CYP2D is Functional in the Brain and Alters Haloperidol-induced Side Effects

The human cytochrome P450 2D6 (CYP2D6) enzyme metabolizes numerous neurotoxins and centrally-acting drugs, including first generation antipsychotics such as haloperidol. These antipsychotics are used to treat schizophrenia and can cause adverse events in patients following acute and chronic intake. CYP2D6 expression in the liver is essentially uninducible and is regulated by genetics, whereas CYP2D6 expression in the brain is dependent on many factors, including CYP2D6 genetic variation, brain-specific induction of CYP2D6, and drug-drug interactions. Variation in human CYP2D6 activity in the brain may alter local drug and metabolite levels sufficiently to change drug response, including therapeutic efficacy and adverse events. This thesis investigated the impact of brain-specific manipulation of CYP2D on haloperidol-induced responses. CYP2D in rat brain (but not in rat liver) was inhibited by 24-hour pre-treatment with intracerebroventricular propranolol and induced by 7-day subcutaneous nicotine treatment. We found that acute haloperidol-induced catalepsy was decreased after inhibiting, and increased after inducing, CYP2D selectively in rat brain. In contrast, chronic haloperidol-induced vacuous chewing movements were increased after inhibiting, and decreased after inducing, CYP2D selectively in rat brain. Further, we investigated human CYP2D6 drug metabolism in vivo using CYP2D6-transgenic mice (TG) which express human CYP2D6 and mouse CYP2D, and in wildtype mice (WT). Mouse CYP2D and human CYP2D6 in TG liver, and mouse CYP2D in WT liver, were inhibited by 24-hour pre-treatment with intraperitoneal propranolol. In contrast, a 24-hour pre-treatment with intracerebroventricular propranolol irreversibly inhibited human CYP2D6 in TG brain, but not mouse CYP2D in TG or WT brain; there was no inhibition of hepatic CYP2D in TG or WT. Brain-specific inhibition of human CYP2D6 in TG brain reduced acute haloperidol-induced catalepsy, without affecting plasma haloperidol levels. This thesis demonstrated that CYP2D, including human CYP2D6, in the brain plays a role in in vivo haloperidol-induced responses. We have developed a new tool that enables the investigation of human CYP2D6 in brain on in vivo drug-response. In conclusion, we demonstrated that human CYP2D6 in the brain is functional and sufficiently able to alter drug-induced behaviour, suggesting a role in altering therapeutic efficacy and adverse events in humans.Ph.D