatively high binding affinities.5-8 It has been reported that curcumin may bind low micromolar concentrations of copper,5-7 which are much lower than the copper levels in WD. The copper-chelating properties of curcumin have been thought to be involved in its protective effects against Alzheimer's disease,5, 8 which is also characterized by excessive transition-metal ions in the brain.

More interestingly, it has been demonstrated that Cu(II)-curcumin complexes possess SOD activity, an ability to neutralize free radicals, and antioxidant potential.6-8 For instance, Cu(II)-curcumin complexes are excellent superoxide radical scavengers and can be regenerated when causing superoxide neutralization.6, 7 This means that after chelating copper, the complexes still possess the ability to alleviate oxidative stress, which is a potential advantage of curcumin in comparison with other copper-chelating agents.

In summary, as shown in Fig. 1, the antioxidant and copper-chelating activities, the SOD activity of Cu(II)-curcumin complexes, and the ability to restore the protein expression of most ATP7B mutants imply the potential of curcumin as a multifunctional agent to combat WD. Rigorous trials of curcumin in WD should be conducted to test the therapeutic effect. The intensive preclinical and clinical studies in the past few decades have provided fruitful information on various properties of curcumin,9, 10 such as bioavailability, pharmacodynamics, and pharmacokinetics, which will be helpful for future trials in WD.

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Figure 1. Potential mechanisms making curcumin a multifunctional agent to combat WD.

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References

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  • 1
    van den Berghe PV, Stapelbroek JM, Krieger E, de Bie P, van de Graaf SF, de Groot RE, et al. Reduced expression of ATP7B affected by Wilson disease-causing mutations is rescued by pharmacological folding chaperones 4-phenylbutyrate and curcumin. HEPATOLOGY 2009; 50: 1783-1795.
  • 2
    Sreejayan, Rao MN. Nitric oxide scavenging by curcuminoids. J Pharm Pharmacol 1997; 49: 105-107.
  • 3
    Shen L, Ji HF. Theoretical study on physicochemical properties of curcumin. Spectrochim Acta A Mol Biomol Spectrosc 2007; 67: 619-623.
  • 4
    Dickinson DA, Iles KE, Zhang H, Blank V, Forman HJ. Curcumin alters EpRE and AP-1 binding complexes and elevates glutamate-cysteine ligase gene expression. FASEB J 2003; 17: 473-475.
  • 5
    Baum L, Ng A. Curcumin interaction with copper and iron suggests one possible mechanism of action in Alzheimer's disease animal models. J Alzheimers Dis 2004; 6: 367-377.
  • 6
    Barik A, Mishra B, Shen L, Mohan H, Kadam RM, Dutta S, el al. Evaluation of a new copper(II)-curcumin complex as superoxide dismutase mimic and its free radical reactions. Free Radic Biol Med 2005; 39: 811-822.
  • 7
    Barik A, Mishra B, Kunwar A, Kadam RM, Shen L, Dutta S, et al. Comparative study of copper(II)-curcumin complexes as superoxide dismutase mimics and free radical scavengers. Eur J Med Chem 2007; 42: 431-439.
  • 8
    Shen L, Zhang HY, Ji HF. A theoretical study on Cu(II)-chelating properties of curcumin and its implications for curcumin as a multipotent agent to combat Alzheimer's disease. J Mol Struct (Theochem) 2005; 757: 199-202.
  • 9
    Aggarwal BB, Sung B. Pharmacological basis for the role of curcumin in chronic diseases: an age-old spice with modern targets. Trends Pharmacol Sci 2009; 30: 85-94.
  • 10
    Aggarwal BB, Harikumar KB. Potential therapeutic effects of curcumin, the anti-inflammatory agent, against neurodegenerative, cardiovascular, pulmonary, metabolic, autoimmune and neoplastic diseases. Int J Biochem Cell Biol 2009; 41: 40-59.

Hong-Fang Ji*, Liang Shen*, * Shandong Provincial Research Center for Bioinformatic Engineering and Technique, Shandong University of Technology, Zibo, People's Republic of China.