glycodeoxycholic-acid and Chemical-and-Drug-Induced-Liver-Injury

Metabolomics approaches have enabled the study of new mechanisms of liver injury in experimental models of drug toxicity. Disruption of bile acid homeostasis is a known mechanism of drug induced liver injury. The relationship of individual bile acids to indicators of oxidative drug metabolism (acetaminophen protein adducts) and liver injury was examined in children with acetaminophen overdose, hospitalized children with low dose exposure to acetaminophen, and children with no recent exposure to acetaminophen. Nine bile acids were quantified through targeted metabolomic analysis in the serum samples of the three groups. Bile acids were compared to serum levels of acetaminophen protein adducts and alanine aminotransferase. Glycodeoxycholic acid, taurodeoxycholic acid, and glycochenodeoxycholic acid were significantly increased in children with acetaminophen overdose compared to healthy controls. Among patients with acetaminophen overdose, bile acids were higher in subjects with acetaminophen protein adduct values > 1.0 nmol/mL and modest correlations were noted for three bile acids and acetaminophen protein adducts as follows: taurodeoxycholic acid (R=0.604; p<0.001), glycodeoxycholic acid (R=0.581; p<0.001), and glycochenodeoxycholic acid (R=0.571; p<0.001). Variability in bile acids was greater among hospitalized children receiving low doses of acetaminophen than in healthy children with no recent acetaminophen exposure. Compared to bile acids, acetaminophen protein adducts more accurately discriminated among children with acetaminophen overdose, children with low dose exposure to acetaminophen, and healthy control subjects. In children with acetaminophen overdose, elevations of conjugated bile acids were associated with specific indicators of acetaminophen metabolism and non-specific indicators of liver injury.

Topics: Acetaminophen; Adolescent; Alanine Transaminase; Bile Acids and Salts; Biomarkers; Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Diagnosis, Differential; Drug Overdose; Female; Glycochenodeoxycholic Acid; Glycodeoxycholic Acid; Homeostasis; Humans; Male; Metabolomics; Protein Binding; Sensitivity and Specificity; Taurodeoxycholic Acid

A UPLC-MS/MS method based on metabonomic skills was developed to study the serum metabolic changes of rats after acute liver injury induced by CCl4 and to evaluate the action mechanism of Si-Ni-San. The integrated data were exported for principal components analysis (PCA) by using SIMCA-P software, in order to find the potential biomarkers. It showed that clear separation of healthy control group, model group, silymarin group, Si-Ni-San group was achieved by using the PCA method. Nine significantly changed metabolites were identified as potential biomarkers of acute liver injury. Compared with the health control group, the model group rats showed higher levels of phenylalanine, tryptophan and GCDCA together with lower levels of LPC 16 : 0, LPC 18 : 0, LPC 18 : 1, LPC 16 : 1, LPC 20 : 4 and LPC 22 : 6. These changes of serum metabolites suggested that the disorders of amino acid metabolism, lipid metabolism, bile acid biosynthesis and anti-oxidative damage were related to acute liver injury induced by CCl4. Si-Ni-San might have the anti-liver injury effect on all these four metabolic pathways.

Topics: Animals; Carbon Tetrachloride Poisoning; Chemical and Drug Induced Liver Injury; Chromatography, High Pressure Liquid; Drugs, Chinese Herbal; Glycodeoxycholic Acid; Lysophosphatidylcholines; Male; Metabolomics; Phenylalanine; Plants, Medicinal; Principal Component Analysis; Random Allocation; Rats; Rats, Sprague-Dawley; Tandem Mass Spectrometry; Tryptophan

