Alehaideb Zeyad, Sheriffdeen Mohamed, Law Francis C P
Department of Medical Research Core Facility and Platforms, King Abdullah International Medical Research Center, Riyadh, Saudi Arabia.
King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia.
Front Pharmacol. 2021 Apr 29;12:641090. doi: 10.3389/fphar.2021.641090. eCollection 2021.
Daily consumption of caffeinated beverages is considered safe but serious health consequences do happen in some individuals. The and families of plant (ARFP) products are popular foods and medicines in the world. We previously reported significant amounts of furanocoumarin bioactive such as 8-methoxypsoralen, 5-methoxypsoralen, and isopimpinellin in ARFP products. 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. The objectives of the present study were to study 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 incubations containing C-caffeine, a furanocoumarin bioactive, and human liver microsomes (HLMs), and provide a mechanistic explanation for both and data using the irreversible inhibition mechanism. The study results showed pre-treatment of volunteers with four ARFP extracts increased the area-under-the-concentration-time-curve (AUC) 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 increases in AUC 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. incubation studies also showed individual furanocoumarin bioactive were potent inhibitors of caffeine-N-demethylation; the IC for 8-methoxypsoralen 5-methoxypsoralen, and isopimpinellin were 0.09, 0.13, and 0.29 µM, respectively. In addition, CYP1A2 inactivation by individual furanocoumarin bioactive was concentration- and time-dependent involving the irreversible inhibition mechanism. The proposed irreversible inhibition mechanism was investigated further using C-labeled 8-methoxypsoralen and HLMs. The formation of C-adducts due to C-8-MOP-derived radioactivity bound to HLMs confirmed the irreversible inhibition of CYP1A2 activity. Thus, furanocoumarin bioactive metabolism in humans would result in reactive metabolite(s) formation inactivating CYP1A2 isozyme and inhibiting caffeine metabolism. Once the CYP1A2 isozyme was deactivated, the enzymic activity could only be regained by isozyme re-synthesis which took a long time. 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.
每日饮用含咖啡因的饮料被认为是安全的，但在一些个体中确实会发生严重的健康后果。植物（ARFP）产品的 和 家族是世界上受欢迎的食品和药物。我们之前报道过ARFP产品中含有大量呋喃香豆素生物活性成分，如8-甲氧基补骨脂素、5-甲氧基补骨脂素和异茴芹内酯。由于咖啡因和呋喃香豆素生物活性成分在人体内均由相同的肝脏CYP1A1/2同工酶代谢，联合给药后可能会发生咖啡因/ARFP产品相互作用。本研究的目的是通过比较志愿者在接受ARFP提取物预处理前后咖啡因的药代动力学来研究咖啡因代谢活性的丧失，研究肝脏CYP1A2活性降低与ARFP提取物中呋喃香豆素生物活性成分含量之间的相关性，使用含有C-咖啡因、一种呋喃香豆素生物活性成分和人肝微粒体（HLMs）的孵育体系来表征CYP1A2的失活，并使用不可逆抑制机制为 和 数据提供机理解释。研究结果表明，与未处理的志愿者相比，用四种ARFP提取物预处理志愿者后，血浆中咖啡因的浓度-时间曲线下面积（AUC）比值增加了1.3至4.3倍，表明咖啡因代谢受到显著抑制。AUC比值的增加也与ARFP提取物中基于效应的呋喃香豆素剂量呈线性相关，这一发现表明咖啡因代谢抑制与ARFP产品中呋喃香豆素生物活性成分的含量有关。孵育研究还表明，单个呋喃香豆素生物活性成分是咖啡因-N-去甲基化的有效抑制剂；8-甲氧基补骨脂素、5-甲氧基补骨脂素和异茴芹内酯的IC分别为0.09、0.13和0.29 μM。此外，单个呋喃香豆素生物活性成分对CYP1A2的失活具有浓度和时间依赖性，涉及不可逆抑制机制。使用C标记的8-甲氧基补骨脂素和HLMs进一步研究了所提出的不可逆抑制机制。由于C-8-MOP衍生的放射性与HLMs结合形成C-加合物，证实了CYP1A2活性的不可逆抑制。因此，人类体内呋喃香豆素生物活性成分的代谢会导致活性代谢物的形成，从而使CYP1A2同工酶失活并抑制咖啡因代谢。一旦CYP1A2同工酶失活，酶活性只能通过同工酶的重新合成来恢复，这需要很长时间。因此，在给人类志愿者口服ARFP提取物前3.0小时，单次口服剂量仍能够抑制咖啡因代谢。
