Protective Effects of macelignan on cisplatin-induced hepatotoxicity is associated with JNK activation.
Cisplatin is one of the most effective antineoplastic drugs, but it has undesirable side effects such as hepatotoxicity at high doses. This study investigated the protective effect of macelignan, isolated from Myristica fragrans HOUTT. (nutmeg), against cisplatin-induced hepatotoxicity and the possible mechanisms involved in these effects in mice. Pretreatment with macelignan for 4 d significantly prevented the increased serum enzymatic activities of alanine and aspartate aminotransferase in a dose-dependent manner. The results also showed that the protective effects of macelignan on cisplatin-induced hepatotoxicity may be associated with the mitogen activated protein kinase (MAPK) signaling pathway. Cisplatin-induced phosphorylation of c-Jun N-terminal kinase1/2 (JNK1/2) and extracellular signal-regulated kinase1/2 (ERK1/2) was abrogated by pretreatment with macelignan, however, that of p38 was not significantly affected. It was also found that macelignan attenuated the expression of phosphorylated c-Jun in cisplatin-treated mice. Accordingly, it is suggested that the hepatoprotective effects of macelignan could be related to activation of the MAPK signaling pathway, especially JNK and c-Jun, its substrate. The present findings suggest that co-treatment of cisplatin with macelignan may provide more advantage than cisplatin treatment alone in cancer therapy.
Sohn
Jong Hee
JH
Department of Biotechnology, Yonsei University, Seodaemun-gu, Seoul, Korea.
Han
Kyu Lee
KL
Kim
Jeong-Hwan
JH
Rukayadi
Yaya
Y
Hwang
Jae-Kwan
JK
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000970:Antineoplastic Agents / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D001219:Aspartate Aminotransferases / Q000097:blood; D015153:Blotting, Western; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology / Q000517:prevention & control*; D002945:Cisplatin / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D048031:JNK Mitogen-Activated Protein Kinases / Q000502:physiology*; D017705:Lignans / Q000494:pharmacology*; D008111:Liver Function Tests; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D026323:Myristica / Q000737:chemistry; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014157:Transcription Factors / Q000187:drug effects
D000970:Antineoplastic Agents; D017705:Lignans; D014157:Transcription Factors; C502026:macelignan; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D002945:Cisplatin