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Title: Effects of prostaglandins and prostaglandin synthetase inhibitors on liver toxicity
Author: Nielsch, A. S.
Awarding Body: University of Aberdeen
Current Institution: University of Aberdeen
Date of Award: 1987
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A total of 22 non-steroidal anti-inflammatory drugs and derivatives were added to microsomes to study the denaturation of cytochrome P-450 to cytochrome P-420 in the absence of an NADPH-generating system. There was a highly significant correlation among the different compounds between the extent of denaturation of cytochrome P-450 and their surfactant potency. Endotoxin administration to rats caused a maximum decrease in hepatic microsomal enzymes after 24 hours. Significant decreases in cytochrome P-450 (40%), cytochrome b5 levels (22%), aminopyrine N-demethylase (31%) and biphenyl 4-hydroxylase (54%) activities were obtained. Concomitant intravenous injection of 16,16-DMPG F2 and 16,16-DMPG E2 prevented some of the endotoxin-induced changes in hepatic microsomal enzymes. Three days treatment with cocaine was required to obtain hepatic damage in mice. Decreases in cytochrome P-450 content (41%), aminopyrine N-demethylase (31%) and FAD-monooxygenase (35%) activities were obtained, when compared to saline treated mice. The serum enzyme activities were markedly increased (SGOT 13-fold and SOCT 44-fold). Histological changes in form of centrilobular necrosis and fatty changes were present. Repeated subcutaneous administration of iloprost or synthetic prostaglandins just before cocaine prevented some of the hepatic lesions. Iloprost was found to be a better hepatoprotective agent than synthetic prostaglandins against the cocaine mediated liver toxicity. Carbon tetrachloride administration to mice produced similar lesions to those obtained with cocaine. Administration of iloprost prevented some of the lesions caused by carbon tetrachloride, giving a partial protection to the carbon tetrachloride-induced decrease in cytochrome P-450 and the increase in SGOT. Iloprost also partially prevented the carbon tetrachloride mediated centrilobular necrosis.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Anti-inflammatory drug testing Pharmacology