Cytochrome P450 2D6 (CYP2D6) is primarily expressed in the liver and in the central nervous system. It is known to be highly polymorphic in nature. It metabolizes several endogenous substrates such as anandamide (AEA). Concomitantly, it is involved in phase 1 metabolism of several antidepressants, antipsychotics, and other drugs. Research in the field of phytocannabinoids (pCBs) has recently accelerated owing to their legalization and increasing medicinal use for pain and inflammation. The primary component of cannabis is THC, which is well-known for its psychotropic effects. Since CYP2D6 is an important brain and liver P450 and is known to be inhibited by CBD, we investigated the interactions of four important highly prevalent CYP2D6 polymorphisms with selected phytocannabinoids (CBD, THC, CBDV, THCV, CBN, CBG, CBC, β-carophyllene) that are rapidly gaining popularity. We show that there is differential binding of CYP2D6*17 to pCBs as compared to WT CYP2D6. We also perform a more detailed comparison of WT and *17 CYP2D6, which reveals the possible regulation of AEA metabolism by CBD. Furthermore, we use molecular dynamics to delineate the mechanism of this binding, inhibition, and regulation. Taken together, we have found that the interactions of CYP2D6 with pCBs vary by polymorphism and by specific pCB class.

中文翻译：

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选定的植物大麻素与人类 CYP2D6 多态性的差异相互作用

细胞色素 P450 2D6 (CYP2D6) 主要在肝脏和中枢神经系统中表达。众所周知，它在性质上是高度多态的。它代谢多种内源性底物，例如 anandamide (AEA)。同时，它参与了几种抗抑郁药、抗精神病药和其他药物的第一阶段代谢。由于植物大麻素 (pCB) 的合法化以及治疗疼痛和炎症的药用越来越多，植物大麻素 (pCB) 领域的研究最近加速了。大麻的主要成分是 THC，它以其精神作用而闻名。由于 CYP2D6 是一种重要的大脑和肝脏 P450，并且已知会被 CBD 抑制，我们研究了四种重要的高度流行的 CYP2D6 多态性与选定的植物大麻素（CBD、THC、CBDV、THCV、CBN、CBG、CBC、β-胡萝卜素）迅速普及。我们表明，与 WT CYP2D6 相比，CYP2D6*17 与 pCB 的结合存在差异。我们还对 WT 和 *17 CYP2D6 进行了更详细的比较，揭示了 CBD 对 AEA 代谢的可能调节。此外，我们使用分子动力学来描述这种结合、抑制和调节的机制。总之，我们发现 CYP2D6 与 pCB 的相互作用因多态性和特定 pCB 类别而异。