Disruption of mdr1a p-glycoprotein gene results in dysfunction of blood-inner ear barrier in mice

P-glucoprotein (p-gp), a drug transporter in multidrug-resistant cancer cells, is a transmembrane protein encoded by mdr1a, mdr1b and mdr2 genes in mice. Tn our previous report, high level p-gp was immunohistochemically detected in capillary endothelial cells of the guinea pig inner ear, supporting a possible role as an extrusion pump in the blood-inner ear barrier (BIB). We investigated the functional involvement of p-gp in the inner ear using mdr1a gene knock-out mice [mdr1a(-/-) mice]. Pharmacokinetic analyses showed that mdr1a(-/-) mice displayed obviously increased accumulations of the p-gp-transported drugs doxorubicin (adriamycin, ADM) and vinblastine in the inner ear tissues compared with those in mdr1a(+/+) mice. Subsequent functional studies using auditory-evoked brainstem responses showed hearing impairment only in mdr1a(-/-) mice after administering these drugs. Furthermore, inhibition of p-gp function by co-administration of cyclosporin A (CsA) with doxorubicin (ADM) in mdr1a(+/+) mice resulted in increased accumulation of ADM in inner ear tissues and hearing impairment similar to that noted in mdr1a(-/-) mice. We conclude that mdr1a p-gp which acts as an efflux pump in the inner ear, prevents ototoxicity induced by p-gp substrate drugs and contributes to a new functional mechanism in the BIB. (C) 2000 Elsevier Science B.V. All rights reserved.