Abstract
Garcinol is an active constituent of Garcinia indica and Garcinia cambogia. Recent studies have proven that garcinol has anti-inflammatory, anti-cancer, and anti-oxidant activities. The objective of this study was to evaluate the inhibitory effects of garcinol on the activities of the drug metabolizing cytochrome P450 (CYP) isozymes to predict potential herb-drug interactions with co-administered drugs. Garcinol was incubated with a mixture of rat liver microsomes and eight CYP probe substrate cocktail under optimized incubation conditions and the samples were analyzed using a validated method on LC-MS/MS. Garcinol showed strong inhibition with IC50 values of CYP1A2 (7.6 µM), CYP2C9 (8.0 µM), CYP2B6 (2.1 µM), CYP2D6 (9.5 µM), and CYP3A4 (5.1 µM), respectively, and moderate inhibition towards CYP2C19 (16.4 µM) and CYP2E1 (19.0 µM). Molecular docking studies were performed on garcinol against the active sites of CYP2B6 and CYP3A4 proteins. These results further confirmed that the inhibitory activity of garcinol occurred by occupying the active sites of these human CYPs and by making favorable interactions with its key residues. In-vivo CYP inhibition studies were carried out in Sprague-Dawley rats. These results suggest garcinol may cause herb-drug interactions, mediated by inhibition of CYPs involved in drug metabolism in-vivo by altering the pharmacokinetic parameters like AUC and Cmax in a clinically significant manner. Garcinol was found to upregulate the expression and activity of P-gp in western blotting study and P-gp inhibition study in-vivo. These findings give a clear understanding to predict potential herb-drug/drug-drug interactions of garcinol for safe clinical use in future.
Highlights
Garcinia cambogia (Malabar tamarind) and Garcinia indica are small tropical trees grown in Africa, Asia, and Pacific regions [1]
Garcinol was found to be structurally similar to curcumin, because of the presence of β-diketone and showed better anticancer activity compared to curcumin [7]
These results revealed that the docked garcinol showed comparable glide docking score to the reference known inhibitors and they interacted with active site amino acid residues of CYP3A4 and CYP2B6
Summary
Garcinia cambogia (Malabar tamarind) and Garcinia indica (kokum) are small tropical trees grown in Africa, Asia (western ghats of India), and Pacific regions [1]. Many natural products have been extracted from various parts of these trees namely hydroxycitric acid (HCA), hydroxycitricacid lactone, citric acid, oxalic acid, malic acid, ascorbic acid, polyphenols, anthocyanin, garcinol, camboginol, isogarcinol, guttiferones, and xanthochymol [3,4]. Garcinol reduces obesity by acting on the AMPK-ER stress axis [8] and was reported to modulate gut microbiota and reduce obesity in mice [9]. To further support these preclinical studies and to accelerate the development of garcinol as a potential drug candidate, additional studies like in-vitro transport and metabolism are required [6]
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