RT Journal Article
SR Electronic
T1 Differential Expression of Human Cytochrome P450 Enzymes from the CYP3A Subfamily in the Brains of Alcoholics and Drug Free Controls
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP dmd.113.051359
DO 10.1124/dmd.113.051359
A1 Iris M. Booth Depaz
A1 Francesca Toselli
A1 Peter A. Wilce
A1 Elizabeth M. J. Gillam
YR 2013
UL http://dmd.aspetjournals.org/content/early/2013/03/14/dmd.113.051359.abstract
AB Cytochrome P450 (P450, CYP) enzymes are responsible for the metabolism of most commonly used drugs. Amongst 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 utilized to characterize the expression of these forms in the human brain. Both CYP3A4 and CYP3A5 immunoreactivity was 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.