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    Biochem Biophys Res Commun. 2008 Nov 28;376(4):775-80. Epub 2008 Sep 22.

    Generation of a 'humanized' hCYP1A1_1A2_Cyp1a1/1a2(-/-)_Ahrd mouse line harboring the poor-affinity aryl hydrocarbon receptor.

    Shi Z, Chen Y, Dong H, Amos-Kroohs RM, Nebert DW.

    Source

    Department of Environmental Health and Center for Environmental Genetics, University of Cincinnati Medical Center, PO Box 670056, Cincinnati, OH 45267-0056, USA.

    Abstract

    Herein, we describe generation of the hCYP1A1_1A2_Cyp1a1/1a2(-/-)_Ahr(d) mouse line, which carries human functional CYP1A1 and CYP1A2 genes in the absence of mouse Cyp1a1 and Cyp1a2 genes, in a (>99.8%) background of the C57BL/6J genome and harboring the poor-affinity aryl hydrocarbon receptor (AHR) from the DBA/2J mouse. We have characterized this line by comparing it to our previously created hCYP1A1_1A2_Cyp1a1/1a2(-/-)_Ahr(b1) line-which carries the same but has the high-affinity AHR of the C57BL/6J mouse. By quantifying CYP1A1 and CYP1A2 mRNA in liver, lung and kidney of dioxin-treated mice, we show that dose-response curves in hCYP1A1_1A2_Cyp1a1/1a2(-/-)_Ahr(d) mice are shifted to the right of those in hCYP1A1_1A2_Cyp1a1/1a2(-/-)_Ahr(b1) mice-similar to, but not as robust as, dose-response curves in DBA/2J versus C57BL/6J mice. This new mouse line is perhaps more relevant than the former to human risk assessment vis-à-vis human CYP1A1 and CYP1A2 substrates, because poor-affinity rather than high-affinity AHR occurs in the vast majority of the human population.

    PMID:
    18814841
    [PubMed - indexed for MEDLINE]
    PMCID:
    PMC2582963
    Free PMC Article

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