title: Potential role of CYP2D6 in the central nervous system.
abstract: 1. Cytochrome P450 2D6 (CYP2D6) is a pivotal enzyme responsible for a major drug oxidation polymorphism in human populations. Distribution of CYP2D6 in brain and its role in serotonin metabolism suggest that CYP2D6 may have a function in the central nervous system. 2. To establish an efficient and accurate platform for the study of CYP2D6 in vivo, a human CYP2D6 (Tg-2D6) model was generated by transgenesis in wild-type (WT) C57BL/6 mice using a P1 phage artificial chromosome clone containing the complete human CYP2D locus, including the CYP2D6 gene and 5'- and 3'-flanking sequences. 3. Human CYP2D6 was expressed not only in the liver but also in the brain. The abundance of serotonin and 5-hydroxyindoleacetic acid in brain of Tg-2D6 is higher than in WT mice, either basal levels or after harmaline induction. Metabolomics of brain homogenate and cerebrospinal fluid revealed a significant up-regulation of L-carnitine, acetyl-L-carnitine, pantothenic acid, 2'-deoxycytidine diphosphate (dCDP), anandamide, N-acetylglucosaminylamine and a down-regulation of stearoyl-L-carnitine in Tg-2D6 mice compared with WT mice. Anxiety tests indicate Tg-2D6 mice have a higher capability to adapt to anxiety. 4. Overall, these findings indicate that the Tg-2D6 mouse model may serve as a valuable in vivo tool to determine CYP2D6-involved neurophysiological metabolism and function.
authors.affiliation: Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health , Bethesda, MD , USA .
authors.forename: Jie
authors.initials: J
authors.lastname: Cheng
authors.forename: Yueying
authors.initials: Y
authors.lastname: Zhen
authors.forename: Sharon
authors.initials: S
authors.lastname: Miksys
authors.forename: Diren
authors.initials: D
authors.lastname: Beyoğlu
authors.forename: Kristopher W
authors.initials: KW
authors.lastname: Krausz
authors.forename: Rachel F
authors.initials: RF
authors.lastname: Tyndale
authors.forename: Aiming
authors.initials: A
authors.lastname: Yu
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Idle
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D002490:Central Nervous System / Q000201:enzymology*; D002555:Cerebrospinal Fluid / Q000378:metabolism; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism*; D016002:Discriminant Analysis; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008099:Liver / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010641:Phenotype; D025341:Principal Component Analysis; D012701:Serotonin / Q000378:metabolism; D014018:Tissue Distribution; D019076:Transgenes; D014556:Urine
chemical_list: D012701:Serotonin; D019389:Cytochrome P-450 CYP2D6