Potential role of CYP2D6 in the central nervous system

Jie Cheng, Yueying Zhen, Sharon Miksys, Diren Beyoǧlu, Kristopher W. Krausz, Rachel F. Tyndale, Aiming Yu, Jeffrey R. Idle, Frank J. Gonzalez

Research output: Contribution to journalArticle

37 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)973-984
Number of pages12
JournalXenobiotica
Volume43
Issue number11
DOIs
StatePublished - Nov 2013
Externally publishedYes

Keywords

  • Anxiety
  • Brain
  • CYP2D6
  • Serotonin

ASJC Scopus subject areas

  • Pharmacology
  • Toxicology
  • Biochemistry
  • Health, Toxicology and Mutagenesis

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  • Cite this

    Cheng, J., Zhen, Y., Miksys, S., Beyoǧlu, D., Krausz, K. W., Tyndale, R. F., Yu, A., Idle, J. R., & Gonzalez, F. J. (2013). Potential role of CYP2D6 in the central nervous system. Xenobiotica, 43(11), 973-984. https://doi.org/10.3109/00498254.2013.791410