Drug induced idiosyncratic agranulocytosis has been attributed to oxidation by hypochlorite formed by bone marrow myeloperoxidase (MPO). Idiosyncratic liver toxicity could also involve drug oxidative activation by cytochrome P450 (in hepatocytes) or MPO (in Kupffer cells or infiltrating neutrophil/macrophages). Such drug reactive metabolites could cause cytotoxicity or release “danger signals” that attract immune cells which release H2O2 resulting from nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase) activation. In vivo animal studies have shown that low level tissue inflammation markedly increased drug-induced tissue toxicity which was prevented by immune cell inhibitors and increased by cell activators. It is suggested that idiosyncratic drugs are much more toxic, taken during symptomless inflammation periods. Furthermore, it is hypothesized that hepatocytes are much more susceptible to some idiosyncratic drugs if they are exposed to hydrogen peroxide (H2O2)/myeloperoxidase or cytokines released by inflammatory cells. A hepatocyte inflammation model, in which hepatocytes were exposed to a non-toxic H2O2 generating system and peroxidase, was found to be much more vulnerable to four idiosyncratic drugs e.g., troglitazone, isoniazid, hydralazine and amodiaquine. The molecular cytotoxic mechanisms for this marked increase in cytotoxicity were investigated as follows: 1) A P450/H2O2-catalyzed pathway not involving oxidative stress e.g., hydralazine and isoniazid; 2) A P450/H2O2-catalyzed oxidative stress-mediated cytotoxic pathway e.g., hydrazine (an isoniazid metabolite) and hydralazine; and 3) A peroxidase/H2O2-catalyzed oxidative stress-mediated cytotoxic pathway e.g,, hydralazine, amodiaquine and troglitazone. Before cytotoxicity ensued, GSH oxidation, protein carbonyl formation and often lipid peroxidation occurred followed by a decrease in mitochondrial membrane potential indicating that oxidative stress was the molecular mechanism of cytotoxicity. In summary, a H2O2-enhanced hepatocyte system in the presence and absence of peroxidase may prove useful for a more robust screening of drugs for assessing the enhanced drug toxicity risk associated with taking drugs during periods of inflammation.
| Identifer | oai:union.ndltd.org:TORONTO/oai:tspace.library.utoronto.ca:1807/17294 |
| Date | 26 February 2009 |
| Creators | Tafazoli, Shahrzad |
| Contributors | O'Brien, Peter J. |
| Source Sets | University of Toronto |
| Language | en_ca |
| Detected Language | English |
| Type | Thesis |
| Format | 1066702 bytes, application/pdf |
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