Sohn Jong Hee, Han Kyu Lee, Kim Jeong-Hwan, Rukayadi Yaya, Hwang Jae-Kwan
Department of Biotechnology, Yonsei University, Seodaemun-gu, Seoul, Korea.
Biol Pharm Bull. 2008 Feb;31(2):273-7. doi: 10.1248/bpb.31.273.
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.
顺铂是最有效的抗肿瘤药物之一，但它有不良副作用，如高剂量时会导致肝毒性。本研究调查了从肉豆蔻（Myristica fragrans HOUTT.）中分离得到的芝麻素对顺铂诱导的小鼠肝毒性的保护作用及其可能的作用机制。用芝麻素预处理4天可显著剂量依赖性地预防丙氨酸和天冬氨酸转氨酶血清酶活性的升高。结果还表明，芝麻素对顺铂诱导的肝毒性的保护作用可能与丝裂原活化蛋白激酶（MAPK）信号通路有关。顺铂诱导的c-Jun氨基末端激酶1/2（JNK1/2）和细胞外信号调节激酶1/2（ERK1/2）的磷酸化被芝麻素预处理所消除，然而，p38的磷酸化没有受到显著影响。还发现芝麻素可减弱顺铂处理小鼠中磷酸化c-Jun的表达。因此，提示芝麻素的肝保护作用可能与MAPK信号通路的激活有关，尤其是JNK及其底物c-Jun。目前的研究结果表明，在癌症治疗中，顺铂与芝麻素联合治疗可能比单独使用顺铂治疗具有更多优势。
