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Title: Metabolic and mechanistic studies on hydrazine hepatotoxicity in the rat
Author: Delaney, Jane
Awarding Body: University of London
Current Institution: University College London (University of London)
Date of Award: 1996
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Hydrazine, a chemical with numerous applications in industry, is carcinogenic and acutely toxic to the central nervous system and liver. Metabolism and mechanisms of toxicity are not yet fully understood. Previous workers have observed increased acute hydrazine hepatotoxicity in cytochrome P4502E1-induced rats (isoniazid pretreated). In contrast apparent induction of this isoenzyme by pretreatment of rats with hydrazine protected against hydrazine-induced cytotoxicity in isolated hepatocytes but had little effect in vivo. These results may indicate that P4502E1 catalyses a detoxication pathway for hydrazine which plays only a minor role in vivo. Cytochromes P4501A1/2 and P4502B1/2 appear to catalyse detoxication pathways as a reduction in their activities correlates with increased hydrazine toxicity. A further study failed to clarify the induction of P4502E1 by hydrazine as, despite a dose dependent increase in p-nitrophenol hydroxylase activity, there was no apparent increase in enzyme protein, determined by immunohistochemical staining. This could explain the discrepancy between isoniazid and hydrazine pretreatments with regard to acute hydrazine toxicity. There is conflicting data regarding the effect of hydrazine on protein synthesis. Incorporation of 3H-leucine into protein in vitro in isolated rat hepatocytes was reduced 2 hours after exposure to 0.5mM hydrazine and 1 hour after higher concentrations. In vivo there was some evidence of protein synthesis inhibition 3 hours after 30 and 60mg/Kg hydrazine administration, followed by stimulation 24 hours post dose. The mechanism of action is currently unknown. Fatty liver is the major acute toxic manifestation in liver after exposure to hydrazine and appears to be unrelated to hydrazine metabolism. Microsomal phosphatidate phosphohydrolase activity and triglyceride content (NMR analysis) were raised 24 hours after hydrazine dosing, consistent with increased lipid synthesis. Raised serum triglycerides and control levels of phosphatidylcholine, required for VLDL synthesis, tend to suggest normal triglyceride secretion at this time, however there may have been a transient drop in VLDL production, due to decreased protein synthesis 3 hours post dose, which may have facilitated the accumulation of fat. Phosphatidylinositol was also raised but the reason for this is unknown.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available