Mangafodipir prevents liver injury induced by acetaminophen in the mouse.
OBJECTIVE
Acute liver failure (ALF), characterized by massive hepatocyte necrosis, is often caused by drug poisoning, particularly with acetaminophen (APAP). Hepatocyte necrosis is consecutive to glutathione depletion by NAPQI, a metabolite of APAP, and to mitochondrial damages caused by reactive oxygen species (ROS) overproduction. Considering the structure of Mangafodipir, a contrast agent currently used in magnetic resonance imaging of the liver, we hypothesized that this molecule could exert an antioxidant activity and be possibly used as a treatment of APAP-induced ALF.


RESULTS
Mangafodipir is endowed with superoxide dismutase, catalase, and glutathione reductase activities. It can inhibit ROS production by hepatocytes in culture, and protect those cells from oxidative stresses induced by exposure to xanthine oxidase, H(2)O(2), or UV light. Moreover, preventive or curative administration of Mangafodipir to mice with APAP-induced ALF significantly increases survival rates, and abrogates aspartate aminotransferase elevation and histological damage.


CONCLUSIONS
Those data point out the potential interest of Mangafodipir in the treatment of toxic ALF in humans.
Laboratoire d'Immunologie, UPRES 1833, Faculté Cochin, Pavillon Hardy, Université Paris V, AP-HP, 75679 Paris Cedex 14, France.
Sassia
S
Bedda
Alexis
A
Laurent
Filomena
F
Conti
Chistiane
C
Chéreau
Agnès
A
Tran
Jeanne
J
Tran-Van Nhieu
Patrick
P
Jaffray
Olivier
O
Soubrane
Claire
C
Goulvestre
Yvon
Y
Calmus
Bernard
B
Weill
Frédéric
F
Batteux
D000082:Acetaminophen / Q000378:metabolism / Q000506:poisoning*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology; D053148:Caspase 3; D061945:Caspase Inhibitors; D045744:Cell Line, Tumor; D045304:Cytochromes c / Q000037:antagonists & inhibitors; D004492:Edetic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D004798:Enzymes / Q000097:blood; D005260:Female; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000473:pathology; D017114:Liver Failure, Acute / Q000139:chemically induced* / Q000503:physiopathology / Q000517:prevention & control*; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D010088:Oxidoreductases / Q000494:pharmacology; D011732:Pyridoxal Phosphate / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors; D013481:Superoxides / Q000037:antagonists & inhibitors; D016019:Survival Analysis; D019014:fas Receptor / Q000276:immunology
D000911:Antibodies, Monoclonal; D000975:Antioxidants; D061945:Caspase Inhibitors; D004798:Enzymes; D017382:Reactive Oxygen Species; D019014:fas Receptor; D013481:Superoxides; D000082:Acetaminophen; D011732:Pyridoxal Phosphate; D045304:Cytochromes c; D004492:Edetic Acid; D010088:Oxidoreductases; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D005978:Glutathione; C060076:N,N'-bis(pyridoxal-5-phosphate)ethylenediamine-N,N'-diacetic acid