Human CYP2D6 in the Brain Is Protective Against Harmine-Induced Neurotoxicity: Evidence from Humanized CYP2D6 Transgenic Mice.

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.

Human CYP2D6 Is Functional in Brain In Vivo: Evidence from Humanized CYP2D6 Transgenic Mice.

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.