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Research ArticleTOXICOLOGY

β-Lyase-Dependent Attenuation of Cisplatin-Mediated Toxicity by Selenocysteine Se-Conjugates in Renal Tubular Cell Lines

Martijn Rooseboom, Gerben Schaaf, Jan N. M. Commandeur, Nico P. E. Vermeulen and Johanna Fink-Gremmels
Journal of Pharmacology and Experimental Therapeutics June 2002, 301 (3) 884-892; DOI: https://doi.org/10.1124/jpet.301.3.884
Martijn Rooseboom
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Gerben Schaaf
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Jan N. M. Commandeur
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Nico P. E. Vermeulen
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Johanna Fink-Gremmels
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Abstract

Cisplatin [cis-diamminedichloroplatinum(II)] is a widely used antitumor drug with dose-limiting nephrotoxic side effects due to selective toxicity to the proximal tubule. In the present study, the chemoprotective potential of three selenocysteineSe-conjugates,Se-methyl-l-selenocysteine,Se-(2-methoxyphenyl)-l-selenocysteine, andSe-(2-chlorobenzyl)-l-selenocysteine, belonging to three structural classes, against the nephrotoxic effects of cisplatin was investigated. SelenocysteineSe-conjugates have previously been proposed as kidney-selective prodrugs of pharmacologically active selenols because of their active uptake and bioactivation by cysteine conjugate β-lyases in the kidney. To elucidate whether chemoprotection is β-lyase-dependent wild-type LLC-PK1 cells, possessing a very low β-lyase activity, and LLC-PK1 cells stably transfected with full-length cDNA coding for rat kidney cysteine conjugate β-lyase/glutamine transaminase K (R1J) were used. The results indicate that all three selenocysteineSe-conjugates were able to attenuate the cisplatin-induced loss of viability in R1J cells but not in the parental LLC-PK1 cells, as determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and neutral red uptake. In addition, cisplatin-induced reactive oxygen species (ROS) production was determined using 2′,7′-dichlorodihydrofluorescein diacetate. The selenocysteineSe-conjugates were able to decrease ROS levels after cisplatin exposure in both cell types. However, this ROS-protective effect was more profound in R1J cells.Se-Methyl-l-selenocysteine provided the strongest protection. The protective activity against cisplatin-induced cytotoxicity and ROS generation was blocked by aminooxyacetic acid, a selective inhibitor of pyridoxal 5′-phosphate-dependent cysteine conjugate β-lyases, further supporting the role of β-lyase in the observed chemoprotection. The precise molecular mechanism by which selenols, generated by β-lyase, provide protection against cisplatin-induced cytotoxicity, however, remains to be established.

Footnotes

  • ↵1 M.R. and G.S. contributed equally to this study.

  • This work was supported by Grant C95.1535 from the Dutch Kidney Foundation.

  • Abbreviations:
    SeCys
    selenocysteine Se
    PLP
    pyridoxal 5′-phosphate
    β-lyase/GTK
    cysteine conjugate β-lyase/glutamine transaminase K
    ROS
    reactive oxygen species
    PTC
    proximal tubular cell
    AOAA
    aminooxyacetic acid
    MTT
    3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
    MSeCys
    Se-methyl-l-selenocysteine
    H2DCF-DA
    2′,7′-dichlorodihydrofluorescein diacetate
    MPSeCys
    Se-(2-methoxyphenyl)-l-selenocysteine
    CBSeCys
    Se-(2-chlorobenzyl)-l-selenocysteine
    TFE-Cys
    S-(1,1,2,2-tetrafluoroethyl)-l-cysteine
    DMEM
    Dulbecco's modified Eagle's medium
    FCS
    fetal calf serum
    PBS
    phosphate-buffered saline
    ANOVA
    analysis of variance
    • Received October 10, 2001.
    • Accepted January 28, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 301 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 301, Issue 3
1 Jun 2002
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Research ArticleTOXICOLOGY

β-Lyase-Dependent Attenuation of Cisplatin-Mediated Toxicity by Selenocysteine Se-Conjugates in Renal Tubular Cell Lines

Martijn Rooseboom, Gerben Schaaf, Jan N. M. Commandeur, Nico P. E. Vermeulen and Johanna Fink-Gremmels
Journal of Pharmacology and Experimental Therapeutics June 1, 2002, 301 (3) 884-892; DOI: https://doi.org/10.1124/jpet.301.3.884

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Research ArticleTOXICOLOGY

β-Lyase-Dependent Attenuation of Cisplatin-Mediated Toxicity by Selenocysteine Se-Conjugates in Renal Tubular Cell Lines

Martijn Rooseboom, Gerben Schaaf, Jan N. M. Commandeur, Nico P. E. Vermeulen and Johanna Fink-Gremmels
Journal of Pharmacology and Experimental Therapeutics June 1, 2002, 301 (3) 884-892; DOI: https://doi.org/10.1124/jpet.301.3.884
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