Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.6.1.1 (aspartate aminotransferase)
 21,665 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The adverse effects on an in vitro model of oxmetidine, an H2-blocking agent which has been shown to produce hepatic injury in 1 to 4% of patients, were compared with those of cimetidine and ranitidine which have led to only rare instances of hepatic injury. Suspensions of hepatocytes, freshly isolated from Sprague-Dawley rats, were exposed to the three drugs. Oxmetidine, in concentrations of 3 X 10(-3) M or greater, led to leakage of AST into the medium after 4 hr of incubation. Ranitidine and cimetidine, in concentrations up to 5 X 10(-3) M, produced no identifiable leakage. Pretreatment of rats with phenobarbital, 3-methylcholanthrene, or SKF 525A resulted in no significant enhancement or inhibition of the oxmetidine effects. These results suggest that the adverse effects of oxmetidine on the hepatocytes are produced by the native compound, not a metabolite. The positive correlation between in vivo and in vitro toxicity supports the view that in vitro testing may prove to be of use in predicting the hepatotoxic potential of a drug.
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PMID:Effects of H2-blocking agents on hepatocytes in vitro: correlation with potential for causing hepatic disease in patients. 287 63

Inflammation of the liver may be caused by a variety of factors that include infectious agents and toxins. Reactive oxygen species (ROS) generated by the NADPH oxidase in Kupffer cells and infiltrating leukocytes play an important role in the pathogenesis of early alcohol-induced hepatitis. Histamine dihydrochloride (histamine) suppresses the generation of ROS through the histamine type-2 receptor (H2 receptor). Histamine was studied as a potential protective treatment against early alcohol-induced liver injury in an experimental hepatitis model. Female Wistar rats were given ethanol (5 g/kg) intragastrically by gavage once daily for 4 weeks, while a control group not receiving ethanol was fed an isocaloric high-fat diet. Animals receiving ethanol had elevated serum levels of alanine and aspartate transaminase (ALT/AST) and developed steatosis, inflammation, and necrosis of the liver. Histamine treatment (0.5 or 5.0 mg/kg, twice daily) protected against this liver injury as evident by normal serum transaminase levels and significantly reduced liver pathology scores. Ranitidine (10 mg/kg), an H2 receptor antagonist, blocked the protective effect of histamine, indicating that the histamine effect is predominantly mediated through the H2 receptor. In conclusion, these results suggest that histamine protects against early alcohol-induced liver injury in rats.
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PMID:Histamine dihydrochloride protects against early alcohol-induced liver injury in a rat model. 1463 89

Idiosyncratic liver injury occurs in a small fraction of people on certain drug regimens. The cause of idiosyncratic hepatotoxicity is not known; however, it has been proposed that environmental factors such as concurrent inflammation initiated by bacterial lipopolysaccharide (LPS) increase an individual's susceptibility to drug toxicity. Ranitidine (RAN), a histamine-2 receptor antagonist, causes idiosyncratic liver injury in humans. In a previous report, idiosyncrasy-like liver toxicity was created in rats by cotreating them with LPS and RAN. In the present study, the ability of metabonomic techniques to distinguish animals cotreated with LPS and RAN from those treated with each agent individually was investigated. Rats were treated with LPS or its vehicle and with RAN or its vehicle, and urine was collected for nuclear magnetic resonance (NMR)- and mass spectroscopy-based metabonomic analyses. Blood and liver samples were also collected to compare metabonomic results with clinical chemistry and histopathology. NMR metabonomic analysis indicated changes in the pattern of metabolites consistent with liver damage that occurred only in the LPS/RAN cotreated group. Principal component analysis of urine spectra by either NMR or mass spectroscopy produced a clear separation of the rats treated with LPS/RAN from the other three groups. Clinical chemistry (serum alanine aminotransferase and aspartate aminotransferase activities) and histopathology corroborated these results. These findings support the potential use of a noninvasive metabonomic approach to identify drug candidates with potential to cause idiosyncratic liver toxicity with inflammagen coexposure.
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PMID:Metabonomic evaluation of idiosyncrasy-like liver injury in rats cotreated with ranitidine and lipopolysaccharide. 1605 Dec 91

The polymer, OEI-HD, based on beta-propionamide-cross-linked oligoethylenimine and its chemical transferrin conjugate were evaluated for siRNA delivery into murine Neuro2A neuroblastoma cells in vitro and in vivo. An 80% silencing of luciferase expression in neuroblastoma cells, stably transfected with a luciferase gene, was obtained using standard OEI-HD polyplexes or transferrin-conjugated shielded OEI-HD polyplexes. The Ras-related nuclear protein Ran was selected as a therapeutically relevant target protein. Systemic delivery of transferrin-conjugated OEI-HD/RAN siRNA formulations (three intravenous applications at 3 days interval) resulted in >80% reduced Ran protein expression, apoptosis, and a reduced tumor growth in Neuro2A tumors of treated mice. The treatment was not associated with signs of acute toxicity or significant changes in weight, hematology parameters, or liver enzymes (AST, ALT, or AP) of mice. All our results demonstrate that OEI-HD/siRNA formulations can knockdown genes in tumor cells in vitro and in vivo in mice in the absence of unspecific toxicity.
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PMID:Induction of apoptosis in murine neuroblastoma by systemic delivery of transferrin-shielded siRNA polyplexes for downregulation of Ran. 1863 33