title: Phosphorylation of c-Jun N-terminal Kinases (JNKs) is involved in the preventive effect of xanthorrhizol on cisplatin-induced hepatotoxicity.
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).
authors.affiliation: Department of Oral Biology, College of Dentistry, Yonsei University, 134 Shinchon-Dong, Seodaemun-Gu, 120-749, Seoul, South Korea.
authors.forename: Kyoung Ok
authors.initials: KO
authors.lastname: Hong
authors.forename: Jae Kwan
authors.initials: JK
authors.lastname: Hwang
authors.forename: Kwang-Kyun
authors.initials: KK
authors.lastname: Park
authors.forename: Seong Hwan
authors.initials: SH
authors.lastname: Kim
mesh_terms: 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
chemical_list: 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