Regional and cellular expression of CYP2D6 in human brain: Higher levels in alcoholics

Sharon Miksys, Yushu Rao, Ewa Hoffmann, Deborah C Mash, Rachel F. Tyndale

Research output: Contribution to journalArticle

109 Citations (Scopus)

Abstract

Cytochrome P450 (CYP) 2D6 is expressed in liver, brain and other extrahepatic tissues where it metabolizes a range of centrally acting drugs and toxins. As ethanol can induce CYP2D in rat brain, we hypothesized that CYP2D6 expression is higher in brains of human alcoholics. We examined regional and cellular expression of CYP2D6 mRNA and protein by RT-PCR, Southern blotting, slot blotting, immunoblotting and immunocytochemistry. A significant correlation was found between mean mRNA and CYP2D6 protein levels across 13 brain regions. Higher expression was detected in 13 brain regions of alcoholics (n = 8) compared to nonalcoholics (n = 5) (ANOVA p < 0.0001). In hippocampus this was localized in CA1-3 pyramidal cells and dentate gyrus granular neurons. In cerebellum this was localized in Purkinje cells and their dendrites. Both of these brain regions, and these same cell-types, are known to be susceptible to alcohol damage. For one case, a poor metabolizer (CYP2D6*4/*4), there was no detectable CYP2D6 protein, confirming the specificity of the antibody used. These data suggest that in alcoholics elevated brain CYP2D6 expression may contribute to altered sensitivity to centrally acting drugs and to the mediation of neurotoxic and behavioral effects of alcohol.

Original languageEnglish
Pages (from-to)1376-1387
Number of pages12
JournalJournal of Neurochemistry
Volume82
Issue number6
DOIs
StatePublished - Sep 1 2002

Fingerprint

Cytochrome P-450 CYP2D6
Alcoholics
Brain
Alcohols
Messenger RNA
Proteins
Antibody Specificity
Pyramidal Cells
Purkinje Cells
Dentate Gyrus
Dendrites
Analysis of variance (ANOVA)
Southern Blotting
Immunoblotting
Pharmaceutical Preparations
Liver
Cerebellum
Neurons
Rats
Hippocampus

Keywords

  • Alcoholism
  • Cytochrome P450 CYP2D6
  • Drug metabolism
  • Human brain
  • Neurotoxicity

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

Regional and cellular expression of CYP2D6 in human brain : Higher levels in alcoholics. / Miksys, Sharon; Rao, Yushu; Hoffmann, Ewa; Mash, Deborah C; Tyndale, Rachel F.

In: Journal of Neurochemistry, Vol. 82, No. 6, 01.09.2002, p. 1376-1387.

Research output: Contribution to journalArticle

Miksys, Sharon ; Rao, Yushu ; Hoffmann, Ewa ; Mash, Deborah C ; Tyndale, Rachel F. / Regional and cellular expression of CYP2D6 in human brain : Higher levels in alcoholics. In: Journal of Neurochemistry. 2002 ; Vol. 82, No. 6. pp. 1376-1387.
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