CYP2D6 metabolically inactivates several neurotoxins, including beta-carbolines, which are implicated in neurodegenerative diseases. Variation in CYP2D6 within the brain may alter local inactivation of neurotoxic beta-carbolines, thereby influencing neurotoxicity. The beta-carboline harmine, which induces hypothermia and tremor, is metabolized by CYP2D6 to the non-hypothermic/non-tremorgenic harmol. Transgenic mice (TG), expressing human CYP2D6 in addition to their endogenous mouse CYP2D, experience less harmine-induced hypothermia and tremor compared with wild-type mice (WT). We first sought to elucidate the role of CYP2D in general within the brain in harmine-induced hypothermia and tremor severity. A 4-h intracerebroventricular (ICV) pretreatment with the CYP2D inhibitor propranolol increased harmine-induced hypothermia and tremor in TG and increased harmine-induced hypothermia in WT. We next sought to specifically demonstrate that human CYP2D6 expressed in TG brain altered harmine response severity. A 24-h ICV propranolol pretreatment, which selectively and irreversibly inhibits human CYP2D6 in TG brain, increased harmine-induced hypothermia. This 24-h pretreatment had no impact on harmine response in WT, as propranolol is not an irreversible inhibitor of mouse CYP2D in the brain, thus confirming no off-target effects of ICV propranolol pretreatment. Human CYP2D6 activity in TG brain was sufficient in vivo to mitigate harmine-induced neurotoxicity. These findings suggest that human CYP2D6 in the brain is protective against beta-carboline-induced neurotoxicity and that the extensive interindividual variability in CYP2D6 expression in human brain may contribute to variation in susceptibility to certain neurotoxin-associated neurodegenerative disorders.

CYP2D6 在代谢上使几种神经毒素失活，包括与神经退行性疾病有关的 β-咔啉。脑内 CYP2D6 的变化可能会改变神经毒性 β-咔啉的局部失活，从而影响神经毒性。可诱导体温过低和震颤的 β-咔啉哈尔碱被 CYP2D6 代谢为非低温/非震颤的哈莫尔。与野生型小鼠 (WT) 相比，除了表达其内源性小鼠 CYP2D 外，还表达人 CYP2D6 的转基因小鼠 (TG) 经历较少的哈敏诱导的体温过低和震颤。我们首先试图阐明 CYP2D 在大脑中一般在有害碱引起的体温过低和震颤严重程度中的作用。用 CYP2D 抑制剂普萘洛尔进行 4 小时的脑室内 (ICV) 预处理增加了 TG 中harmine 诱导的低温和震颤，并增加了 WT 中harmine 诱导的低温。我们接下来试图具体证明在 TG 脑中表达的人类 CYP2D6 改变了有害反应的严重程度。24 小时 ICV 普萘洛尔预处理，选择性和不可逆地抑制 TG 脑中的人 CYP2D6，增加了哈敏诱导的体温过低。这种 24 小时预处理对 WT 中的harmine 反应没有影响，因为普萘洛尔不是大脑中小鼠 CYP2D 的不可逆抑制剂，因此证实 ICV 普萘洛尔预处理没有脱靶效应。TG 脑中的人 CYP2D6 活性在体内足以减轻有害物质诱导的神经毒性。