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Aryl hydrocarbon receptor‐mediated up‐regulation of ATP‐driven xenobiotic efflux transporters at the blood‐brain barrier
Author(s) -
Wang Xueqian,
Hawkins Brian T.,
Miller David S.
Publication year - 2011
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/fj.10-169227
Subject(s) - aryl hydrocarbon receptor , xenobiotic , efflux , transporter , blood–brain barrier , chemistry , microbiology and biotechnology , atp binding cassette transporter , biophysics , biochemistry , biology , neuroscience , gene , central nervous system , enzyme , transcription factor
Many widespread and persistent organic pollutants, e.g. , 2,3,7,8‐tetrachlorodibenzo‐ p ‐dioxin (TCDD), activate the aryl hydrocarbon receptor (AhR), causing it to translocate to the cell nucleus, where it transactivates target genes. AhR's ability to target the blood‐brain barrier is essentially unexplored. We show here that exposing isolated rat brain capillaries to 0.05–0.5 nM TCDD roughly doubled transport activity and protein expression of P‐glycoprotein, an ATP‐driven drug efflux pump and a critical determinant of drug entry into the CNS. These effects were abolished by actinomycin D or cycloheximide or by the AhR antagonists resveratrol and α‐naphthoflavone. Brain capillaries from TCDD‐dosed rats (1–5 µg/kg, i.p.) exhibited increased transport activity and protein expression of 3 xenobiotic efflux pumps, P‐glycopro‐tein, multidrug resistance‐associated protein 2, and breast cancer resistance polypeptide, as well as expression of Cyplal and Cyplbl, both AhR target genes. Consistent with increased P‐glycoprotein expression in capillaries from TCDD‐dosed rats, in situ brain perfusion indicated significantly reduced brain accumulation of verapamil, a P‐glycoprotein substrate. These findings suggest a new paradigm for the field of environmental toxicology: toxicants acting through AhR to target xenobiotic efflux transporters at the blood‐brain barrier and thus reduce brain accumulation of CNS‐acting therapeutic drugs.—Wang, X., Hawkins, B. T., Miller, D. S. Aryl hydrocarbon receptor‐mediated up‐regulation of ATP‐driven xenobiotic efflux transporters at the blood‐brain barrier. FASEB J. 25, 644–652 (2011). www.fasebj.org