CYP2D in the Brain Alters Response to Drugs and Neurotoxins

Cytochrome P450 2D (CYP2D) is a subfamily of enzymes that metabolize many centrally acting drugs and neurotoxins. In humans, CYP2D6 is genetically polymorphic, resulting in variable activity. CYP2D in the liver is regulated primarily by genetics, while CYP2D in the brain is affected by genetics and other factors, including xenobiotic induction and hormonal regulation. Thus, CYP2D in the brain is highly variable and may alter brain drug concentrations and drug response. This thesis investigated the impact of inhibiting CYP2D specifically in the brain, without affecting CYP2D in the liver, on brain drug metabolism and resulting responses. CYP2D in rat brain was inhibited using a twenty-hour intracerebroventricular pretreatment with an irreversible inhibitor of CYP2D. We found that inhibiting CYP2D in rat brain increased brain methamphetamine concentrations and decreased the methamphetamine p-hydroxylation metabolic ratio in the brain, enhanced striatal dopamine and serotonin release, exacerbated acute methamphetamine-induced rearing, and enhanced repeated methamphetamine-induced stereotypy sensitization. Next, to assess the role of human CYP2D6 in brain in vivo, humanized CYP2D6-expressing transgenic mice and wild-type mice were given intracerebroventricular pretreatments with a CYP2D inhibitor. A four-hour inhibitor pretreatment irreversibly inhibited human CYP2D6 in transgenic brain and competitively inhibited mouse CYP2D in transgenic and wild-type brain. This four-hour inhibitor pretreatment exacerbated harmine-induced hypothermia and tremor in transgenic mice and exacerbated only hypothermia in wild-type mice. A twenty-four-hour inhibitor pretreatment irreversibly inhibited human CYP2D6 in transgenic brain only and was thus used to test the specific contribution of human CYP2D6 in vivo in brain. The twenty-four-hour inhibitor pretreatment exacerbated harmine-induced hypothermia in transgenic mice, having no effect in wild-type mice. Confirming an impact of human CYP2D6 in brain, the twenty-four-hour inhibitor pretreatment also reduced haloperidol-induced catalepsy in transgenic mice. We demonstrated that CYP2D in rat brain alters brain methamphetamine concentrations and methamphetamine-induced neurotransmitter release and behavioral sensitization. Further, we demonstrated that human CYP2D6 is active in vivo in brain, and its activity is sufficient to alter haloperidol-induced adverse effects and harmine-induced neurotoxicity. In conclusion, the extensive variation in CYP2D6 in the human brain may contribute to interindividual differences in drug-induced neurochemical and behavioral responses, adverse effects, and neurotoxicity.Ph.D