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Phosphorylation of c-Jun N-terminal Kinases (JNKs) is involved in the preventive effect of xanthorrhizol on cisplatin-induced hepatotoxicity

  • Organ Toxicity and Mechanisms
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Abstract

Cisplatin is a potent anti-cancer chemotherapeutic agent but has the undesirable side effect of hepatotoxicity at high doses. In a previous study, abrogation of cisplatin-induced hepatotoxicity by pretreatment with xanthorrhizol was observed in mice, but the mechanism has not yet been studied. We therefore investigated whether the protective effect of xanthorrhizol on cisplatin-induced hepatotoxicity is associated with the mitogen-activated protein (MAP) kinase-signaling pathway. Cisplatin caused phosphorylation of both c-Jun N-terminal kinases 1/2 (JNK1/2) and the extracellular signal-regulated kinase 1/2 (ERK1/2), but not that of p38. However, cisplatin-induced phosphorylation of JNKs, especially JNK1, was highly attenuated by pretreatment with xanthorrhizol in a dose-dependent manner. This study suggested that the phosphorylation of JNKs could be involved in the protective effect of xanthorrhizol on cisplatin-induced hepatotoxicity and it also affects gene transcription by regulating the expression of transcription factor subunits such as c-fos and p50 in part. In addition, considering that the expression of both cytochrome c and caspase-9 were not changed in this model, its mechanism might be independent of mitochondria-related apoptosis. This is the first report giving evidence that the physiological function of xanthorrhizol is linked to regulation of the phosphorylation of JNK(s).

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Abbreviations

AP-1:

Activator protein 1

COX-2:

Cyclooxygenase-2

ERK:

Extracellular signal-regulated kinase

JNK:

c-Jun N-terminal kinase

MAP:

Mitogen-activated protein

iNOS:

Inducible nitric oxide synthase

NF-κB:

Nuclear factor-kappaB.

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Acknowledgment

PKK work was supported by the Research Fund from Yonsei University College of Dentistry Research Fund of 1999.

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Authors and Affiliations

  1. Department of Oral Biology, College of Dentistry, Yonsei University, 134 Shinchon-Dong, Seodaemun-Gu, 120-749, Seoul, South Korea

    Kyoung Ok Hong, Kwang-Kyun Park & Seong Hwan Kim

  2. Department of Biotechnology, Yonsei University, 134 Shinchon-Dong, Seodaemun-Gu, 120-749, Seoul, South Korea

    Jae Kwan Hwang

  3. Brain Korea 21 project for Medical Science and Department of Oral Biology, College of Dentistry, Yonsei University, 134 Shinchon-Dong, Seodaemun-Gu, 120–749, Seoul, South Korea

    Kwang-Kyun Park & Seong Hwan Kim

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  1. Kyoung Ok Hong
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  2. Jae Kwan Hwang
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  3. Kwang-Kyun Park
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  4. Seong Hwan Kim
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Correspondence to Seong Hwan Kim.

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Hong, K.O., Hwang, J.K., Park, KK. et al. Phosphorylation of c-Jun N-terminal Kinases (JNKs) is involved in the preventive effect of xanthorrhizol on cisplatin-induced hepatotoxicity. Arch Toxicol 79, 231–236 (2005). https://doi.org/10.1007/s00204-004-0623-7

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  • DOI: https://doi.org/10.1007/s00204-004-0623-7

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