Inhibition of aldose reductase by dietary antioxidant curcumin: Mechanism of inhibition, specificity and significance

Abstract

Edited by Vladimir SkulachevKeywords: Aldo-keto reductase ALR2 AKR1B10 Curcumin Sorbitol a b s t r a c t Accumulation of intracellular sorbitol due to increased aldose reductase (ALR2) activity has been implicated in the development of various secondary complications of diabetes. In this study we show that curcumin inhibits ALR2 with an IC 50 of 10 lM in a non-competitive manner, but is a poor inhibitor of closely-related members of the aldo-keto reductase superfamily, particularly aldehyde reductase. Results from molecular docking studies are consistent with the pattern of inhibition of ALR2 by curcumin and its specificity. Moreover, curcumin is able to suppress sorbitol accumulation in human erythrocytes under high glucose conditions, demonstrating an in vivo potential of curcumin to prevent sorbitol accumulation. These results suggest that curcumin holds promise as an agent to prevent or treat diabetic complications.

The Molecular Basis for the Pharmacokinetics and Pharmacodynamics of Curcumin and Its Metabolites in Relation to Cancer

“…2 and 3, which revealed that curcumin tends to adopt an entirely different configuration for each molecular target. For instance, curcumin bends only slightly and retains most of its planar structure when interacting with the minor groove of duplexed oligonucleotides (Zsila et al, 2004;Koonammackal et al, 232 2011), whereas it becomes entirely nonplanar and often rotates around the longitudinal axis when interacting with, e.g., the C1B domain of PKCu (Majhi et al, 2010;Das et al, 2011), PfATP6 (Ji and), aldose reductases (Muthenna et al, 2009;Katsori et al, 2011), and beta amyloid peptides (Ngo and Li, 2012). As a result, curcumin is able to associate with a plethora of biomolecules due to its structural adaptability, which is "exploited" to maximize the number of interatomic bonds between curcumin and its target.…”

“…References used in Fig. 3: [1] (Yoo and Medina-Franco, 2011); [2] (Muthenna et al, 2009);[5] (Milacic et al, 2008); [9] (Ngo and Li, 2012); [10] ; [11] (Majhi et al, 2010); [12] (Mamidi et al, 2012); [13] (Das et al, 2011);[15] (Bustanji et al, 2009). The data set has been included in Supplemental Table 1. 230 distances between curcumin and several amino acid residues ($2.7 Å), indicating that the metal-diketone interaction is quite significant in the binding of curcumin to HIV-1 integrase.…”

“…3 for the H-bond donating enolic proton. Some of the proteins that curcumin interacts with through the b-diketone moiety that may bear relevance to cancer include DNA methyltransferase 1 (Yoo and Medina-Franco, 2011), aldose reductase 1 and 2 (Muthenna et al, 2009), lipoxygenase (Katsori et al, 2011), 20S proteasome (Milacic et al, 2008), tubulin , cyclooxygenase (COX)-2 (Selvam et al, 2005) (sections III. E.1.e and III.E.7), glycogen synthase kinase-3 b (GSK3b) (Bustanji et al, 2009) (section III.E.1.b.ii), and glyoxalase I .…”

“…References used in Fig. 2: [1] (Yoo and Medina-Franco, 2011); [2] (Muthenna et al, 2009);[3] (Katsori et al, 2011);[4] (Kaur et al, 2010); [5] (Milacic et al, 2008); [6] ; [7] (Bustanji et al, 2009). The data set has been included in Supplemental Table 1.…”

Molecular Interactions and Implications of Aldose Reductase Inhibition by PGA1 and Clinically Used Prostaglandins

“…Consequently, the search for AKR1B1 inhibitors is an active field of research. However, the clinical use of various compounds, including tolrestat (Drugbank ID DB02383) and sorbinil (Drugbank ID DB02712) has been hampered by their poor effectiveness and severe adverse effects, such as hepatitis or renal toxicity, attributed to inhibition of the related enzyme aldehyde reductase (AKR1A1 or ALR1) (Muthenna et al, 2009). Therefore, inhibitor selectivity for AKR1B1 over AKR1A1 is preferred over inhibitory potency if it implies fewer side effects (Suzen and Buyukbingol, 2003).…”