The polymorphic drug-metabolizing enzyme CYP2D6, which is responsible for the metabolism of most psychoactive compounds, is expressed not only in the liver, but also in the brain. The effects of its marked genetic polymorphism on the individual capacity to metabolize drugs are well known, but its role in metabolism of neural substrates affecting behavior personality or cognition, suggested by its CNS expression, is a long-standing unresolved issue. To verify earlier findings suggesting a potential effect on attentional processes, we collected functional imaging data while N=415 participants performed a simple task in which the reward for correct responses varied. CYP2D6 allelic variants predicting higher levels of enzymatic activity level were positively associated with cortical activity in occipito-parietal areas as well as in a right lateralized network known to be activated by spatial attentional tasks. Reward-related modulation of activity in cortical areas was more pronounced in poor metabolizers. In conjunction with effects on reaction times, our findings provide evidence for reduced cognitive efficiency in rapid metabolizers compared to poor metabolizers in on-task attentional processes manifested through differential recruitment of a specific neural substrate.

中文翻译：

---

CYP2D6基因变异对任务活动期间持续注意的神经基质的影响

负责大多数精神活性化合物代谢的多态性药物代谢酶CYP2D6不仅在肝脏中表达，而且在大脑中表达。其明显的遗传多态性对个体代谢药物的能力的影响是众所周知的，但是其在CNS表达所暗示的影响行为个性或认知的神经底物的代谢中的作用是一个长期未解决的问题。为了验证较早的发现暗示对注意过程可能产生影响，我们收集了功能成像数据，同时N = 415名参与者执行了一项简单的任务，其中正确答案的奖励有所不同。CYP2D6等位基因变异体预测较高的酶活性水平与枕叶顶区以及已知由空间注意任务激活的右侧外侧网络中的皮质活性正相关。在不良代谢者中，与皮质相关的活动的奖励相关调节更为明显。结合对反应时间的影响，我们的发现提供了证据，表明与通过特定神经底物的差异募集而表现出来的在职注意过程中不良代谢者相比，快速代谢者认知效率降低。