Protection by bicyclol derivatives against acetaminophen‐induced acute liver failure in mice and its active mechanism

Abstract

To find a novel drug against acute liver failure, a methionine derivative of bicyclol (WLP-S-10) was studied in acetaminophen-injected mice. 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. 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. 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.