微粒体
化学
体外
对乙酰氨基酚
细胞色素
生物化学
体内
肝毒素
代谢物
烟酰胺腺嘌呤二核苷酸磷酸
氧化酶试验
结合位点
毒性
酶
生物
生物技术
有机化学
作者
William Z. Potter,Dawn C. Davis,John R. Mitchell,David J. Jollow,J R Gillette,B.B. Brodie
出处
期刊:PubMed
日期:1973-10-01
卷期号:187 (1): 203-10
被引量:495
摘要
The binding of 3 H-acetaminophen to hepatic microsomes was studied in vitro . Binding of 3 H-acetaminophen to rat and mouse microsomal protein was linear with time and with protein concentration. Binding occurred by covalent linkage to amino acids of protein. Reduced nicotinamide adenine dinueleotide phosphate and oxygen were necessary for the binding while carbon monoxide or cobaltous chloride pretreatment inhibited it, demonstrating that a cytochrome P-450-dependent. mixed function oxidase mediated the binding. The extent of in vitro binding correlated with treatments that alter hepatic necrosis and in vivo binding, indicating that in vitro binding was a valid index of acetaminophen-induced hepatotoxicity. Analogous studies with 2-acetylaminofluorene showed that its binding to microsomal protein also was dependent on cytochrome P-450. Since the toxicity of 2-acetylaminofluorene results from its conversion to an N-hydroxy derivative, the collective data are consistent with the hypothesis that the hepatotoxic metabolite of acetaminmophen may be an N-hydroxy derivative.
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