Bacterial Lipopolysaccharide Chlorpromazine, Z24 Liver Toxic Effects

Some adverse drug reactions occur in a small fraction of patients and have no obvious relationship to dose or duration of therapy, and some result in permanent disability or death. This idiosyncratic toxicity often attributed to the liver, and has brought some of the promised pharmaceutics withdrawal from the market. Some studies proposed some drug induced liver toxicity accompanied by a modest inflammatory response. Lipopolysaccharide (LPS) is a potent inflammagen, and causes liver damage at relatively large doses in rats. Smaller doses, however, may influence the response to other hepatotoxicants. Recently some studies suggested that concurrent inflammation may be a critical factor in precipitating idiosyncratic liver response to some drugs. Some even proposed an animal model bases on these observation to predict drug idiosyncrasy in humans and to study underlying mechanisms.The purpose of this study was to characterize the hepatotoxicity induced by a tricyclic antidepressant Chlorpromazine (CPZ) and a investigative antineoplastic Z24, to investigate the relationship between the episodes of inflammatory reaction and the drug induced liver injury, by examining the effect of the modest inflammatory response of the liver evoked by exposuring to relatively small doses of LPS on the hepatotoxicity of CPZ and Z24, to explore the underlying mechanism and importance of nonparenchymal cells and their mediators in the liver toxicity of CPZ and Z24, by employing the specific inhibition probe of Kupffer cells and the inflammatory mediators.The SD rats were pretreated with LPS (2mg/kg) 2 hr before treatment with a minimally toxic dose of CPZ(75mg/kg) or Z24(200mg/kg). Twenty-two hrs after dosing, all animals were euthanized and bled for blood biochemical analysis and liver histopathology examination. Results shown that LPS enhaced the liver toxicity of CPZ, but reduced the liver toxicity of Z24, compared to controls. Analysed the markers of MDA and SOD in liver homogenate, there were no difference to the controls.Pretreatment of rats with 10mg/kg gadolinium chloride(GdCl3, a known inactivator of Kupffer cell phagocytic function), 22 hrs before treatment with the LPS,decreased the potentiation effect by LPS of the liver toxicity of CPZ, but for the same pretreatment to Z24, there is no influence to either the Z24 hepatotoxicity itself or the protection effects afforded by LPS. Pretreatment of rats with interleukin-1α(1.25μg/kg), the liver toxicity of Z24 have been largely antagonized, but there are some manifestation of liver injury which suggested a directed hepatotoxicity for Z24.