Acetaminophen (APAP)-induced acute liver failure (ALF) remains a major clinical problem. Although a majority of patients recovers after severe liver injury, a subpopulation of patients proceeds to ALF. Bile acids are generated in the liver and accumulate in blood during liver injury, and as such, have been proposed as biomarkers for liver injury and dysfunction. The goal of this study was to determine whether individual bile acid levels could determine outcome in patients with APAP-induced ALF (AALF). Serum bile acid levels were measured in AALF patients using mass spectrometry. Bile acid levels were elevated 5-80-fold above control values in injured patients on day 1 after the overdose and decreased over the course of hospital stay. Interestingly, glycodeoxycholic acid (GDCA) was significantly increased in non-surviving AALF patients compared with survivors. GDCA values obtained at peak alanine aminotransferase (ALT) and from day 1 of admission indicated GDCA could predict survival in these patients by receiver-operating characteristic analysis (AUC = 0.70 for day 1, AUC = 0.68 for peak ALT). Of note, AALF patients also had significantly higher levels of serum bile acids than patients with active cholestatic liver injury. These data suggest measurements of GDCA in this patient cohort modestly predicted outcome and may serve as a prognostic biomarker. Furthermore, accumulation of bile acids in serum or plasma may be a result of liver cell dysfunction and not cholestasis, suggesting elevation of circulating bile acid levels may be a consequence and not a cause of liver injury.

Topics: Acetaminophen; Adult; Biomarkers; Case-Control Studies; Chemical and Drug Induced Liver Injury; Cholestasis; Drug Overdose; Female; Glycodeoxycholic Acid; Humans; Liver Function Tests; Male; Middle Aged; Predictive Value of Tests; Young Adult

The interrelationship between the biliary secretion of phospholipids, bilirubin and bile acids was studied in New Zealand rabbits after acinar zone 3 hepatocyte damage induced by bromobenzene (4 mmol/kg body wt; i.p.). Treatment with the toxin did not significantly modify biliary phospholipid secretion, suggesting that the transport of phospholipids is mainly a zone 1 function. Bilirubin infusion at 1 mumol/min kg body wt induced a significant inhibition in biliary phospholipid secretion both in control and treated animals. This effect was overcome by the additional infusion of sodium glycodeoxycholate at 1.6 mumol/min kg body wt, although higher increases in phospholipid output were found in the control than in the treated rabbits. This would be related to the lowered recruitment of zone 3 cells for secretion in bromobenzene-damaged livers.

Topics: Animals; Bile; Bile Acids and Salts; Bilirubin; Bromobenzenes; Chemical and Drug Induced Liver Injury; Glycodeoxycholic Acid; Liver Diseases; Male; Phospholipids; Rabbits

Anaesthetized rabbits were used to study the effect of bromobenzene-induced hepatic damage to the acinar zone 3 on bile flow, bile salt, sodium secretion as well as bilirubin transport in basal conditions or with infusion of sodium glycodeoxycholate. The bromobenzene-pretreated animals exhibited in basal conditions a lower bile flow (44%) than that of the controls, with a smaller decrease in bile salt output (27%) and sodium output (29%), whereas no modification in endogenous bilirubin excretion was observed. The bile salt independent fraction of secretion (BSIF) was reduced significantly after the toxic lesion both in terms of absolute and relative values. The hepatocytes of the periportal zone were capable of excreting the totality of bilirubin presented to the liver, regardless of the extent of bile flow or the input of bile salts. The infusion of bilirubin at 1.0 mumole/kg/min led to a fall in bile flow which was attributed to the interference of the pigment with the BSIF. The maximal bilirubin excretion was significantly smaller in bromobenzene-pretreated animals than in the controls, which could be due to the incapacity of the intoxicated rabbits to recruit quiescent hepatocytes. When glycodeoxycholate was administered under conditions of maximal bilirubin transport, bile flow increased as did bile salt secretion in both controls and animals with damaged livers. However, clear differences persisted between the two, which could be attributed not only to the volume fraction of necrosis but also to an interference by bilirubin with the hepatic handling of bile salts. Maximal bilirubin excretion increased in a similar way in both groups after glycodeoxycholate administration. It is proposed that glycodeoxycholate infusion facilitates the hepatic depletion of bilirubin, probably by stimulating transport processes.

Topics: Animals; Bile; Bile Acids and Salts; Bilirubin; Bromobenzenes; Chemical and Drug Induced Liver Injury; Female; Glycodeoxycholic Acid; Infusions, Parenteral; Liver; Liver Diseases; Male; Rabbits