Acetaminophen inhibits cytochrome c redox cycling induced lipid peroxidation.
Cytochrome (cyt) c can uncouple from the respiratory chain following mitochondrial stress and catalyze lipid peroxidation. Accumulating evidence shows that this phenomenon impairs mitochondrial respiratory function and also initiates the apoptotic cascade. Therefore, under certain conditions a pharmacological approach that can inhibit cyt c catalyzed lipid peroxidation may be beneficial. We recently showed that acetaminophen (ApAP) at normal pharmacologic concentrations can prevent hemoprotein-catalyzed lipid peroxidation in vitro and in vivo by reducing ferryl heme to its ferric state. We report here, for the first time, that ApAP inhibits cytochrome c-catalyzed oxidation of unsaturated free fatty acids and also the mitochondrial phospholipid, cardiolipin. Using isolated mitochondria, we also showed that ApAP inhibits cardiolipin oxidation induced by the pro-apoptotic protein, tBid. We found that the IC(50) of the inhibition of cardiolipin oxidation by ApAP is similar in both intact isolated mitochondria and cardiolipin liposomes, suggesting that ApAP penetrates well into the mitochondria. Together with our previous results, the findings presented herein suggest that ApAP is a pleiotropic inhibitor of peroxidase catalyzed lipid peroxidation. Our study also provides a potentially novel pharmacological approach for inhibiting the cascade of events that can result from redox cycling of cyt c.
Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University School of Medicine, TN 37232, USA. hyyin@sibs.ac.cn
Huiyong
H
Yin
Aurélia
A
Vergeade
Qiong
Q
Shi
William E
WE
Zackert
Katherine C
KC
Gruenberg
Magdalena
M
Bokiej
Taneem
T
Amin
Weizhen
W
Ying
Tina S
TS
Masterson
Sandra S
SS
Zinkel
John A
JA
Oates
Olivier
O
Boutaud
L Jackson
LJ
Roberts
D000082:Acetaminophen / Q000494:pharmacology*; D018712:Analgesics, Non-Narcotic / Q000494:pharmacology*; D016718:Arachidonic Acid / Q000378:metabolism; D002308:Cardiolipins / Q000378:metabolism; D002384:Catalysis; D045304:Cytochromes c / Q000378:metabolism*; D005231:Fatty Acids, Unsaturated / Q000378:metabolism*; D006801:Humans; D015227:Lipid Peroxidation / Q000187:drug effects*; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology; D010084:Oxidation-Reduction / Q000187:drug effects
D018712:Analgesics, Non-Narcotic; D002308:Cardiolipins; D005231:Fatty Acids, Unsaturated; D016718:Arachidonic Acid; D000082:Acetaminophen; D045304:Cytochromes c