pantetheine and Chemical-and-Drug-Induced-Liver-Injury

Pretreatment of mice with the peroxisome proliferator clofibrate (CFB) protects against acetaminophen (APAP)-induced hepatotoxicity. Previous studies have shown that activation of the nuclear peroxisome proliferator activated receptor-alpha (PPARalpha) is required for this effect. The present study utilizes gene expression profile analysis to identify potential pathways contributing to PPARalpha-mediated hepatoprotection. Gene expression profiles were compared between wild type and PPARalpha-null mice pretreated with vehicle or CFB (500 mg/kg, i.p., daily for 10 days) and then challenged with APAP (400 mg/kg, p.o.). Total hepatic RNA was isolated 4 h after APAP treatment and hybridized to Affymetrix Mouse Genome MGU74 v2.0 GeneChips. Gene expression analysis was performed utilizing GeneSpring software. Our analysis identified 53 genes of interest including vanin-1, cell cycle regulators, lipid-metabolizing enzymes, and aldehyde dehydrogenase 2, an acetaminophen binding protein. Vanin-1 could be important for CFB-mediated hepatoprotection because this protein is involved in the synthesis of cysteamine and cystamine. These are potent antioxidants capable of ameliorating APAP toxicity in rodents and humans. HPLC-ESI/MS/MS analysis of liver extracts indicates that enhanced vanin-1 gene expression results in elevated cystamine levels, which could be mechanistically associated with CFB-mediated hepatoprotection.

Topics: Acetaminophen; Acyl-CoA Oxidase; Amidohydrolases; Animals; Anticholesteremic Agents; Cell Adhesion Molecules; Chemical and Drug Induced Liver Injury; Clofibrate; Cluster Analysis; Cystamine; Cysteamine; Enoyl-CoA Hydratase; Gene Expression Profiling; GPI-Linked Proteins; Liver; Liver Diseases; Malate Dehydrogenase; Male; Mice; Mice, Inbred Strains; Mice, Knockout; Oligonucleotide Array Sequence Analysis; Pantetheine; Pantothenic Acid; Peroxisome Proliferators; PPAR alpha; Proteasome Endopeptidase Complex; Reverse Transcriptase Polymerase Chain Reaction

The daily ip administration of pantethine (500 mg/kg), pantothenic acid (100 mg/kg) or cystamine (50 mg/kg) for 5 days conferred significant protection against the hepatotoxic and peroxidative actions of a 0.5 mL/kg ip dose of CCl4 in rats. All three treatments lessened the increases in serum ALT and liver TBARS values, and the reductions in serum triglyceride levels, and prevented the development of hepatic steatosis caused by the halocarbon. Pantethine was found to offer the greatest protection.

Topics: Alanine Transaminase; Animals; Carbon Tetrachloride; Carbon Tetrachloride Poisoning; Chemical and Drug Induced Liver Injury; Cholesterol; Cystamine; Lipid Metabolism; Liver; Male; Pantetheine; Pantothenic Acid; Rats; Rats, Inbred Strains; Sulfhydryl Compounds; Triglycerides

Topics: Adult; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Pantetheine; Sulfhydryl Compounds; Tuberculosis, Pulmonary