Phosphorylation of c-Jun N-terminal Kinases (JNKs) is involved in the preventive effect of xanthorrhizol on cisplatin-induced hepatotoxicity.
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).
Hong
Kyoung Ok
KO
Department of Oral Biology, College of Dentistry, Yonsei University, 134 Shinchon-Dong, Seodaemun-Gu, 120-749, Seoul, South Korea.
Hwang
Jae Kwan
JK
Park
Kwang-Kyun
KK
Kim
Seong Hwan
SH
D000818:Animals; D000970:Antineoplastic Agents / Q000037:antagonists & inhibitors* / Q000633:toxicity; D015153:Blotting, Western; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism* / Q000517:prevention & control*; D002945:Cisplatin / Q000037:antagonists & inhibitors* / Q000633:toxicity; D003474:Curcumin / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D010636:Phenols / Q000494:pharmacology*; D010766:Phosphorylation; D015398:Signal Transduction / Q000187:drug effects
D000970:Antineoplastic Agents; D016328:NF-kappa B; D010636:Phenols; C120248:xanthorrhizol; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D003474:Curcumin; D002945:Cisplatin