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Research ArticleArticle

Differential Expression of Human Cytochrome P450 Enzymes from the CYP3A Subfamily in the Brains of Alcoholic Subjects and Drug-Free Controls

Iris M. Booth Depaz, Francesca Toselli, Peter A. Wilce and Elizabeth M. J. Gillam
Drug Metabolism and Disposition June 2013, 41 (6) 1187-1194; DOI: https://doi.org/10.1124/dmd.113.051359
Iris M. Booth Depaz
School of Biomedical Sciences (I.M.B.D.), and School of Chemistry and Molecular Biosciences (F.T., P.A.W., E.M.J.G.), The University of Queensland, Brisbane, Queensland, Australia
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Francesca Toselli
School of Biomedical Sciences (I.M.B.D.), and School of Chemistry and Molecular Biosciences (F.T., P.A.W., E.M.J.G.), The University of Queensland, Brisbane, Queensland, Australia
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Peter A. Wilce
School of Biomedical Sciences (I.M.B.D.), and School of Chemistry and Molecular Biosciences (F.T., P.A.W., E.M.J.G.), The University of Queensland, Brisbane, Queensland, Australia
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Elizabeth M. J. Gillam
School of Biomedical Sciences (I.M.B.D.), and School of Chemistry and Molecular Biosciences (F.T., P.A.W., E.M.J.G.), The University of Queensland, Brisbane, Queensland, Australia
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Abstract

Cytochrome P450 enzymes are responsible for the metabolism of most commonly used drugs. Among these enzymes, CYP3A forms mediate the clearance of around 40–50% of drugs and may also play roles in the biotransformation of endogenous compounds. CYP3A forms are expressed both in the liver and extrahepatically. However, little is known about the expression of CYP3A proteins in specific regions of the human brain. In this study, form-selective antibodies raised to CYP3A4 and CYP3A5 were used to characterize the expression of these forms in the human brain. Both CYP3A4 and CYP3A5 immunoreactivity were found to varying extents in the microsomal fractions of cortex, hippocampus, basal ganglia, amygdala, and cerebellum. However, only CYP3A4 expression was observed in the mitochondrial fractions of these brain regions. N-terminal sequencing confirmed the principal antigen detected by the anti-CYP3A4 antibody in cortical microsomes to be CYP3A4. Immunohistochemical analysis revealed that CYP3A4 and CYP3A5 expression was primarily localized in the soma and axonal hillock of neurons and varied according to cell type and cell layer within brain regions. Finally, analysis of the frontal cortex of chronic alcohol abusers revealed elevated expression of CYP3A4 in microsomal but not mitochondrial fractions; CYP3A5 expression was unchanged. The site-specific expression of CYP3A4 and CYP3A5 in the human brain may have implications for the role of these enzymes in both normal brain physiology and the response to drugs.

Footnotes

    • Received February 10, 2013.
    • Accepted March 14, 2013.
  • This research was supported by the National Health and Medical Research Council [Grant 210215 to P.A.W. and E.M.J.G.].

  • This work was previously presented in preliminary form at the following meeting: Depaz IM, Wilce PA and Gillam EMJ (2006) Detection of specific members of the cytochrome P450 2C and 3A subfamilies in the human brain. Fourteenth North American International Society for the Study of Xenobiotics Meeting; 2006 Oct 22–26; Rio Grande, Puerto Rico.

  • dx.doi.org/10.1124/dmd.113.051359.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 41 (6)
Drug Metabolism and Disposition
Vol. 41, Issue 6
1 Jun 2013
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Research ArticleArticle

CYP3A Expression in the Human Brain

Iris M. Booth Depaz, Francesca Toselli, Peter A. Wilce and Elizabeth M. J. Gillam
Drug Metabolism and Disposition June 1, 2013, 41 (6) 1187-1194; DOI: https://doi.org/10.1124/dmd.113.051359

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Research ArticleArticle

CYP3A Expression in the Human Brain

Iris M. Booth Depaz, Francesca Toselli, Peter A. Wilce and Elizabeth M. J. Gillam
Drug Metabolism and Disposition June 1, 2013, 41 (6) 1187-1194; DOI: https://doi.org/10.1124/dmd.113.051359
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