A comparison of two cytotoxicity assays for the detection of metabolism-mediated toxicity in vitro: a study with cyclophosphamide

S. A. Horner Department of Human Morphology, Medical School, Queen's Medical Centre, Nottingham, NG7 2UH, UK

J. R. Fry Department of Physiology and Pharmacology, University of Nottingham, Medical School, Queen's Medical Centre, Nottingham, NG7 2UH, UK

R. H. Clothier Department of Human Morphology, Medical School, Queen's Medical Centre, Nottingham, NG7 2UH, UK

M. Balls Department of Human Morphology, Medical School, Queen's Medical Centre, Nottingham, NG7 2UH, UK

Abstract

1. The cytotoxicity to V79 Chinese hamster fibroblasts of cyclophosphamide (CPA) metabolites, generated by rat-liver S9 fractions, has been compared in two assay systems with different endpoints of toxicity, namely, reduction of cloning efficiency and inhibition of cell growth.

2. The two assay systems were found to be equally sensitive in detecting the metabolism-mediated cytotoxicity of CPA and gave similar ID₅₀ values.

3. Further studies confirmed the cytochrome P-450 enzyme requirement for the bioactivation of CPA to cytotoxic metabolites. CPA activation was mediated by phenobarbitone-inducible forms of cytochrome P-450, but not by β-naphthoflavone-inducible forms.

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A comparison of two cytotoxicity assays for the detection of metabolism-mediated toxicity in vitro: a study with cyclophosphamide

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A comparison of two cytotoxicity assays for the detection of metabolism-mediated toxicity in vitro: a study with cyclophosphamide

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