Amalgamation of in-silico, in-vitro and in-vivo approach to establish glabridin as a potential CYP2E1 inhibitor

Abstract

1. CYP2E1 is directly or indirectly involved in the metabolism of ethanol and endogenous fatty acids but it plays a major role in the bio-activation of toxic substances that produce reactive metabolites leading to hepatotoxicity. Therefore, identification of CYP2E1 inhibitor from bioflavonoids class having useful pharmacological properties has dual benefit regarding avoidance of severe food-drug/nutraceutical-drug interaction and scope to develop a phytotherapeutics through an intended pharmacokinetic interaction.

2. In the present study, we aimed to identify CYP2E1 inhibitor from experimental bioflavonoids which are unexplored for CYP2E1 inhibition till date using in-silico, in-vitro and in-vivo approaches.

3. Results of in-vitro CYP2E1 inhibitory studies using CYP2E1-mediated chlorzoxazone 6-hydroxylation in human liver microsomes showed that glabridin have the highest potential than fisetin, epicatechin, nobiletin, and chrysin to inhibit CYP2E1 enzyme. Mechanistic investigations indicate that glabridin is a competitive CYP2E1 inhibitor. Molecular docking study results demonstrate that glabridin strongly interacted with the active site of human CYP2E1 enzyme. Pharmacokinetics of a CYP2E1 substrate in mice model indicates a significant alteration of chlorzoxazone and 6-hydroxychlorzoxazone plasma levels in the presence of glabridin. Further studies are needed to confirm the results at clinical level.

4. Overall, glabridin is found to be a potential CYP2E1 inhibitor.

Keywords:

• Glabridin
• CYP2E1 inhibitor
• bioflavonoids
• pharmacokinetic interaction
• nutraceutical-drug interaction

Correction Statement

This article has been republished with minor changes. These changes do not impact the academic content of the article.

Acknowledgments

Authors are grateful to Director, CSIR-IIIIM for necessary support to carry out this research work. SB and AD are thankful to CSIR and UGC (New Delhi, India), respectively for providing their research fellowship. IIIM publication number: CSIR-IIIM/IPR/00251.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This research work was supported by Phytopharmaceutical Mission Project (HCP0010), Council of Scientific and Industrial Research, New Delhi, India.