Informace o publikaci
The effect of the CB1 antagonist AM251 on cytochrome P450 enzymes in preclinical model
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| Rok publikování | 2025 |
| Druh | Konferenční abstrakty |
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| Popis | Introduction: The endocannabinoid system (ECS) plays a crucial role in regulating diverse physiological processes and has emerged as a promising therapeutic target. Cannabinoid-based medications have been approved for indications such as spasticity in multiple sclerosis, treatment-resistant epilepsy (e.g., Dravet syndrome, Lennox-Gastaut syndrome), chemotherapy-induced nausea and vomiting, and chronic pain. As these therapies become more widespread, understanding their interaction with the cytochrome P450 (CYP) enzymes—responsible for metabolizing many psychotropic and other drugs—is essential. However, the influence of ECS modulation on CYP enzyme activity remains largely unexplored, particularly regarding potential long-term effects and clinically relevant drug-drug interactions. Objectives: This study aimed to comprehensively assess the effects of the CB1 receptor antagonist AM251 on hepatic CYP enzymes in a rat model. Specifically, we investigated both in vitro effects using rat liver microsomes and in vivo effects following subchronic intraperitoneal administration, focusing on changes in metabolic activity and enzyme level to enhance the prediction of potential drug-drug interactions. Methods: In vitro experiments were performed using pooled liver microsomes from control drug-naive rats (n > 6) to evaluate the impact of AM251 on the activity of CYP1A2, CYP2D2, CYP3A, and CYP2C6. For enzymes significantly inhibited by AM251, detailed studies were conducted to determine IC50 and Ki values. In vivo, rats received intraperitoneal AM251 at doses of 0.2, 1, and 5 mg/kg body weight daily for seven days; the vehicle-treated group served as the control, and phenobarbital was used as a positive control. After treatment, liver samples were collected for isolation of microsomal fractions to assess CYP metabolic activity using isoform-selective substrates. Proteomic quantification of CYP enzymes and specific transporters was performed using targeted LC-MS analysis. Results: AM251 reduced the activity of CYP1A2, CYP2D2, and CYP2C6 in vitro, with Ki values below 50 µM, indicating significant inhibitory potential. In contrast, in vivo administration caused a significant, dose-dependent increase in CYP1A2 metabolic activity. Quantitative proteomic analysis of liver tissue confirmed a dose-dependent increase in CYP1A2 protein levels, corresponding to the enhanced metabolic activity, and revealed a significant elevation of CYP2D2 protein levels in the group receiving the lowest cannabinoid dose. No significant changes were observed for CYP3A, suggesting selective modulation of specific CYP isoforms by AM251. Conclusion: This study demonstrates that AM251 inhibits selected CYP enzymes in vitro but enhances their activity and expression in vivo, particularly CYP1A2. The in vivo induction of CYP1A2 may be mediated by activation of the aryl hydrocarbon receptor (AhR)1, though further mechanistic studies are warranted. These findings highlight the potential of endocannabinoid system modulation to influence drug metabolism, emphasizing the need to consider ECS-CYP interactions in the development and safety evaluation of pharmacotherapy. Acknowledgements: This work was supported by the Start-up Grant MUNI/LF-SUp/1365/2023 and the Specific University Research Grant (MUNI/A/1722/2024), funded by the Czech Ministry of Education, Youth and Sports. 1. Solino, M. et al. CB1 Cannabinoid Receptor is a Target for Neuroprotection in Light Induced Retinal Degeneration. Adv. Drug Alcohol Res. 2, 10734 (2022). |