Acetaminophen inhibits hemoprotein-catalyzed lipid peroxidation and attenuates rhabdomyolysis-induced renal failure

被引:134
作者
Boutaud, Olivier [1 ]
Moore, Kevin P. [5 ,6 ]
Reeder, Brandon J. [4 ]
Harry, David [5 ,6 ]
Howie, Alexander J. [5 ,6 ]
Wang, Shuhe [1 ]
Carney, Clare K. [3 ]
Masterson, Tina S. [1 ]
Amin, Taneem [1 ]
Wright, David W. [3 ]
Wilson, Michael T. [4 ]
Oates, John A. [1 ,2 ]
Roberts, L. Jackson, II [1 ,2 ]
机构
[1] Vanderbilt Univ, Dept Pharmacol, Nashville, TN 37232 USA
[2] Vanderbilt Univ, Dept Med, Nashville, TN 37232 USA
[3] Vanderbilt Univ, Dept Chem, Nashville, TN 37232 USA
[4] Univ Essex, Dept Biol Sci, Colchester CO4 3SQ, Essex, England
[5] UCL, Sch Med, Dept Med, London NW3 2QG, England
[6] UCL, Sch Med, Dept Pathol, London NW3 2QG, England
基金
英国生物技术与生命科学研究理事会; 英国医学研究理事会;
关键词
isoprostanes; oxidative damage; hemoglobin; myoglobin; HYDROGEN-PEROXIDE; OXIDATIVE STRESS; SUBARACHNOID HEMORRHAGE; FERRYL HEME; IN-VIVO; MYOGLOBIN; HEMOGLOBIN; RADICALS; F-2-ISOPROSTANES; HYDROPEROXIDE;
D O I
10.1073/pnas.0910174107
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Hemoproteins, hemoglobin and myoglobin, once released from cells can cause severe oxidative damage as a consequence of heme redox cycling between ferric and ferryl states that generates radical species that induce lipid peroxidation. We demonstrate in vitro that acetaminophen inhibits hemoprotein-induced lipid peroxidation by reducing ferryl heme to its ferric state and quenching globin radicals. Severe muscle injury (rhabdomyolysis) is accompanied by the release of myoglobin that becomes deposited in the kidney, causing renal injury. We previously showed in a rat model of rhabdomyolysis that redox cycling between ferric and ferryl myoglobin yields radical species that cause severe oxidative damage to the kidney. In this model, acetaminophen at therapeutic plasma concentrations significantly decreased oxidant injury in the kidney, improved renal function, and reduced renal damage. These findings also provide a hypothesis for potential therapeutic applications for acetaminophen in diseases involving hemoprotein-mediated oxidative injury.
引用
收藏
页码:2699 / 2704
页数:6
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