Potential role of CYP2D6 in the central nervous system. (November 2013)

• Record Type: Journal Article
• Authors: Cheng, Jie; Zhen, Yueying; Miksys, Sharon; Beyoğlu, Diren; Krausz, Kristopher W.; Tyndale, Rachel F.; Yu, Aiming; Idle, Jeffrey R.; Gonzalez, Frank J.
• Is Part Of: Xenobiotica. Volume 43:Number 11(2013:Nov.)
• Page Start: 973
• Page End: 984
• Publication Date: 2013-11
• Subjects: Metabolism -- Periodicals; Drugs -- Physiological effect -- Periodicals; Food additives -- Periodicals; Chemicals -- Physiological effect -- Periodicals; Biochemistry -- Periodicals; Pharmaceutical Preparations -- metabolism -- Periodicals; Metabolism -- Periodicals; 574.133
• DOI: 10.3109/00498254.2013.791410
• Languages: English
• ISSNs: 0049-8254

Abstract

<abstract> <title>Abstract</title> <p>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.</p> <p>2. To establish an efficient and accurate platform for the study of CYP2D6 <italic>in vivo</italic>, 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 <italic>CYP2D6</italic> gene and 5′- and 3′-flanking sequences.</p> <p>3. Human <italic>CYP2D6</italic> 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, <italic>N</italic>-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.</p> <p>4. Overall, these findings indicate that the Tg-2D6 mouse model may serve as a valuable <italic>in vivo</italic> tool to determine CYP2D6-involved neurophysiological metabolism and function.</p> </abstract>