Homozygous disruption of the mdrla P-glycoprotein gene affects blood-nerve barrier function in mice administered with neurotoxic drugs.
We investigated the expression and function of mdr1a p-glycoprotein in peripheral nerves, including the VIIth and VIIIth nerves, using mdr1a p-glycoprotein gene knockout mice [mdr1a(-/-) mice] and wild-type mdr1a(+/+) mice. P-glycoprotein expression in capillary endothelial cells of the peripheral nerve tissues was detected by immunohistochemical and RT-PCR analyses in mdr1a(+/+) mice but not in mdr1a(-/-) mice. Pharmacokinetic analyses indicated that, compared to mdr1a(+/+) mice, mdr1a(-/-) mice showed a significantly higher accumulation of p-glycoprotein substrate drugs such as vinblastine and doxorubicin, which are neurotoxic. Tissue concentrations of vinblastine and doxorubicin were lower in the order of the brain, peripheral nerves and most other organs. However, increased accumulation was not detected after administering another neurotoxic drug, cisplatin, indicating that p-glycoprotein is selective at extruding drugs. These data indicate that mdr1a p-glycoprotein, which acts as an efflux pump, might play an important role in the blood-nerve barrier to prevent side effects induced by neurotoxic p-glycoprotein substrate drugs. The participation of p-glycoprotein in the blood-nerve barrier is considered to represent a new functional mechanism of this barrier.
Saito
T
T
Department of Otolaryngology, Fukui Medical University, Japan. takehisa@fmsrsa.fukui-med.ac.jp
Zhang
Z J
ZJ
Ohtsubo
T
T
Noda
I
I
Shibamori
Y
Y
Yamamoto
T
T
Saito
H
H
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics* / Q000378:metabolism*; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics* / Q000378:metabolism*; D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics*; D001921:Brain / Q000378:metabolism; D004317:Doxorubicin / Q000493:pharmacokinetics*; D018432:Drug Resistance, Multiple / Q000235:genetics; D004730:Endothelium, Vascular / Q000378:metabolism; D015870:Gene Expression / Q000235:genetics; D006720:Homozygote; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010525:Peripheral Nerves / Q000166:cytology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014747:Vinblastine / Q000493:pharmacokinetics*
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D014747:Vinblastine; D004317:Doxorubicin; C095122:multidrug resistance protein 3