Acetaminophen inhibits hemoprotein-catalyzed lipid peroxidation and attenuates rhabdomyolysis-induced renal failure.
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.
Boutaud
Olivier
O
Department of Pharmacology, Medicine, and Chemistry, Vanderbilt University, Nashville, TN 37232, USA. olivier.boutaud@vanderbilt.edu
Moore
Kevin P
KP
Reeder
Brandon J
BJ
Harry
David
D
Howie
Alexander J
AJ
Wang
Shuhe
S
Carney
Clare K
CK
Masterson
Tina S
TS
Amin
Taneem
T
Wright
David W
DW
Wilson
Michael T
MT
Oates
John A
JA
Roberts
L Jackson
LJ
D000082:Acetaminophen / Q000494:pharmacology*; D000818:Animals; D001095:Arachidonic Acids / Q000737:chemistry / Q000378:metabolism; D002384:Catalysis / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006420:Hemeproteins / Q000737:chemistry / Q000378:metabolism*; D006454:Hemoglobins / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration; D007501:Iron / Q000737:chemistry / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects*; D008297:Male; D009211:Myoglobin / Q000737:chemistry / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D051437:Renal Insufficiency / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D012206:Rhabdomyolysis / Q000150:complications* / Q000378:metabolism; D013053:Spectrophotometry
D001095:Arachidonic Acids; D006420:Hemeproteins; D006454:Hemoglobins; D009211:Myoglobin; D000082:Acetaminophen; D006861:Hydrogen Peroxide; D007501:Iron