Effects of metabolizing enzyme modulators on chloral hydrate- and tribromoethanol-induced hepatotoxicity and analgesia.
Published: 2005
Language: eng
Number of pages: 93
Description: Chloral hydrate (CH) and tribromoethanol (TBOH) are anesthetics associated with hepatotoxicity. The metabolites and metabolizing enzymes responsible for anesthesia or toxicity are unknown. This thesis hypothesizes that trihaloethanols caused the anesthesia whereas trihaloacetaldehydes caused the toxicity. The effect of modulating metabolic enzymes in vitro (isolated rat hepatocytes) and in vivo (mice) were investigated. Ethanol reduced the hepatotoxicity of CH, trichloroethanol (TCOH), bromal and TBOH, and lengthened the anesthesia induced by CH and TCOH. This was prevented by inhibiting alcohol dehydydrogenase (ADH), indicating that the ADH-NADH-complex formed by ethanol reduced trihaloacetaldehydes to trihaloethanols. CYP3A induction increased hepatotoxicity and prevented anesthesia because CYP3A catalyzed the oxidation of trihaloethanols and trihaloacetaldehydes to form toxic free radicals. Cellular glutathione, the ferric chelator desferoxamine, and the antioxidant butylated hydroxyanisole prevented the lipid peroxidation, mitochondrial function disruption and hepatocytotoxicity. In conclusion, trihaloethanols caused anesthesia whereas trihaloacetaldehydes caused hepatotoxicity.
Notes: Source: Masters Abstracts International, Volume: 44-01, page: 0325.

Thesis (M.Sc.)--University of Toronto, 2005.

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