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

• Published in: The FASEB journal 2011-02, Vol.25 (2), p.644-652
• Main Authors: Wang, Xueqian, Hawkins, Brian T, Miller, David S
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphate - metabolism; Animals; Blood-Brain Barrier - metabolism; brain capillaries; breast cancer resistance protein; Carrier Proteins - genetics; Carrier Proteins - metabolism; dioxin; Male; multidrug resistance‐associated protein 2; Polychlorinated Dibenzodioxins - analogs & derivatives; Polychlorinated Dibenzodioxins - toxicity; P‐glycoprotein; Rats; Rats, Sprague-Dawley; Receptors, Aryl Hydrocarbon - genetics; Receptors, Aryl Hydrocarbon - metabolism; Research Communications; Up-Regulation; Xenobiotics
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fj.10-169227

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-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.