不可逆转的烷基化与人血清白蛋白的代谢物2-acetylbenzothiophene-S-oxide:一个潜在的肝毒性的模型。
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李F, Chordia MD,伍德尔KA,麦克唐纳TL
不可逆转的烷基化与人血清白蛋白的代谢物2-acetylbenzothiophene-S-oxide:一个潜在的肝毒性的模型。
化学Res Toxicol。2007; 12月20 (12):1854 - 61。Epub 2007年10月19日。
- PubMed ID
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17944539 (在PubMed]
- 文摘
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2-acetylbenzothiophene-S-oxide (2-ABT-S-oxide或M1)是一种与活性代谢物,药物用于治疗哮喘与谷胱甘肽在体外能接合。人血清白蛋白(HSA)等离子体中最丰富的蛋白质,在排毒活性氧中起着至关重要的作用。目前的研究重点是理解之间的交互M1和保险公司。稳定性研究显示M1的半衰期约为0.85 h在HSA, 1.82 h在人类血浆和4.48 h在磷酸盐(PBS)由一阶beplayapp近似。HSA的烷基化速率常数k是20米(1)最小(1)。与乙腈,淬火后的半衰期M1没有显著变化,表明M1是HSA的共价结合。质和质/ MS分析人类的等离子体显示M1烷基化肽P (m / z 870)由HSA接合,伴随水消除。特定氨基酸HSA绑定到M1被确认为Cys-34。烷基化是观察到在人血浆浓度——incubation-time-dependent。HSA氧化×N, N ' -diacetyl-L-cystine展品受损HSA和M1反应的能力。 The alkylated HSA diminished the binding affinity for warfarin. Furthermore, the alkylation was found to be irreversible in the dialysis experiment. In addition, M1 decomposes to 2-ABT in the presence of HSA, presumably acting as an oxidant. The formation of 2-ABT in the incubation and the self-condensation of M1 in PBS indicate that the alkylation of Cys-34 is only one of a number of reactions that occur in the presence of HSA. Irreversible protein modification may potentially lead to a loss of its function. HSA irreversible alkylation represents a model for other proteins to be potentially toxic and thus may help explain zileuton hepatotoxicity.