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Organic cation transporter 2 mediates cisplatin-induced oto- and nephrotoxicity and is a target for protective interventions.
- Source :
-
The American journal of pathology [Am J Pathol] 2010 Mar; Vol. 176 (3), pp. 1169-80. Date of Electronic Publication: 2010 Jan 28. - Publication Year :
- 2010
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Abstract
- The use of the effective antineoplastic agent cisplatin is limited by its serious side effects, such as oto- and nephrotoxicity. Ototoxicity is a problem of special importance in children, because deafness hampers their language and psychosocial development. Recently, organic cation transporters (OCTs) were identified in vitro as cellular uptake mechanisms for cisplatin. In the present study, we investigated in an in vivo model the role of OCTs in the development of cisplatin oto- and nephrotoxicity. The functional effects of cisplatin treatment on kidney (24 hours excretion of glucose, water, and protein) and hearing (auditory brainstem response) were studied in wild-type and OCT1/2 double-knockout (KO) mice. No sign of ototoxicity and only mild nephrotoxicity were observed after cisplatin treatment of knockout mice. Comedication of wild-type mice with cisplatin and the organic cation cimetidine protected from ototoxicity and partly from nephrotoxicity. For the first time we showed that OCT2 is expressed in hair cells of the cochlea. Furthermore, cisplatin-sensitive cell lines from pediatric tumors showed no expression of mRNA for OCTs, indicating the feasibility of therapeutic approaches aimed to reduce cisplatin toxicities by competing OCT2-mediated cisplatin uptake in renal proximal tubular and cochlear hair cells. These findings are very important to establish chemotherapeutical protocols aimed to maximize the antineoplastic effect of cisplatin while reducing the risk of toxicities.
- Subjects :
- Animals
Auditory Threshold drug effects
Blood Urea Nitrogen
Body Weight drug effects
Cation Transport Proteins genetics
Cation Transport Proteins metabolism
Cell Line, Tumor
Cochlea drug effects
Cochlea metabolism
Cochlea pathology
Copper Transporter 1
Ear Diseases pathology
Ear Diseases physiopathology
Glucose metabolism
Humans
Kidney drug effects
Kidney pathology
Kidney Diseases physiopathology
Kidney Function Tests
Male
Mice
Mice, Knockout
Organic Cation Transport Proteins genetics
Organic Cation Transporter 2
Platinum metabolism
Stria Vascularis drug effects
Stria Vascularis metabolism
Stria Vascularis pathology
Cisplatin toxicity
Ear Diseases chemically induced
Ear Diseases metabolism
Kidney Diseases chemically induced
Kidney Diseases metabolism
Organic Cation Transport Proteins metabolism
Protective Agents pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1525-2191
- Volume :
- 176
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- The American journal of pathology
- Publication Type :
- Academic Journal
- Accession number :
- 20110413
- Full Text :
- https://doi.org/10.2353/ajpath.2010.090610