Neuronal expression of copper transporter 1 in rat dorsal root ganglia: association with platinum neurotoxicity.
OBJECTIVE
We report the neuronal expression of copper transporter 1 (CTR1) in rat dorsal root ganglia (DRG) and its association with the neurotoxicity of platinum-based drugs.


METHODS
CTR1 expression was studied by immunohistochemistry and RT-PCR. The toxicity of platinum drugs to CTR1-positive and CTR1-negative neurons was compared in DRG from animals treated with maximum tolerated doses of oxaliplatin (1.85 mg/kg), cisplatin (1 mg/kg) or carboplatin (8 mg/kg) twice weekly for 8 weeks.


RESULTS
Abundant CTR1 mRNA was detected in DRG tissue. CTR1 immunoreactivity was associated with plasma membranes and cytoplasmic vesicular structures of a subpopulation (13.6 +/- 3.1%) of mainly large-sized (mean cell body area, 1,787 +/- 127 microm(2)) DRG neurons. After treatment with platinum drugs, the cell bodies of these CTR1-positive neurons became atrophied, with oxaliplatin causing the greatest percentage reduction in the mean cell body area relative to controls (42%; P < 0.05), followed by cisplatin (18%; P < 0.05) and carboplatin causing the least reduction (3.2%; P = NS). CTR1-negative neurons, with no immunoreactivity or only diffuse cytoplasmic staining, showed less treatment-induced cell body atrophy than CTR1-positive neurons.


CONCLUSIONS
CTR1 is preferentially expressed by a subset of DRG neurons that are particularly vulnerable to the toxicity of platinum drugs. These findings, together with its neuronal membrane localization, are suggestive of CTR1-related mechanisms of platinum drug neuronal uptake and neurotoxicity.
Liu
Johnson J
JJ
Department of Pharmacology and Clinical Pharmacology, School of Medical Sciences, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand.
Jamieson
Stephen M F
SM
Subramaniam
Joshuan
J
Ip
Virginia
V
Jong
Nancy N
NN
Mercer
Julian F B
JF
McKeage
Mark J
MJ
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D000079923:Copper Transporter 1; D005727:Ganglia, Spinal / Q000187:drug effects* / Q000378:metabolism; D007150:Immunohistochemistry; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009944:Organoplatinum Compounds / Q000633:toxicity*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000970:Antineoplastic Agents; D027682:Cation Transport Proteins; D000079923:Copper Transporter 1; D009944:Organoplatinum Compounds; D012333:RNA, Messenger