Abrogation of cisplatin-induced hepatotoxicity in mice by xanthorrhizol is related to its effect on the regulation of gene transcription

Seong Hwan Kim, Kyoung Ok Hong, Won Yoon Chung, Jae Kwan Hwang, Kwang Kyun Park

Research output: Contribution to journalArticle

51 Citations (Scopus)

Abstract

Cisplatin is a widely used anticancer drug, but at high dose, it can produce undesirable side effects such as hepatotoxicity. Because Curcuma xanthorrhiza Roxb. (Zingiberaceae) has been traditionally used to treat liver disorders, the protective effect of xanthorrhizol, which is isolated from C. xanthorrhiza, on cisplatin-induced hepatotoxicity was evaluated in mice. The pretreatment of xanthorrhizol (200 mg/kg/day, po) for 4 days prevented the hepatotoxicity induced by cisplatin (45 mg/kg, ip) with statistical significance. Interestingly, it abrogated cisplatin-induced DNA-binding activity of nuclear factor-kappaB (NF-κB), which consequently affected mRNA expression levels of NF-κB-dependent genes, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2), even in part. It also attenuated the cisplatin-suppressed DNA-binding activity of activator protein 1 (AP-1). Using differential display reverse transcription-polymerase chain reaction (DDRT-PCR), seven upregulated genes including S100 calcium binding protein A9 (S100A9) mRNA and antigenic determinant for rec-A protein mRNA and five downregulated genes including caseinolytic protease X (ClpX) mRNA and ceruloplasmin (CP) mRNA by cisplatin were identified. Although these mRNA expression patterns were not totally consistent with gel shift patterns, altered expression levels by cisplatin were reversed by the pretreatment of xanthorrhizol. In conclusion, the ability of xanthorrhizol to regulate the DNA-binding activities of transcription factors, NF-κB and AP-1, could be one possible mechanism to elucidate the preventive effect of xanthorrhizol on cisplatin-induced hepatotoxicity. Furthermore, genes identified in this study could be helpful to understand the mechanism of cisplatin-induced hepatotoxicity. Finally, the combination treatment of xanthorrhizol and cisplatin may provide more advantage than single treatment of cisplatin in cancer therapy.

Original languageEnglish
Pages (from-to)346-355
Number of pages10
JournalToxicology and Applied Pharmacology
Volume196
Issue number3
DOIs
Publication statusPublished - 2004 May 1

Bibliographical note

Funding Information:
This work was supported by the Research Fund from Yonsei University College of Dentistry Research Fund of 2001.

All Science Journal Classification (ASJC) codes

  • Toxicology
  • Pharmacology

Fingerprint Dive into the research topics of 'Abrogation of cisplatin-induced hepatotoxicity in mice by xanthorrhizol is related to its effect on the regulation of gene transcription'. Together they form a unique fingerprint.

Cite this