A NIH/3T3 cell line stably expressing human cytochrome P450-3A4 used in combination with a lacZ' shuttle vector to study mutagenicity

European Journal of Pharmacology
E M de GroeneG J Horbach

Abstract

An NIH/3T3 cell line, stably expressing human cytochrome P450-3A4 (CYP3A4) cDNA has been developed. This cell line was used in combination with a shuttle vector, containing the bacterial lacZ' gene as reporter gene, to study mutagenicity. Ethylmethanesulphonate and aflatoxin B1 were used as model agents to test this system. The mutation frequency of ethylmethanesulphonate increased concentration dependently and was the same in CYP3A4-expressing cells as in parental NIH/3T3 cells, demonstrating that CYP3A4 activity has no influence on the mutagenicity of ethylmethanesulphonate. The mutation frequency of aflatoxin B1 increased concentration dependently only in the CYP3A4-expressing cells and not in parental nor in vector-transfected cells. This increase in mutation frequency could be completely inhibited by ketoconazole, an inhibitor of cytochrome P450 activity, demonstrating the role of CYP3A4 in the activation of aflatoxin B1. The system described in this paper opens the possibility to study the capacity of single human cytochrome P450s to activate xenobiotics into mutagenic metabolites. Since activation, phase II metabolism, DNA repair and an endpoint for mutations are all present in one cell, this system will be useful in scr...Continue Reading

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Citations

Feb 15, 1996·Environmental Toxicology and Pharmacology·E M de GroeneJ Fink-Gremmels
Mar 30, 2004·Toxicology in Vitro : an International Journal Published in Association with BIBRA·A Y Simarro DoortenJ Fink-Gremmels
Oct 1, 1997·Toxicology in Vitro : an International Journal Published in Association with BIBRA·R H ClothierR Ward
Aug 1, 1999·Toxicology in Vitro : an International Journal Published in Association with BIBRA·R GebhardtJ Doehmer
Apr 26, 2012·Chemical Research in Toxicology·Slobodan Rendic, F Peter Guengerich
Sep 6, 2005·Food and Chemical Toxicology : an International Journal Published for the British Industrial Biological Research Association·Y Simarro DoortenJ Fink-Gremmels
Oct 3, 2015·Pharmaceutical Biology·Xiuwen ZhangNengneng Cheng
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Jul 1, 1999·Alternatives to Laboratory Animals : ATLA·S CoeckeC Westmoreland
Sep 7, 1995·Biochemical Pharmacology·E M De GroeneR F Witkamp

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