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Title: The HepG2 hepatoma cell line : a model for the metabolism and toxicity of xenobiotics in man
Author: Duthie, Susan Joyce
Awarding Body: University of Aberdeen
Current Institution: University of Aberdeen
Date of Award: 1992
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The aim of the study was to determine the suitability of the human hepatoma cell line, HepG2, as an in vitro model for xenobiotic metabolism and toxicity in man. Bromobenzene (BB) toxicity in HepG2 cells was not mediated by cy-tochrome P450 (P450), but was dependent upon culture medium and cell growth. Epoxide hydrase detoxified BB. Reduced glutathione (GSH) did not. Neither lipid peroxidation (LP), nor proteolysis accounted for toxicity. The anticancer agent, cyclophosphamide (CP), induced HepG2 cell death. P450 was protective. Neither GSH nor aldehyde dehydrogenase was important in CP detoxification. CP did not inhibit growth. Both the fluoroquinolones, ciprofloxacin (CX) and pefloxacin (PX), were toxic to HepG2 cells. GSH was depleted prior to cell death, probably by conjugation. One-electron reduction was not responsible for activating CX to a toxic metabolite. Rather P450 may be important. CX inhibited HepG2 cell growth. GSH depletion potentiated CX toxicity in rats in vivo and in vifro. P450 did not activate CX to a toxic derivative in rat hepatocytes. The immunosuppressive, cyclosporin A (CsA), was metabolised to ¥-hydroxycyclosporin A by HepG2 cell homogenate. Ketoconazole inhibited metabolite formation. CsA was hepatotoxic to HepG2 cells, probably through LP. GSH and the radical scavenger, alpha-tocopherol, were important in detoxification. Different isoenzymes of P450 may activate and detoxify CsA. The anticancer agent, tamoxifen (TAM), was highly toxic to HepG2 cells. Cell damage was mediated through LP via the oxygen free radical, super-oxide. Neither GSH, nor catalase, were protective, indicating that hydrogen peroxide was not involved in TAM-induced cell death. NADPH-cytochrome P450 reductase was responsible for TAM toxicity. P450 was not involved. TAM caused an initial stimulation in HepG2 cell growth, followed by inhibition. This study indicates that human hepatoma-derived HepG2 cells are capable of both Phase I and Phase II xenobiotic metabolism and will be a valuable addition to the armamentarium for xenobiotic safety testing in vitro.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available