Potential role of CYP2D6 in the central nervous system

Xenobiotica. 2013 Nov;43(11):973-84. doi: 10.3109/00498254.2013.791410. Epub 2013 Apr 25.

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.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Behavior, Animal
  • Central Nervous System / enzymology*
  • Cerebrospinal Fluid / metabolism
  • Cytochrome P-450 CYP2D6 / metabolism*
  • Discriminant Analysis
  • Female
  • Humans
  • Immunohistochemistry
  • Liver / enzymology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Phenotype
  • Principal Component Analysis
  • Serotonin / metabolism
  • Tissue Distribution
  • Transgenes
  • Urine

Substances

  • Serotonin
  • Cytochrome P-450 CYP2D6