Community Research and Development Information Service - CORDIS

Abstract

Xenobiotics undergoing bioactivation by CYP450 enzymes form reactive metabolites that may exert direct metabolism-mediated toxicity. An in vitro model was developed to study the direct toxic effects that follow the metabolic activation of chemicals. The model uses monolayer cultures of genetically engineered NIH-3T3 or V79 cells that express individual human or rat CYP450 isoforms, respectively. Following exposure to 1,3-dichloropropanol or cyclophosphamide, basal cytotoxicity endpoints, including neutral red uptake and Alamar Blue (TM) reduction were used to assess changes in cell number and functional viability resulting from the formation of metabolites. Cell lines that express cytochrome P450 enzymes metabolised the test compounds, leading to increased toxicity compared with that observed in the control cell line. The use of specific inhibitors confirmed that the formation of reactive metabolites was CYP450-isoform dependent. These results indicate that a panel of genetically engineered cell lines expressing various cytochrome P450 enzyme isoforms can be used to reveal measurable metabolising capabilities, and could become a useful tool for the detection and possible determination of CYP450 isoforms in human liver metabolism-mediated toxicity.

This article is available to subscribers online at: http://altweb.jhsph.edu/publications/journals/atla/atla-index.htm

Additional information

Authors: BULL S, European Commission, Joint Research Centre, Institute for Health & Consumer Protection, ECVAM, Ispra (IT);LANGEZAAL I, European Commission, Joint Research Centre, Institute for Health & Consumer Protection, ECVAM, Ispra (IT);COECKE S, European Commission, Joint Research Centre, Institute for Health & Consumer Protection, ECVAM, Ispra (IT);CLOTHIER R, School of Biomedical Sciences, University of Nottingham (GB)
Bibliographic Reference: An article published in: ATLA 29, 703-716, November/December 2001
Record Number: 200214694 / Last updated on: 2002-05-15
Category: PUBLICATION
Original language: en
Available languages: en