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The aryl hydrocarbon receptor (AhR) upregulates P‐glycoprotein (P‐gp) at the blood‐brain barrier (BBB)
Author(s) -
Miller David S,
Wang Xueqian
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.604.7
Subject(s) - aryl hydrocarbon receptor , cycloheximide , chemistry , downregulation and upregulation , blood–brain barrier , pharmacology , p glycoprotein , nuclear receptor , pregnane x receptor , receptor , cytochrome p450 , microbiology and biotechnology , biochemistry , transcription factor , enzyme , biology , protein biosynthesis , endocrinology , gene , central nervous system , antibiotics , multiple drug resistance
Widespread, persistent organic pollutants, e.g., polychlorinated biphenyls and 2,3,7,8‐tetrachlorodibenzo‐ p ‐dioxin (TCDD), activate AhR causing it to translocate to the cell nucleus where it induces transcription of target genes, e.g., cytochrome P450 1A1 and 1B1 and phase II drug metabolizing enzymes. AhR's ability to modulate expression of xenobiotic transport proteins is largely unexplored. We show here that exposing isolated rat brain capillaries to the AhR ligands, β‐naphthoflavone (βNF, 0.5–5μM) or TCDD (0.05–0.5nM), increased P‐gp‐mediated transport and P‐gp protein expression 2–3 fold. These effects were abolished by actinomycin D or cycloheximide or by the AhR antagonists, resveratrol and αNF. Dosing rats with TCDD (1–5μg/kg, ip) increased P‐gp mediated transport and protein expression in brain capillaries assayed ex vivo . This is the first evidence that AhR ligands upregulate P‐gp mediated transport in any tissue and that AhR can alter drug transport at the BBB. Thus, environmental toxicants that are AhR ligands selectively tighten the BBB, providing increased protection, but at the expense of reduced penetration of therapeutic drugs. Supported by the Intramural Research Program, NIH/NIEHS.