Opposite action of S-adenosyl methionine and its metabolites on CYP2E1-mediated toxicity in pyrazole-induced rat hepatocytes and HepG2 E47 cells
Opposite action of S-adenosyl methionine and its metabolites on CYP2E1-mediated toxicity in pyrazole-induced rat hepatocytes and HepG2 E47 cells
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DOI：
10.1152/ajpgi.00406.2005
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发表时间：
2006-04-01
影响因子：
4.5
通讯作者：
Cederbaum, AI
中科院分区：
文献类型：
--
作者：
Wu, DF;Cederbaum, AI
S-腺苷-L-甲硫氨酸（SAMe）对多种肝毒素具有保护作用，包括乙醇。在吡唑处理的大鼠和HepG 2 E47细胞的肝细胞中研究了SAMe对细胞色素P-450 2 E1（CYP 2 E1）依赖性毒性的保护能力，这两种细胞均主动表达CYP 2 E1。通过添加花生四烯酸（AA）或通过用L-丁硫氨酸亚砜亚胺（BSO）处理后耗尽谷胱甘肽来启动毒性。在吡唑肝细胞中，SAMe（0.25 - 1 mM）可保护AA而非BSO毒性。SAMe升高GSH水平，从而防止AA引起的GSH下降，SAMe防止AA诱导的脂质过氧化。SAMe类似物，如蛋氨酸或S-腺苷高半胱氨酸，提高GSH，也保护免受AA毒性。不能产生GSH的5 '-甲基硫代腺苷（MTA）不能保护。BSO的毒性不能被SAMe和类似物阻止，因为GSH不能合成。相反，在E47细胞中，SAMe和MTA而不是蛋氨酸或S-腺苷高半胱氨酸增强AA和BSO毒性。抗氧化剂如trolox或N-乙酰半胱氨酸分别防止SAMe加AA或SAMe加BSO的这种协同毒性。在吡唑肝细胞中，SAMe防止AA产生的线粒体膜电位下降，而在E47细胞中，SAMe增强线粒体膜电位下降。在E47细胞中，而不是吡唑肝细胞中，SAMe加BSO的组合降低了抗氧化转录因子Nrf 2的水平。由于SAMe可被酶促或自发代谢为MTA，因此MTA可能在SAMe增强AA和BSO毒性中发挥作用，但确切机制需要进一步研究。总之，在吡唑肝细胞和E47细胞中观察到SAMe对CYP 2 E1毒性的对比效应。在肝细胞中，SAMe通过维持或升高GSH水平的机制保护免受CYP 2 E1毒性。
S-adenosyl-L-methionine (SAMe) is protective against a variety of hepatotoxins, including ethanol. The ability of SAMe to protect against cytochrome P-450 2E1 (CYP2E1)-dependent toxicity was studied in hepatocytes from pyrazole-treated rats and HepG2 E47 cells, both of which actively express CYP2E1. Toxicity was initiated by the addition of arachidonic acid ( AA) or by depletion of glutathione after treatment with L-buthionine sulfoximine (BSO). In pyrazole hepatocytes, SAMe (0.25 - 1 mM) protected against AA but not BSO toxicity. SAMe elevated GSH levels, thus preventing the decline in GSH caused by AA, and SAMe prevented AA-induced lipid peroxidation. SAMe analogs such as methionine or S-adenosyl homocysteine, which elevate GSH, also protected against AA toxicity. 5'-Methylthioadenosine (MTA), which cannot produce GSH, did not protect. The toxicity of BSO was not prevented by SAMe and the analogs because GSH cannot be synthesized. In contrast, in E47 cells, SAMe and MTA but not methionine or S-adenosyl homocysteine potentiated AA and BSO toxicity. Antioxidants such as trolox or N-acetyl cysteine prevented this synergistic toxicity of SAMe plus AA or SAMe plus BSO, respectively. In pyrazole hepatocytes, SAMe prevented the decline in mitochondrial membrane potential produced by AA, whereas in E47 cells, SAMe potentiated the decline in mitochondrial membrane potential. In E47 cells, but not pyrazole hepatocytes, the combination of SAMe plus BSO lowered levels of the antioxidant transcription factor Nrf2. Because SAMe can be metabolized enzymatically or spontaneously to MTA, MTA may play a role in the potentiation of AA and BSO toxicity by SAMe, but the exact mechanisms require further investigation. In conclusion, contrasting effects of SAMe on CYP2E1 toxicity were observed in pyrazole hepatocytes and E47 cells. In hepatocytes, SAMe protects against CYP2E1 toxicity by a mechanism involving maintaining or elevating GSH levels.