thromboxane-a2 and Carbon-Tetrachloride-Poisoning

Plasma and urinary levels of malondialdehyde-like products (MDA) and isoprostanes were identified as markers of in vivo lipid peroxidation in an animal model of CCl4 poisoning. We sought to determine the extent to which the formation of these oxidation products is influenced by inhibition of the cyclooxygenase enzymes which catalytically generate proinflammatory lipid peroxidation products known as prostaglandins and thromboxane. In the present studies, after induction of oxidant stress in rats with CCl4, lipid peroxidation products measured in plasma and urine demonstrate that isoprostanes and MDA can be partially inhibited by cyclooxygenase inhibitors, albeit to different extents. The lowering of isoprostane and MDA formation, however, may not to due primarily to the diminution of catalytic generation of isoprostanes or MDA by the cyclooxygenases but, rather, may be the result of the suppression of nonenzymatic lipid peroxidation. This is suggested since 8,12-iso-iPF2alpha-VI is also reduced by indomethacin, yet, unlike other isoprostanes and MDA, it is not generated catalytically by the cyclooxygenase. Thus, although the two cyclooxygenase inhibitors we tested have statistically significant effects on the measurements of both isoprostanes and MDA in this study, the results provide evidence that these lipid-degradation products primarily constitute markers of oxidative stress.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Biomarkers; Carbon Tetrachloride; Carbon Tetrachloride Poisoning; Chromatography, High Pressure Liquid; Free Radicals; Gas Chromatography-Mass Spectrometry; Immunoassay; Indomethacin; Inflammation; Lipid Metabolism; Lipid Peroxidation; Mass Spectrometry; Meclofenamic Acid; Oxidative Stress; Oxygen; Prostaglandins; Protein Isoforms; Rats; Rats, Inbred F344; Thromboxane A2; Time Factors

The effects of OKY-046, a selective thromboxane A2 (TxA2) synthetase inhibitor, ONO-3708, a novel TxA2 receptor antagonist, AA-861, a selective 5-lipoxygenase inhibitor and LY-171883, a peptide leukotrienes (p-LTs) receptor antagonist on the chronic liver injury were investigated in mice. The chronic liver injury was induced by the injection of carbon tetrachloride (CCl4) two times a week for twelve weeks in mice. In chronic liver injury models, significant histopathological changes in the liver and extensive elevation of glutamate transaminase (GOT and GPT) activity were observed. Administration of OKY-046, ONO-3708, AA-861 and LY-171883 for 12 weeks suppressed the elevation of serum GOT and GPT levels and histopathological changes in CCl4-induced chronic liver injury. These results suggest that TxA2 and LTs inhibitors are effective for the onset and development of chronic liver injury in mice.

Topics: Acetophenones; Acrylates; Animals; Azoles; Benzoquinones; Carbon Tetrachloride Poisoning; Chemical and Drug Induced Liver Injury; Leukotriene Antagonists; Lipoxygenase Inhibitors; Male; Methacrylates; Mice; Quinones; Tetrazoles; Thromboxane A2; Thromboxane-A Synthase