Cytochrome P450 and P-gp Mediated Herb-Drug Interactions and Molecular Docking Studies of Garcinol

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.

Metabolic interaction between biflavonoids in Ginkgo biloba leaves and tacrolimus

“…By comparing the differences in the docking forces between five biflavonoids and human CYP3A4, the results suggested that the formation of hydrogen bonds may be the molecular mechanism of inhibition. This was consistent with the previous studies, which reported that saikosaponin and garcinol with inhibitory effects of CYP3A4 also form hydrogen bonds with CYP3A4 (Bolla et al., 2021; Li et al., 2021). By analyzing the molecular structure of each compound, we found that amentoflavone, ginkgetin, and bilobetin have more hydroxyl groups in the structure, which were easy to form hydrogen bonds.…”

Hepatic, Extrahepatic and Extracellular Vesicle Cytochrome P450 2E1 in Alcohol and Acetaminophen-Mediated Adverse Interactions and Potential Treatment Options

“…The authors observed that ADI can suppress activities of several CYP enzymes, including CYP2E1, and may be used in combination with other therapeutic regimens. Moreover, an active constituent of Garcinia indica and Garcinia cambogia, Garcinol, causes herb-drug interaction by inhibiting CYPs involved in drug metabolism [ 109 ]. In a previous study by Trousil et al, the authors included healthy controls and ovarian cancer patients, and gave them caffeine, chlorzoxazone, dextromethorphan, and omeprazole as in vivo probes to analyze CYP activity.…”

Multidisciplinary Insights into the Structure–Function Relationship of the CYP2B6 Active Site

“…2,3',4,4',5-Pentachlorobiphenyl (CB118) is specifically stabilized within CYP2B6 through hydrophobic contacts of V104 and L363 with the 5'-and 2-positions of CB118, respectively (Mise et al, 2016). Molecular docking studies of herbal medicines such as sauchinone and garcinol have revealed similar contributions of the hydrophobic CYP2B6 active site residues to substrate binding (Gong et al, 2018;Bolla et al, 2021). Nearly all residues interacting with triclosan and 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) are nonpolar as well (Zhang et al, 2021).…”