Department of Pharmacology and Toxicology, University of Toronto, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH), Toronto, Ontario, Canada.
Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Mol Neurobiol. 2020 Jun;57(6):2509-2520. doi: 10.1007/s12035-020-01896-4. Epub 2020 Mar 18.
CYP2D metabolizes many drugs that act within the brain, and variable expression of CYP2D in the brain may alter local drug and metabolite levels sufficiently to affect behavioral responses. Transgenic mice that express human CYP2D6 (TG) were compared to wild type mice (WT). Following selective inhibition of human CYP2D6 in TG brain, we demonstrated in vivo that human CYP2D6 in the brain was sufficient to alter a drug-induced behavioral response. After a 4-h pre-treatment with intracerebroventricular (i.c.v.) propranolol, CYP2D activity in vivo and in vitro was reduced in TG brain, whereas CYP2D activity in vivo, but not in vitro, was reduced in WT brain. After a 24-h pre-treatment with i.c.v. propranolol, CYP2D activity in vivo and in vitro was reduced in TG brain, whereas CYP2D activity in vivo and in vitro was not changed in WT brain. These results indicate that i.c.v. propranolol irreversibly inhibited human CYP2D6 in TG brain but not mouse CYP2D in TG and WT brain. Pre-treatments with propranolol did not change liver CYP2D activity in vivo or in vitro. Furthermore, 24-h pre-treatment with i.c.v. propranolol resulted in a significant decrease of the haloperidol-induced catalepsy response in TG, but not in WT, without changing serum haloperidol levels in either mouse line. These studies reveal a new tool to selectively and irreversibly inhibit human CYP2D6 in TG brain and indicate that human CYP2D6 has a functional role within the brain sufficient to impact the central nervous system response from peripherally administered drugs.
CYP2D 代谢许多作用于大脑的药物，大脑中 CYP2D 的表达可变可能足以改变局部药物和代谢物水平，从而影响行为反应。与野生型小鼠（WT）相比，表达人 CYP2D6 的转基因小鼠（TG）。在 TG 脑内选择性抑制人 CYP2D6 后，我们在体内证明脑内人 CYP2D6 足以改变药物诱导的行为反应。用脑室（i.c.v.）给予普萘洛尔预处理 4 小时后，TG 脑内 CYP2D 活性在体内和体外均降低，而 WT 脑内 CYP2D 活性仅在体内降低，而不在体外降低。用 i.c.v.给予普萘洛尔预处理 24 小时后，TG 脑内 CYP2D 活性在体内和体外均降低，而 WT 脑内 CYP2D 活性在体内和体外均不变。这些结果表明，脑室给予普萘洛尔不可逆地抑制 TG 脑内的人 CYP2D6，但不抑制 TG 和 WT 脑内的鼠 CYP2D。普萘洛尔预处理不改变体内或体外的肝 CYP2D 活性。此外，脑室给予普萘洛尔预处理 24 小时导致 TG 中氟哌啶醇诱导的僵住反应显著降低，但 WT 中无变化，两种小鼠品系的血清氟哌啶醇水平均无变化。这些研究揭示了一种新的工具，可以选择性和不可逆地抑制 TG 脑内的人 CYP2D6，并表明人 CYP2D6 在大脑内具有足够的功能作用，足以影响外周给予药物的中枢神经系统反应。
