Harmane inhibits hepatic cytochrome P450 enzymes in rats.

INTRODUCTION: Harmane (HAR) is a beta-carboline alkaloid found in plants, heat-processed foods, and tobacco. It is an active component of widely used antidepressant and anxiolytic herbs. In this study, we investigate the effects of HAR on rat CYP enzymes both in vivo and in vitro and examine the interactions between HAR and human CYP enzymes through in silico methods. METHODS: The impact of subchronic premedication with HAR at doses of 25, 40, and 64 mg/kg on CYP enzyme activity was evaluated in rats using CYP-specific probe substrates of CYP1A2, CYP2A, CYP2B, CYP2C6, CYP2C11, CYP2D1/2, and CYP3A1/2. In vitro inhibitory assays of HAR were conducted. Finally, HAR was docked in silico into human CYP enzyme active sites. RESULTS AND DISCUSSION: HAR premedication significantly decreased the protein content and metabolic activity of rat CYP2B1, CYP2C11, CYP2D1/2, and CYP3A1/2. In vitro, HAR showed moderate inhibition of CYP2A1 and CYP3A1/2 (IC50 values of 14.0 and 1.2 µM, respectively) and no inhibition of the other enzymes tested. In silico docking studies with human CYP enzymes confirmed that HAR has the potential for CYP-mediated drug-drug inhibitory interactions. In summary, HAR significantly inhibited the activities of several drug-metabolizing CYP enzymes in the preclinical model. These findings suggest the need for further research into HAR's pharmacokinetic interactions.