Abrogation of cisplatin-induced hepatotoxicity in mice by xanthorrhizol is related to its effect on the regulation of gene transcription.
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-kappaB), which consequently affected mRNA expression levels of NF-kappaB-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-kappaB 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.
Kim
Seong Hwan
SH
Department of Oral Biology, College of Dentistry, Yonsei University, 134 Shinchon-Dong, Seodaemun-Gu, Seoul 120-752, South Korea.
Hong
Kyoung Ok
KO
Chung
Won-Yoon
WY
Hwang
Jae Kwan
JK
Park
Kwang-Kyun
KK
D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000037:antagonists & inhibitors / Q000633:toxicity*; D001219:Aspartate Aminotransferases / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology / Q000517:prevention & control*; D002945:Cisplatin / Q000037:antagonists & inhibitors / Q000633:toxicity*; D051546:Cyclooxygenase 2; D005786:Gene Expression Regulation / Q000187:drug effects; D007527:Isoenzymes / Q000187:drug effects; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism; D010636:Phenols / Q000627:therapeutic use*; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic; D005723:gamma-Glutamyltransferase / Q000378:metabolism
D000970:Antineoplastic Agents; D007527:Isoenzymes; D016328:NF-kappa B; D010636:Phenols; C120248:xanthorrhizol; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D005723:gamma-Glutamyltransferase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D002945:Cisplatin