Protection by bicyclol derivatives against acetaminophen-induced acute liver failure in mice and its active mechanism.
OBJECTIVE
To find a novel drug against acute liver failure, a methionine derivative of bicyclol (WLP-S-10) was studied in acetaminophen-injected mice.


METHODS
At first, 10 derivatives of bicyclol were tested in male KunMing strain mice injected with CCl(4), acetaminophen or d-galactosamine plus lipopolysaccharide (LPS), serum alanine aminotransferase (ALT) and mortality rate were determined. Among the 10 derivatives, a methionine derivative of bicyclol (WLP-S-10) was shown to be the most effective. A single dose of WLP-S-10 200 mg/kg was intraperitoneally injected 1 h before administration of a lethal dose of acetaminophen; the mortality rate, liver lesions, serum ALT, aspartate aminotransferase (AST) and liver glutathione (GSH) were determined. Mitochondrial GSH and adenosine triphosphate (ATP) levels, cytochrome C and apoptosis-inducing factor (AIF) leakage, mitochondrial swelling and membrane potential were determined.


RESULTS
As a result, WLP-S-10 200 mg/kg significantly reduced liver injury induced by CCl(4) and decreased the mortality rate of mice because of acute liver failure caused by lethal dosage of acetaminophen or d-galactosamine plus LPS. WLP-S-10 200 mg/kg markedly reduced liver necrosis, serum ALT and AST elevation and GSH depletion after injection of acetaminophen. WLP-S-10 inhibited mitochondrial swelling, breakdown of membrane potential and depletion of mitochondrial ATP, and also reduced release of cytochrome C and AIF from mitochondria induced by acetaminophen.


CONCLUSIONS
The results indicate that WLP-S-10 is a novel potential compound against acetaminophen-induced acute liver failure in mice, and its active mechanism is mainly related to protection against necrosis and apoptosis of hepatocytes through inhibition of mitochondrial energy (ATP) depletion and AIF and cytochrome C release.
Hou
Yan
Y
Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Li
Libo
L
Wei
Huailing
H
Wu
Liping
L
Tong
Yuanfeng
Y
Wu
Song
S
Liu
Gengtao
G
D000082:Acetaminophen / Q000009:adverse effects*; D000255:Adenosine Triphosphate / Q000378:metabolism; D018712:Analgesics, Non-Narcotic / Q000009:adverse effects*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051033:Apoptosis Inducing Factor / Q000378:metabolism; D052117:Benzodioxoles / Q000494:pharmacology / Q000627:therapeutic use*; D001713:Biphenyl Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D045304:Cytochromes c / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D017114:Liver Failure, Acute / Q000139:chemically induced / Q000517:prevention & control*; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008715:Methionine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism; D008933:Mitochondrial Swelling / Q000187:drug effects; D009336:Necrosis / Q000517:prevention & control
D018712:Analgesics, Non-Narcotic; D051033:Apoptosis Inducing Factor; D052117:Benzodioxoles; D001713:Biphenyl Compounds; C534890:WLP-S-10; D000082:Acetaminophen; D000255:Adenosine Triphosphate; D045304:Cytochromes c; C477843:bicyclol; D008715:Methionine; D005978:Glutathione