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    Cisplatin-Induced Downregulation of OCTN2 Affects Carnitine Wasting

    154300_154300.pdf (1.476Mb)
    Access Status
    Open access
    Authors
    Lancaster, C.
    Hu, C.
    Franke, R.
    Filipski, K.
    Orwick, S.
    Zhaoyuan, C.
    Zuo, Zhili
    Loos, W.
    Sparreboom, A.
    Date
    2010
    Type
    Journal Article
    
    Metadata
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    Citation
    Lancaster, Cynthia S. and Hu, Chaoxin and Franke, Ryan M. and Filipski, Kelly K. and Orwick, Shelley J. and Zhaoyuan, Chen and Zuo, Zhili and Loos, Walter J. and Sparreboom, Alex. 2010. Cisplatin-Induced Downregulation of OCTN2 Affects Carnitine Wasting. Clinical Cancer Research. 16 (19): pp. 4789-4799.
    Source Title
    Clinical Cancer Research
    DOI
    10.1158/1078-0432.CCR-10-1239
    ISSN
    10780432
    School
    School of Biomedical Sciences
    Remarks

    Copyright © 2010 American Association for Cancer Research

    URI
    http://hdl.handle.net/20.500.11937/12846
    Collection
    • Curtin Research Publications
    Abstract

    Purpose: Carnitine is an essential cofactor for mitochondrial fatty acid oxidation that is actively reabsorbed by the luminal transporter Octn2 (Slc22a5). Because the nephrotoxic agent cisplatin causes urinary loss of carnitine in humans, we hypothesized that cisplatin may affect Octn2 function. Experimental Design: Excretion of carnitine and acetylcarnitine was measured in urine collected from mice with or without cisplatin administration. The transport of carnitine was assessed in cells that were transfected with OCT1 or OCT2. The effect of cisplatin treatment on gene expression was analyzed using a mouse GeneChip array and validated using quantitative reverse transcriptase-PCR.Results: In wild-type mice, urinary carnitine excretion at baseline was ∼3-fold higher than in mice lacking the basolateral cisplatin transporters Oct1 and Oct2 [Oct1/2(−/−) mice], indicating that carnitine itself undergoes basolateral uptake into the kidney. Transport of carnitine by OCT2, but not OCT1, was confirmed in transfected cells. We also found that cisplatin caused an increase in the urinary excretion of carnitine and acetylcarnitine in wild-type mice but not in Oct1/2(−/−) mice, suggesting that tubular transport of cisplatin is a prerequisite for this phenomenon. Cisplatin did not directly inhibit the transport of carnitine by Octn2 but downregulated multiple target genes of the transcription factor peroxisome proliferator activated receptor α, including Slc22a5, in the kidney of wild-type mice that were absent in Oct1/2(−/−) mice. Conclusion: Our study shows a pivotal role of Oct1 and Oct2 in cisplatin-related disturbances in carnitine homeostasis. We postulate that this phenomenon is triggered by deactivation of peroxisome proliferator activated receptor α and leads to deregulation of carnitine-shuttle genes.

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