bicyclol and Liver-Failure--Acute

Bicyclol [4,4'-dimethoxy-5,6,5',6'-bis(methylenedioxy)-2-hydroxy-methyl-2'-methoxycarbonyl biphenyl] is a synthetic hepatoprotectant widely used in clinical practice, but resistance to this treatment is often observed. We found that the hepatoprotective effect of bicyclol was greatly compromised in female and castrated male mice. This study was to dissect the molecular basis behind the sex difference, which might underlie the clinical uncertainty. We compared bicyclol-induced hepatoprotection between male and female mice using acute liver damage models. Inducible knockout by the Cre/loxp system was used to decipher the role of heat shock transcription factor 1 (HSF1). Functional experiments, western blot, and histopathological analysis were used to determine the key causative factors which might antagonize bicyclol in female livers. HSF1 activation and heat shock protein 70 (Hsp70) expression, which were responsible for bicyclol-induced hepatoprotection, were compromised in female and castrated male livers. Compromised HSF1 activation was a result of HSF1 phosphorylation at serine 303, which was catalyzed by glycogen synthase kinase 3β (GSK3β). Testosterone was necessary for bicyclol to inhibit hepatic GSK3β activity. Administration of testosterone or GSK3β inhibitors restored bicyclol-induced protection in females. Bicyclol induces sex-specific hepatoprotection based on a sex-specific HSF1/Hsp70 response, in which testosterone and GSK3β play key roles. Because a lot of patients suffering from liver diseases have very low testosterone levels, our results give a possible explanation for the clinical variation in bicyclol-induced hepatoprotection, as well as practicable solutions to improve the effect of bicyclol.

Topics: Animals; Biphenyl Compounds; Cytoprotection; Disease Models, Animal; DNA-Binding Proteins; Female; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Heat Shock Transcription Factors; HSP70 Heat-Shock Proteins; Liver Failure, Acute; Male; Mice; Orchiectomy; Phosphorylation; Sex Characteristics; Testosterone; Transcription Factors

The aim of present study is to evaluate the pharmacokinetics of bicyclol in carbon tetrachloride (CCl(4))-intoxicated rats. The plasma concentration of bicyclol was detected in rats after a single oral or intravenous administration by high-performance liquid chromatography (HPLC) analysis. Rat intestinal and hepatic perfusion models were employed to clarify the respective effect of gut and liver on the pharmacokinetics of bicyclol in acute hepatic failure (AHF) rats. Rat in vitro microsomal incubation was also conducted. The bioavailability of bicyclol was increased 3.1-fold after CCl(4) intoxication in rats. The area under the curve (AUC)((0-infinity)), C(max), and clearance (CL) of bicyclol after intravenous administration were 13.4 mg h l(-1), 18.8 mg l(-1), and 1.8 l h(-1) kg(-1) in control rats, and 130 mg h l(-1), 33.1 mg l(-1), and 0.15 l h(-1) kg(-1) in AHF rats, respectively. In the present study we investigated the pharmacokinetics of bicyclol in CCl(4)-intoxicated rats and differentiated the respective role of intestine and liver by using in situ intestinal and hepatic perfusion in rats, and in vitro rat microsomes incubation. The studies are expected to provide a better understanding related to the alteration of pharmacokinetics of bicyclol in pathological situation.

Topics: Animals; Biphenyl Compounds; Carbon Tetrachloride; Liver Failure, Acute; Male; Microsomes, Liver; Protective Agents; Rats; Rats, Sprague-Dawley

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.

Topics: Acetaminophen; Adenosine Triphosphate; Analgesics, Non-Narcotic; Animals; Apoptosis; Apoptosis Inducing Factor; Benzodioxoles; Biphenyl Compounds; Cytochromes c; Glutathione; Liver; Liver Failure, Acute; Male; Membrane Potential, Mitochondrial; Methionine; Mice; Mitochondria, Liver; Mitochondrial Swelling; Necrosis

Bicyclol, a new anti-hepatitis drug, has been found to protect against liver injury induced by certain hepatotoxins. The present study was to investigate the effect of bicyclol on acute hepatic failure caused by an intraperitoneal injection of lipopolysaccharide (LPS, 15 microg/kg) and D-galactosamine (800 mg/kg) in mice. Bicyclol (150, 300 mg/kg) was given to mice orally once or three doses before the injection of LPS/D-galactosamine. The liver injury was assessed biochemically and histologically. The mortality in mice was monitored for 48 h after LPS/D-galactosamine poisoning. The expressions of cytokines, adhesion molecules and LPS receptors were determined. As a result, bicyclol showed significant protection as evidenced by the decrease of elevated aminotransferases and total bilirubin, reversion of prolonged prothrombin time and improvement of liver pathological injury in a dose-dependent manner. Pretreatment with bicyclol (300 mg/kg) also lowered the mortality after LPS/GalN intoxication. Furthermore, bicyclol inhibited the elevation of serum tumor necrosis factor-alpha, interferon-gamma and markedly enhanced interleukin-10. The expressions of intercellular adhesion molecule-1, lymphocyte function-associated antigen 1 and the transcription of CD14 and toll-like receptor 4 were also suppressed by bicyclol. These results suggest that bicyclol has remarkable hepatoprotective effects on LPS/D-galactosamine-induced liver injury and the possible mechanism is related to its anti-inflammatory action.

Topics: Animals; Anti-Inflammatory Agents; Biphenyl Compounds; Blood Coagulation; Dose-Response Relationship, Drug; Galactosamine; Gene Expression Regulation; Intercellular Adhesion Molecule-1; Interferon-gamma; Interleukin-10; Lipopolysaccharide Receptors; Lipopolysaccharides; Liver; Liver Failure, Acute; Lymphocyte Function-Associated Antigen-1; Male; Mice; Mice, Inbred ICR; RNA, Messenger; Time Factors; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha