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Anit-Induced Choleostasis in the Rat.

Connolly, Ann K. (1988) Anit-Induced Choleostasis in the Rat. Doctoral thesis, University of Surrey (United Kingdom)..

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Abstract

The primary target cell for the toxicity of ANIT in the liver was investigated. Livers were examined histologically at 0-48 hours after a single 300 mg/kg dose of ANIT to identify the primary site of the lesion. Initial changes were observed in the portal tract areas, as bile duct degeneration, occuring at 6. -8 hours after dosing, this was followed by parenchymal focal necrosis at 12 hours after dosing. Ultrastructural examination of the primary lesion showed a loss of integrity of tight junction complexes between bile duct lining cells. This may allow leakage of bile between the cells causing their lysis by the strong detergent activity of bile. The primary destruction of bile duct lining cells was confirmed histochemically by staining for glutamyl transpeptidase, there was a progressive decrease in stamina from 0-8 hours after dosing, and biochemically by measurement of biliary YGT This was elevated from 4 hours after dosing. Tight junction integrity was examined biochemically by monitoring the appearance of albumin in bile. Albumin concentration was found to increase with time after dosing up to 8 hours. The development of the lesion was potentiated by induction of the cytochrome P450 drug metabolising enzyme system indicating that metabolism of ANIT is a requirement for its hepatotoxicity, a role for gut microfloral metabolism was eliminated. The toxic metabolite was found to be bile borne, exerting similar toxicity on the epithelium of the gall bladder. A method was developed by HPLC to monitor ANIT and any detectable metabolites in bile. ANIT and three metabolites were measured, one, the most greatly potentiated after phenobarbitone treatment, was subsequently identified as naphthylamine. A mechanism of action for the hepatotoxicity of ANIT, based on an active sulphur moiety, is suggested.

Item Type: Thesis (Doctoral)
Divisions : Theses
Authors : Connolly, Ann K.
Date : 1988
Additional Information : Thesis (Ph.D.)--University of Surrey (United Kingdom), 1988.
Depositing User : EPrints Services
Date Deposited : 24 Apr 2020 15:27
Last Modified : 24 Apr 2020 15:27
URI: http://epubs.surrey.ac.uk/id/eprint/854938

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