大鼠肝脏ADP - 核糖焦磷酸酶 - I作为对乙酰氨基酚代谢产物N - 乙酰 - 对苯醌亚胺的体外靶点。

Rat liver ADP-ribose pyrophosphatase-I as an in vitro target of the acetaminophen metabolite N-acetyl-p-benzoquinoneimine.

作者信息

Ribeiro J M, Agudo A, Costas M J, Cameselle J C

机构信息

Unidad de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad de Extremadura, Badajoz, Spain.

出版信息

Biochim Biophys Acta. 1997 Oct 20;1336(3):403-8. doi: 10.1016/s0304-4165(97)00051-2.

DOI:10.1016/s0304-4165(97)00051-2

PMID:9367167

Abstract

N-acetyl-p-benzoquinoneimine (NAPQI) is the metabolite responsible for acetaminophen hepatotoxicity. ADP-ribose pyrophosphatase-I (ADPRibase-I; EC 3.6.1.13) hydrolyzes protein-glycating ADP-ribose. The results show NAPQI-dependent alterations of ADPRibase-I leading to strong inhibition: a fast Km increase produced by low concentrations, and a time-dependent Vmax decrease by higher NAPQI concentrations. Both effects were prevented by thiols, but not reverted by them, nor by gel filtration of NAPQI-treated enzyme. Liver ADPRibase-I can be a target of NAPQI-dependent arylation. The inhibition or inactivation of the enzyme would contribute to increasing the free ADP-ribose concentration and nonenzymatic ADP-ribosylation, which is coherent with results linking free ADP-ribose-producing pathways to acetaminophen toxicity.

摘要

N-乙酰对苯醌亚胺（NAPQI）是对乙酰氨基酚肝毒性的代谢产物。ADP-核糖焦磷酸酶-I（ADPRibase-I；EC 3.6.1.13）可水解蛋白质糖化的ADP-核糖。结果显示，NAPQI会导致ADPRibase-I发生改变，从而产生强烈抑制作用：低浓度时会快速增加Km值，高浓度NAPQI则会使Vmax随时间降低。这两种效应均可被硫醇类物质阻止，但不能被其逆转，也不能通过对经NAPQI处理的酶进行凝胶过滤来逆转。肝脏ADPRibase-I可能是NAPQI依赖性芳基化的靶点。该酶的抑制或失活将有助于增加游离ADP-核糖的浓度以及非酶促ADP-核糖基化，这与将游离ADP-核糖产生途径与对乙酰氨基酚毒性联系起来的结果相一致。