Kim Dong-Hyun, Lee Youn-Sun, Lee Yong-Moon, Oh Seikwan, Yun Yeo-Pyo, Yoo Hwan-Soo
College of Pharmacy and CBITRC, Chungbuk National University, Cheongju, Korea.
Arch Pharm Res. 2007 Aug;30(8):962-9. doi: 10.1007/BF02993964.
Fumonisins are causative agents of diseases in mice and rats, including liver and renal toxicities, as well as cancer, and are specific inhibitors of ceramide synthase in the metabolism of sphingolipid. The purpose of this study was to determine whether an elevated level of sphingoid base 1-phosphate was related to the expressions of metabolism enzymes in the liver of fumonisin B1 (FB1)-treated mice and acted as a contributing factor to hepatotoxicity. In our previous study, FB1 was confirmed to be toxic to both liver and kidneys, coupled with simultaneous elevation of sphinganine 1-phosphate. ICR mice were treated intraperitoneally with 10 mg/kg/day FB1 for 5 days, with the concentrations of sphingolipid metabolites in the serum and liver measured using HPLC following Bligh-Dyer extraction. The levels of sphingoid bases and their 1-phosphates in the serum and liver were markedly elevated in response to treatment with FB1. In the liver, FB1 increased the expression of sphingosine kinase and inhibited the expression of sphingosine 1-phosphate lyase. The cleaved form of caspase-3 was detected in the liver of FB1-treated mice, indicating the occurrence of apoptosis in the liver following exposure to FB1. The expressions of proapoptotic signaling molecules, such as phosphorylated forms of c-Jun N-terminus kinase (JNK), p38 MAPK and extracellular signal-regulated kinase (ERK), were increased in the liver of FB1-treated mice. In conclusion, these results suggest the elevation of sphingoid base 1-phosphate, as a result of the activation of sphingosine kinase and the inhibition of sphingosine 1-phosphate lyase, may be a major target for FB1-induced hepatotoxicity via the activation of an apoptotic signaling pathway.
伏马毒素是小鼠和大鼠疾病的致病因子，包括肝脏和肾脏毒性以及癌症，并且是鞘脂代谢中神经酰胺合酶的特异性抑制剂。本研究的目的是确定鞘氨醇-1-磷酸水平升高是否与伏马毒素B1（FB1）处理的小鼠肝脏中代谢酶的表达有关，并是否是肝毒性的一个促成因素。在我们之前的研究中，已证实FB1对肝脏和肾脏均有毒性，同时伴有鞘氨醇-1-磷酸升高。将ICR小鼠腹腔注射10 mg/kg/天的FB1，持续5天，采用布莱-戴尔萃取法提取血清和肝脏中的鞘脂代谢物，然后用高效液相色谱法测定其浓度。FB1处理后，血清和肝脏中鞘氨醇及其1-磷酸的水平显著升高。在肝脏中，FB1增加了鞘氨醇激酶的表达并抑制了鞘氨醇-1-磷酸裂解酶的表达。在FB1处理的小鼠肝脏中检测到了裂解形式的半胱天冬酶-3，表明暴露于FB1后肝脏发生了细胞凋亡。在FB1处理的小鼠肝脏中，促凋亡信号分子的表达增加，如c-Jun氨基末端激酶（JNK）、p38丝裂原活化蛋白激酶（MAPK）和细胞外信号调节激酶（ERK）的磷酸化形式。总之，这些结果表明，由于鞘氨醇激酶的激活和鞘氨醇-1-磷酸裂解酶的抑制导致鞘氨醇-1-磷酸升高，可能是FB1诱导肝毒性的主要靶点，其通过激活凋亡信号通路实现。
