Disruption of mdr1a p-glycoprotein gene results in dysfunction of blood-inner ear barrier in mice.
P-glycoprotein (p-gp), a drug transporter in multidrug-resistant cancer cells, is a transmembrane protein encoded by mdr1a, mdr1b and mdr2 genes in mice. In 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.
Zhang
Z J
ZJ
Department of Otolaryngology, Fukui Medical University, Japan.
Saito
T
T
Kimura
Y
Y
Sugimoto
C
C
Ohtsubo
T
T
Saito
H
H
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000502:physiology*; D000818:Animals; D001769:Blood / Q000378:metabolism*; D016572:Cyclosporine / Q000494:pharmacology; D003638:Deafness / Q000139:chemically induced / Q000235:genetics / Q000503:physiopathology; D004317:Doxorubicin / Q000493:pharmacokinetics / Q000506:poisoning; D004338:Drug Combinations; D018432:Drug Resistance, Multiple / Q000235:genetics; D007758:Ear, Inner / Q000187:drug effects / Q000378:metabolism*; D016057:Evoked Potentials, Auditory, Brain Stem / Q000187:drug effects; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout / Q000235:genetics; D012016:Reference Values; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014747:Vinblastine / Q000493:pharmacokinetics / Q000506:poisoning
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004338:Drug Combinations; D014747:Vinblastine; D004317:Doxorubicin; D016572:Cyclosporine