Measurement of CYP1A2 and CYP3A4 activity by a simplified Geneva cocktail approach in a cohort of free-living individuals: a pilot study.

Autor:	Sobsey CA; Segal Cancer Proteomics Centre, Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montreal, QC, Canada.; Division of Experimental Medicine, Faculty of Medicine, McGill University, Montreal, QC, Canada., Mady N; Division of Experimental Medicine, Faculty of Medicine, McGill University, Montreal, QC, Canada.; Peter Brojde Lung Cancer Centre, Jewish General Hospital, Montreal, QC, Canada., Richard VR; Segal Cancer Proteomics Centre, Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montreal, QC, Canada., LeBlanc A; Segal Cancer Proteomics Centre, Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montreal, QC, Canada., Zakharov T; Division of Experimental Medicine, Faculty of Medicine, McGill University, Montreal, QC, Canada.; Peter Brojde Lung Cancer Centre, Jewish General Hospital, Montreal, QC, Canada., Borchers CH; Segal Cancer Proteomics Centre, Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montreal, QC, Canada.; Gerald Bronfman Department of Oncology, Jewish General Hospital, McGill University, Montreal, QC, Canada., Jagoe RT; Peter Brojde Lung Cancer Centre, Jewish General Hospital, Montreal, QC, Canada.; Department of Medicine, Jewish General Hospital, Montreal, QC, Canada.
Jazyk:	angličtina
Zdroj:	Frontiers in pharmacology [Front Pharmacol] 2024 Feb 02; Vol. 15, pp. 1232595. Date of Electronic Publication: 2024 Feb 02 (Print Publication: 2024).
DOI:	10.3389/fphar.2024.1232595
Abstrakt:	Introduction: The cytochrome P450 enzyme subfamilies, including CYP3A4 and CYP1A2, have a major role in metabolism of a range of drugs including several anti-cancer treatments. Many factors including environmental exposures, diet, diseaserelated systemic inflammation and certain genetic polymorphisms can impact the activity level of these enzymes. As a result, the net activity of each enzyme subfamily can vary widely between individuals and in the same individual over time. This variability has potential major implications for treatment efficacy and risk of drug toxicity, but currently no assays are available for routine use to guide clinical decision-making. Methods: To address this, a mass spectrometry-based method to measure activities of CYP3A4, CYP1A2 was adapted and tested in free-living participants. The assay results were compared with the predicted activity of each enzyme, based on a self-report tool capturing diet, medication, chronic disease state, and tobacco usage. In addition, a feasibility test was performed using a low-volume dried blood spots (DBS) on two different filter-paper supports, to determine if the same assay could be deployed without the need for repeated standard blood tests. Results: The results confirmed the methodology is safe and feasible to perform in free-living participants using midazolam and caffeine as test substrates for CYP3A4 and CYP1A2 respectively. Furthermore, though similar methods were previously shown to be compatible with the DBS format, the assay can also be performed successfully while incorporating glucuronidase treatment into the DBS approach. The measured CYP3A4 activity score varied 2.6-fold across participants and correlated with predicted activity score obtained with the self-report tool. The measured CYP1A2 activity varied 3.5-fold between participants but no correlation with predicted activity from the self-report tool was found. Discussion: The results confirm the wide variation in CYP activity between individuals and the important role of diet and other exposures in determining CYP3A4 activity. This methodology shows great potential and future cross-sectional and longitudinal studies using DBS are warranted to determine how best to use the assay results to guide drug treatments. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2024 Sobsey, Mady, Richard, LeBlanc, Zakharov, Borchers and Jagoe.)
Databáze:	MEDLINE
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