Potential role of CYP2D6 in the central nervous system

Cheng, Jie; Zhen, Yueying; Miksys, Sharon; Beyoglu, Diren; Krausz, Kristopher W.; Tyndale, Rachel F.; Yu, Aiming; Idle, Jeffrey R.; Gonzalez, Frank J. (2013). Potential role of CYP2D6 in the central nervous system. Xenobiotica, 43(11), pp. 973-984. Informa Healthcare 10.3109/00498254.2013.791410

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Gastro-intestinal, Liver and Lung Disorders (DMLL) > Clinic of Visceral Surgery and Medicine > Hepatology
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Hepatologie
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Hepatologie

UniBE Contributor:

Beyoglu, Diren and Idle, Jeffrey

Subjects:

600 Technology > 610 Medicine & health

ISSN:

0049-8254

Publisher:

Informa Healthcare

Language:

English

Submitter:

Lilian Karin Smith-Wirth

Date Deposited:

18 Jun 2014 09:17

Last Modified:

06 Nov 2015 09:50

Publisher DOI:

10.3109/00498254.2013.791410

PubMed ID:

23614566

BORIS DOI:

10.7892/boris.53763

URI:

https://boris.unibe.ch/id/eprint/53763

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