INSERM U 1129, Pediatric Neurology, Necker-Enfants Malades Hospital, University of Paris Descartes, Inserm U1129, Paris, France
Pharmacol Rev. 2018 Apr;70(2):384-411. doi: 10.1124/pr.117.014407. Epub 2018 Mar 7.
Most individuals adjust their caffeine intake according to the objective and subjective effects induced by the methylxanthine. However, to reach the desired effects, the quantity of caffeine consumed varies largely among individuals. It has been known for decades that the metabolism, clearance, and pharmacokinetics of caffeine is affected by many factors such as age, sex and hormones, liver disease, obesity, smoking, and diet. Caffeine also interacts with many medications. All these factors will be reviewed in the present document and discussed in light of the most recent data concerning the genetic variability affecting caffeine levels and effects at the pharmacokinetic and pharmacodynamic levels that both critically drive the level of caffeine consumption. The pharmacokinetics of caffeine are highly variable among individuals due to a polymorphism at the level of the CYP1A2 isoform of cytochrome P450, which metabolizes 95% of the caffeine ingested. Moreover there is a polymorphism at the level of another critical enzyme, -acetyltransferase 2. At the pharmacodynamic level, there are several polymorphisms at the main brain target of caffeine, the adenosine A2A receptor or ADORA2. Genetic studies, including genome-wide association studies, identified several loci critically involved in caffeine consumption and its consequences on sleep, anxiety, and potentially in neurodegenerative and psychiatric diseases. We start reaching a better picture on how a multiplicity of biologic mechanisms seems to drive the levels of caffeine consumption, although much more knowledge is still required to understand caffeine consumption and effects on body functions.
大多数人会根据甲基黄嘌呤引起的客观和主观效果来调整咖啡因的摄入量。然而，为了达到预期的效果，每个人消耗的咖啡因量差异很大。几十年来，人们已经知道咖啡因的代谢、清除和药代动力学受到许多因素的影响，如年龄、性别和激素、肝脏疾病、肥胖、吸烟和饮食。咖啡因还与许多药物相互作用。所有这些因素都将在本文件中进行审查，并根据最近关于影响咖啡因水平和药代动力学和药效动力学水平的遗传变异的数据进行讨论，这些因素都对咖啡因的消耗水平起着至关重要的作用。由于细胞色素 P450 中 CYP1A2 同工酶水平的多态性，咖啡因的药代动力学在个体之间存在很大差异，这种同工酶代谢了摄入的咖啡因的 95%。此外，在另一个关键酶——乙酰基转移酶 2 的水平上也存在多态性。在药效动力学水平上，咖啡因的主要脑靶标腺苷 A2A 受体或 ADORA2 存在多个多态性。遗传研究，包括全基因组关联研究，确定了几个与咖啡因消耗及其对睡眠、焦虑的影响，以及潜在的神经退行性和精神疾病密切相关的关键位点。我们开始对多种生物学机制似乎如何驱动咖啡因消耗水平有了更好的了解，尽管要了解咖啡因的消耗及其对身体功能的影响，还需要更多的知识。
