menthofuran and Chemical-and-Drug-Induced-Liver-Injury

Acetaminophen and pulegone are just two examples for many agents that can form reactive metabolites that can cause acute liver injury. Two other classic organic compounds that have been extensively studied are carbon tetrachloride (for a recent review see Ref. 159, and for other discussions see Refs. 8 and 9) and bromobenzene (for review see Ref. 160). Different kinds of protein adducts of reactive metabolites of bromobenzene have been partially characterized [161], and specific antibodies to these adducts are now being used to isolate and identify the proteins that are modified (162). In contrast, carbon tetrachloride and other agents, such as the herbicide diquat, may form radicals that bind to and/or oxidize lipids and proteins in causing liver injury (163, 164). Therefore, the recent development [165] of antibodies to detect oxidative damage to proteins will be important in the identification and characterization of macromolecules that do not form adducts with reactive metabolites but are damaged oxidatively. Thus, some major challenges in the coming years are to identify hepatocellular macromolecules that are modified by reactive metabolites, and then approach the more difficult task of integrating this information into a time course and sequence of events leading to lethal hepatocellular injury.

Topics: Acetaminophen; Animals; Chemical and Drug Induced Liver Injury; Cyclohexane Monoterpenes; Humans; Menthol; Monoterpenes; Pharmaceutical Preparations; Terpenes

Topics: Acetaminophen; Aged; Biological Variation, Individual; Biomarkers; Chemical and Drug Induced Liver Injury; Cyclohexane Monoterpenes; Female; Humans; Liver; Male; MicroRNAs; Middle Aged; Monoterpenes

Drug-induced liver injury is the most common cause of market withdrawal of pharmaceuticals, and thus, there is considerable need for better prediction models for DILI early in drug discovery. We present a study involving 223 marketed drugs (51% associated with clinical hepatotoxicity; 49% non-hepatotoxic) to assess the concordance of in vitro bioactivation data with clinical hepatotoxicity and have used these data to develop a decision tree to help reduce late-stage candidate attrition. Data to assess P450 metabolism-dependent inhibition (MDI) for all common drug-metabolizing P450 enzymes were generated for 179 of these compounds, GSH adduct data generated for 190 compounds, covalent binding data obtained for 53 compounds, and clinical dose data obtained for all compounds. Individual data for all 223 compounds are presented here and interrogated to determine what level of an alert to consider termination of a compound. The analysis showed that 76% of drugs with a daily dose of <100 mg were non-hepatotoxic (p < 0.0001). Drugs with a daily dose of ≥100 mg or with GSH adduct formation, marked P450 MDI, or covalent binding ≥200 pmol eq/mg protein tended to be hepatotoxic (∼ 65% in each case). Combining dose with each bioactivation assay increased this association significantly (80-100%, p < 0.0001). These analyses were then used to develop the decision tree and the tree tested using 196 of the compounds with sufficient data (49% hepatotoxic; 51% non-hepatotoxic). The results of these outcome analyses demonstrated the utility of the tree in selectively terminating hepatotoxic compounds early; 45% of the hepatotoxic compounds evaluated using the tree were recommended for termination before candidate selection, whereas only 10% of the non-hepatotoxic compounds were recommended for termination. An independent set of 10 GSK compounds with known clinical hepatotoxicity status were also assessed using the tree, with similar results.

Topics: Chemical and Drug Induced Liver Injury; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Decision Trees; Drug Evaluation, Preclinical; Drug-Related Side Effects and Adverse Reactions; Glutathione; Humans; Liver; Pharmaceutical Preparations; Protein Binding

Effect of C-phycocyanin (from Spirulina platensis) pretreatment on carbontetrachloride and R-(+)-pulegone-induced hepatotoxicity in rats was studied. Intraperitoneal (i.p.) administration (200 mg/kg) of a single dose of phycocyanin to rats, one or three hours prior to R-(+)-pulegone (250 mg/kg) or carbontetrachloride (0.6 ml/kg) challenge, significantly reduced the hepatotoxicity caused by these chemicals. For instance, serum glutamate pyruvate transaminase (SGPT) activity was almost equal to control values. The losses of microsomal cytochrome P450, glucose-6-phosphatase and aminopyrine-N-demethylase were significantly reduced, suggesting that phycocyanin provides protection to liver enzymes. It was noticed that the level of menthofuran, the proximate toxin of R-(+)-pulegone was nearly 70% more in the urine samples collected from rats treated with R-(+)-pulegone alone than rats treated with the combination of phycocyanin and R-(+)-pulegone. The possible mechanism involved in the hepatoprotection is discussed.

Topics: Alanine Transaminase; Aminopyrine N-Demethylase; Animals; Carbon Tetrachloride; Chemical and Drug Induced Liver Injury; Cyclohexane Monoterpenes; Cytochrome P-450 Enzyme System; Glucose-6-Phosphatase; Liver; Liver Diseases; Male; Menthol; Microsomes, Liver; Monoterpenes; Phycocyanin; Rats; Terpenes