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Aryl hydrocarbon receptor-mediated up-regulation of ATP-driven xenobiotic efflux transporters at the blood-brain barrier

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 -naphthoflavone.
Brain capillaries from TCDD-dosed rats (1–5 g/kg,
i.p.) exhibited increased transport activity and protein
expression of 3 xenobiotic efflux pumps, P-glycoprotein,
multidrug resistance-associated protein 2, and
breast cancer resistance polypeptide, as well as expression
of Cyp1a1 and Cyp1b1, 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. F

Citation

Wang, X., Hawkins, B., & Miller, D. S. (2011). Aryl hydrocarbon receptor-mediated up-regulation of ATP-driven xenobiotic efflux transporters at the blood-brain barrier. The FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology, 25(2), 644 - 652. DOI: 10.1096/fj.10-169227

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