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Altered Expression of Small Intestinal Drug Transporters and Hepatic Metabolic Enzymes in a Mouse Model of Familial Alzheimer’s Disease
journal contribution
posted on 2018-08-03, 00:00 authored by Yijun Pan, Kotaro Omori, Izna Ali, Masanori Tachikawa, Tetsuya Terasaki, Kim L. R. Brouwer, Joseph A. NicolazzoDrug transporter expression and function
at the blood–brain
barrier is altered in Alzheimer’s disease (AD). However, the
impact of AD on the expression of transporters and metabolizing enzymes
in peripheral tissues has received little attention. The current study
evaluated the expression of drug transporters and metabolizing enzymes
in the small intestine and liver from 8- to 9-month-old female wild-type
(WT) and APPswe/PSEN 1dE9 (APP/PS1) transgenic mice, a widely used
AD model, using a quantitative targeted absolute proteomics (QTAP)
approach. Furthermore, the general morphological appearance of the
liver was assessed by immunohistochemistry, and lipid content was
visualized using Oil Red O staining. The small intestines of APP/PS1
mice exhibited a significant 2.3-fold increase in multidrug resistance-associated
protein 2 (Mrp2), a 1.9-fold decrease in monocarboxylate transporter
1 (Mct1), and a 3.6-fold increase in UDP-glucuronosyltransferase (Ugt)
2b5 relative to those from WT mice based on QTAP analysis. While the
liver from APP/PS1 mice exhibited no changes in drug transporter expression,
there was a 1.3-fold elevation in cytochrome P450 (Cyp) 51a1 and a
1.2-fold reduction in Cyp2c29 protein expression, and this was associated
with morphological alterations including accumulation of hepatocyte
lipids. These studies are the first to demonstrate that the protein
expression of transporters and metabolizing enzymes important in oral
drug absorption are modified in a mouse model of familial AD, which
may lead to altered disposition of some orally administered drugs
in AD.