Antidotal effectiveness of N-acetylcysteine in reversing acetaminophen-induced hepatotoxicity. Enhancement of the proteolysis of arylated proteins.
Antidotal effectiveness of N-acetylcysteine in reversing acetaminophen-induced hepatotoxicity. Enhancement of the proteolysis of arylated proteins.
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N-乙酰半胱氨酸在逆转对乙酰氨基酚诱导的肝毒性方面的解毒功效。
DOI：
10.1016/0006-2952(88)90613-2
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发表时间：
1988
影响因子：
5.8
通讯作者：
Khairallah,EA
中科院分区：
文献类型：
--
作者：
Bruno,MK;Cohen,SD;Khairallah,EA
在原代培养的小鼠肝细胞上，研究了乙酰半胱氨酸(NAC)减轻对乙酰氨基酚(APAP)所致肝毒性的后芳基化机制。当在去除含有10 mM APAP的培养液后立即给予选定的时间时，2.0 mM NAC被证明通过16小时的APAP预处理恢复谷胱甘肽水平，并最大限度地减少因前8小时的药物暴露而导致的谷草转氨酶的泄漏。这种时间差异意味着细胞对NAC有反应的关键时期，并允许研究解毒剂的潜在芳香化后机制。在恢复期没有NAC的情况下，细胞中共价结合的APAP的损失可以通过在培养液中出现芳基化蛋白而没有任何APAP结合蛋白的明显降解来解释。相反，当NAC在恢复期存在时，细胞内蛋白结合的APAP减少，这不能用在培养液中检测到的来解释。由于在恢复期内低浓度的APAP不能显著促进该体系中的任何额外的共价结合，NAC不能仅仅作为反应性电泳体的亲核陷阱。此外，NAC不太可能将共价结合的APAP从蛋白质中解离。因此，在先前暴露于APAP长达8小时的培养中观察到的共价结合的总体下降一定是由于依赖于NAC促进芳基化蛋白质的降解。然而，在长期接触APAP后，NAC的无效可能是由于APAP对细胞内蛋白分解系统造成了不可修复的破坏。这些数据表明，NAC的芳基化后效果可能存在于解毒剂恢复蛋白分解系统的功能能力以清除细胞芳基化蛋白的能力。
The post-arylative mechanisms by whichN-acetylcysteine (NAC) reduces the severity of the hepatotoxicity induced by acetaminophen (APAP) were investigated in primary cultures of mouse hepatocytes. When administered at selected times immediately following removal of medium containing 10 mM APAP, 2.0mM NAC was shown to restore glutathione levels through 16 hr of APAP pretreatment and to minimize the leakage of glutamate-oxaloacetate transaminase resulting from the first 8 hr of drug exposure. This temporal difference denned a critical period in which cells were responsive to NAC and permitted the investigation of potential post-arylative mechanisms of the antidote. In the absence of NAC during the recovery period, the cellular loss of covalently-bound APAP could be accounted for by the appearance of arylated proteins in the medium without any apparent degradation of APAP-bound proteins. By contrast, when NAC was present during the recovery period, there was a decrease in intracellular protein-bound APAP which could not be accounted for by that detected in the medium. Since during the recovery period the low residual intracellular concentration of APAP could not contribute significantly to any additional covalent binding in this system, NAC could not merely be acting as a nucleophilic trap for the reactive electrophile. Furthermore, NAC is not likely to dissociate covalently bound APAP from proteins. Hence, the overall decrease in covalent binding observed in cultures previously exposed to APAP for up to 8hr must have arisen from an NAC-dependent enhancement of the degradation of the arylated proteins. However, after a more prolonged exposure to APAP, the ineffectiveness of NAC may have resulted from APAP-induced irreparable damage to the intracellular proteolytic system. These data suggest that the post-arylative efficacy of NAC may reside in the ability of the antidote to restore the functional capacity of the proteolytic system to rid the cells of arylated proteins.
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评估灌注大鼠肝脏中的蛋白质周转率。
DOI：
10.1016/s0021-9258(17)33750-x
发表时间：
1976
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
E. Khairallah;G. E. Mortimore
通讯作者：
G. E. Mortimore
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影响因子：
3.5
作者：
D. Di Cola;P. Sacchetta
通讯作者：
P. Sacchetta
DOI：
10.1016/s0021-9258(17)38834-8
发表时间：
1985-10
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
M. Moore;H. Thor;G. Moore;Sid Nelsons;P. Moldéus;S. Orrenius
通讯作者：
M. Moore;H. Thor;G. Moore;Sid Nelsons;P. Moldéus;S. Orrenius
N-乙酰半胱氨酸对乙酰氨基酚诱导的小鼠肝毒性的吸收后解毒作用。
影响因子：
2.1
作者：
L. Whitehouse;L. Wong;C. Paul;A. Pakuts;G. Solomonraj
通讯作者：
G. Solomonraj
影响因子：
4.1
作者：
D. Schneider;J. Burnside;F. Gorga;C. Nettleton
通讯作者：
C. Nettleton