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Title: Development of functional in vitro toxicity tests
Author: Holmes, Jan L.
ISNI:       0000 0001 3580 7718
Awarding Body: Aston University
Current Institution: Aston University
Date of Award: 1998
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In vitro toxicity tests which detect evidence of the formation of reactive metabolites have previously relied upon cell death as a toxicity end point. Therefore these tests determine cytotoxicity in terms of quantitative changes in specified cell functions. In the studies involving the CaCO-2 cell model, there was no significant change in the transport of [3H] l-proJine by the cell after co-incubation with either dapsone or cyclophosphamide (50!!M) and rat liver microsomal metabolite generating system. The pre incubation of the cells with N-ethylmalemide to inhibit Phase II sulphotransferase activity, prior to the microsomal incubations, resulted in cytotoxcity in all incubation groups. Studies involving the L6 cell model showed that there was no significant effect in the cell signalling pathway producing the second messenger cAMP, after incubation with dapsone or cyclophosphamide (50!!M) and the rat microsomal metabolite generating system. There was also no significant affect on the vasopressin stimulated production of the second messenger IP3, after incubation with the hydroxylamine metabolite of dapsone, although there were some morphological changes observed with the cells at the highest concentration of dapsone hydroxylamine (1 OO!!M ) . With the test involving the NG11 S-401l-C3 cell model, there was no significant changes in DNA synthesis in terms of [3H] thymidine incorporation, after co-incubation with either phenytoin or cyclophosphamide (50!!M) and the rat microsomal metabolite generating system. In the one compartment erythrocyte studies, there were significant decreases in glutathione with cyclophosphamide (SO!!M) (0.44 + 0.04 mM), sulphamethoxazole (SOIlM) (0.43 + 0.08mM) and carbamazepine (SO!!M) (0.47 + 0.034 mM), when coincubated with the rat microsomal system, compared to the control (0.52 + 0.07mM). There was no significant depletion in glutathione when the erythrocytes were coincubated with phenytoin and the rat microsomal system. In the two compartment erythrocyte studies, there was a significant decrease in the erythrocyte glutathione with cyclophosphamide (50~lM) (0.953 + 011 OmM) when co-incubated the rat microsomal system, compared to the control (1.124 + 0.032mM). Differences were considered statistically significant for p
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Pharmacy ; Biological Sciences