sodium-propionate and Chemical-and-Drug-Induced-Liver-Injury

Drug-induced liver injury is one of the main causes of drug attrition. The ability to predict the liver effects of drug candidates from their chemical structures is critical to help guide experimental drug discovery projects toward safer medicines. In this study, we have compiled a data set of 951 compounds reported to produce a wide range of effects in the liver in different species, comprising humans, rodents, and nonrodents. The liver effects for this data set were obtained as assertional metadata, generated from MEDLINE abstracts using a unique combination of lexical and linguistic methods and ontological rules. We have analyzed this data set using conventional cheminformatics approaches and addressed several questions pertaining to cross-species concordance of liver effects, chemical determinants of liver effects in humans, and the prediction of whether a given compound is likely to cause a liver effect in humans. We found that the concordance of liver effects was relatively low (ca. 39-44%) between different species, raising the possibility that species specificity could depend on specific features of chemical structure. Compounds were clustered by their chemical similarity, and similar compounds were examined for the expected similarity of their species-dependent liver effect profiles. In most cases, similar profiles were observed for members of the same cluster, but some compounds appeared as outliers. The outliers were the subject of focused assertion regeneration from MEDLINE as well as other data sources. In some cases, additional biological assertions were identified, which were in line with expectations based on compounds' chemical similarities. The assertions were further converted to binary annotations of underlying chemicals (i.e., liver effect vs no liver effect), and binary quantitative structure-activity relationship (QSAR) models were generated to predict whether a compound would be expected to produce liver effects in humans. Despite the apparent heterogeneity of data, models have shown good predictive power assessed by external 5-fold cross-validation procedures. The external predictive power of binary QSAR models was further confirmed by their application to compounds that were retrieved or studied after the model was developed. To the best of our knowledge, this is the first study for chemical toxicity prediction that applied QSAR modeling and other cheminformatics techniques to observational data generated by the means of automate

Topics: Animals; Chemical and Drug Induced Liver Injury; Cluster Analysis; Databases, Factual; Humans; MEDLINE; Mice; Models, Chemical; Molecular Conformation; Quantitative Structure-Activity Relationship

The first objective of this work was to study the conversion of propionate to glucose by liver of the sheep during experimentally induced liver necrosis. An additional objective was to determine the most appropriate sampling time after a propionate load has been given to use glucose concentration as an aid in the diagnosis of disturbed liver function. Sodium propionate (3 mmol/kg) was injected IV into 6 healthy sheep before and after they were given carbon tetrachloride (20% CCl4 in mineral oil; 0.25 ml of CCl4/kg, orally). To differentiate the effects of liver necrosis from the effects of decrease in food intake after CCl4 administration, 5 sheep which were fasted for 2 days, but not given CCl4, were studied. Microscopically, liver necrosis was observed, as well as an increase of fatty infiltration in nonnecrotic liver tissue. After sheep were given CCl4, the plasma liver-specific enzyme activities (namely, those of iditol dehydrogenase and gamma-glutamyl-transferase) were elevated. Microscopic and enzymatic changes were not observed in fasted animals. Serum sulfobromophthalein (BSP) half-life (t1/2) was markedly increased in the sheep given CCl4 treatment (t1/2 = 22.8 +/- 11 minutes) when compared with the t1/2 before treatment (t1/2 = 2.5 +/- 0.2 minutes). The BSP t1/2 did not differ between fed and fasted sheep. The t1/2 of the IV propionate load increased significantly, from 6.9 +/- 0.4 minutes in the control sheep to 12.8 +/- 2 minutes in the CCl4-treated sheep, whereas an insignificant increase was seen after fasting (6.8 +/- 1 minutes to 8.3 +/- 1 minutes.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Blood Glucose; Carbon Tetrachloride; Chemical and Drug Induced Liver Injury; Female; Gluconeogenesis; Liver; Liver Diseases; Liver Function Tests; Necrosis; Propionates; Sheep; Sheep Diseases