Patterns of P-glycoprotein activity in the nervous system during vincristine-induced neuropathy in rats.
Vincristine (VCT) is a neurotoxic agent and also a substrate of multidrug resistance (MDR) transporters such as P-glycoprotein (P-gp) and MDR-associated proteins 1 and 2 (MRP1 and MRP2). These proteins are expressed in the central and peripheral nervous systems (CNS and PNS) and normally protect these structures against the harmful effects of VCT. The aim of this study was to elucidate the paradoxical relation between the MDR transporters and the VCT neurotoxicity. With a validated rat model of VCT-induced neuropathy, (1) the expressions of mdr1a (P-gp), mdr1b (P-gp), mrp1 (MRP1), and mrp2 (MRP2) genes were assessed by quantitative real-time polymerase chain reaction, and (2) the transporter activity was monitored using a radioactive tracer, (99m)Tc-sestamibi, in the CNS and PNS. The results showed higher expression of mdr1a and mdr1b genes (x3 and x35, respectively) in the brain than in the spinal ganglia in both control and treated animals. Transporter activity was higher (x10) in the CNS than in the PNS. Hence, P-gp protection may be lower in the PNS than in the CNS, and this may be responsible for the peripheral neurotoxicity of P-gp substrates. VCT treatment increased expression of the mdr1a gene in the CNS and PNS (both x1.7), mrp1 gene in the PNS (x1.7), and transporter activity in both the CNS and the PNS (x4 and x8, respectively). This transporter induction may induce adverse effects when analgesic drugs are administered to treat neuropathic pain.
Balayssac
David
D
Laboratory of Toxicology, Faculty of Pharmacy, CHU Clermont-Ferrand, France. david.balayssac@libertysurf.fr
Cayre
Anne
A
Authier
Nicolas
N
Bourdu
Sophie
S
Penault-Llorca
Frederique
F
Gillet
Jean Pierre
JP
Maublant
Jean
J
Eschalier
Alain
A
Coudore
François
F
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001522:Behavior, Animal; D004195:Disease Models, Animal; D015870:Gene Expression / Q000187:drug effects; D019450:Genes, MDR; D008297:Male; D046529:Microscopy, Electron, Transmission / Q000379:methods; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000145:classification / Q000235:genetics / Q000378:metabolism; D009420:Nervous System / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D015609:Organotechnetium Compounds / Q000378:metabolism; D010147:Pain Measurement / Q000379:methods; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D010808:Physical Examination / Q000379:methods; D010812:Physical Stimulation / Q000379:methods; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D018709:Statistics, Nonparametric; D013997:Time Factors; D014750:Vincristine
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D015609:Organotechnetium Compounds; D012333:RNA, Messenger; D014750:Vincristine