![]() ![]() ![]() ![]() Caffeine is often used to improve physical and/or cognitive performance in humans ( Glade, 2010). The caffeine consumption level would be higher if energy drinks, fitness supplements, and caffeine-containing drugs were included in the estimation ( Goldstein et al., 2010 Lipton et al., 2017). About 100 mg of caffeine is consumed by each person daily in the form of coffee, tea and/or cocoa ( FAOSTAT, 2009). IntroductionĬaffeine ( Figure 1) is a popular human stimulant. The long inhibitory effects of ARFP on caffeine metabolism are explainable by CYP 1A2 inactivation.Individual furanocoumarin chemicals inactivate CYP 1A2 enzyme in a time- and concentration-dependent manner which indicates involvement of the irreversible inhibition mechanism.The degree of caffeine metabolism inhibition is linearly related to an increasing effect-based dose of the furanocoumarin mixture in the ARFP extracts.A single oral dose of an ARFP extract administered to humans 3 h before is still able to inhibit caffeine metabolizing activity.As a result, a single oral dose of ARFP extract administered to the human volunteers 3.0 h before still was able to inhibit caffeine metabolism. Once the CYP1A2 isozyme was deactivated, the enzymic activity could only be regained by isozyme re-synthesis which took a long time. Thus, furanocoumarin bioactive metabolism in humans would result in reactive metabolite(s) formation inactivating CYP1A2 isozyme and inhibiting caffeine metabolism. The formation of 14C-adducts due to 14C-8-MOP-derived radioactivity bound to HLMs confirmed the irreversible inhibition of CYP1A2 activity. The proposed irreversible inhibition mechanism was investigated further using 14C-labeled 8-methoxypsoralen and HLMs. ![]() In addition, CYP1A2 inactivation by individual furanocoumarin bioactive was concentration- and time-dependent involving the irreversible inhibition mechanism. In vitro incubation studies also showed individual furanocoumarin bioactive were potent inhibitors of caffeine-N-demethylation the IC 50 for 8-methoxypsoralen 5-methoxypsoralen, and isopimpinellin were 0.09, 0.13, and 0.29 µM, respectively. The increases in AUC 0-inf ratio also were linearly related to the effect-based doses of the furanocoumarins in the ARFP extracts, a finding which indicated caffeine metabolism inhibition was related to the content of furanocoumarin bioactive in an ARFP product. The study results showed pre-treatment of volunteers with four ARFP extracts increased the area-under-the-concentration-time-curve (AUC 0-inf) ratio of caffeine in the plasma ranging from 1.3 to 4.3-fold compared to the untreated volunteers indicating significant caffeine metabolism inhibition. The objectives of the present study were to study in vivo loss of caffeine metabolizing activity by comparing the pharmacokinetics of caffeine in volunteers before and after pre-treatment with an ARFP extract, study the correlation between the decrease in hepatic CYP1A2 activity and the content of furanocoumarin bioactive in ARFP extracts, characterize CYP1A2 inactivation using in vitro incubations containing 14C-caffeine, a furanocoumarin bioactive, and human liver microsomes (HLMs), and provide a mechanistic explanation for both in vivo and in vitro data using the irreversible inhibition mechanism. As both caffeine and furanocoumarin bioactive are metabolized by the same hepatic CYP1A1/2 isozyme in humans, caffeine/ARFP product interactions may occur after co-administration. We previously reported significant amounts of furanocoumarin bioactive such as 8-methoxypsoralen, 5-methoxypsoralen, and isopimpinellin in ARFP products. The Apiaceous and Rutaceae families of plant (ARFP) products are popular foods and medicines in the world. 5Department of Biological Sciences, Faculty of Science, Simon Fraser University, Burnaby, BC, Canadaĭaily consumption of caffeinated beverages is considered safe but serious health consequences do happen in some individuals.4Life Sciences Division, SGS Canada Inc., Mississauga, ON, Canada.3Ministry of National Guard ‐ Health Affairs, Riyadh, Saudi Arabia.2King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia.1Department of Medical Research Core Facility and Platforms, King Abdullah International Medical Research Center, Riyadh, Saudi Arabia.Zeyad Alehaideb 1,2,3*, Mohamed Sheriffdeen 4 and Francis C. ![]()
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