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

Authors: Shi, Zhanquan; Chen, Ying; Dong, Hongbin; Amos-Kroohs, Robyn M; Nebert, Daniel W

Published In Biochem Biophys Res Commun, (2008 Nov 28)

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.

PubMed ID: 18814841

MeSH Terms: Animals; Cytochrome P-450 CYP1A1/genetics*; Cytochrome P-450 CYP1A2/genetics*; Humans; Kidney/enzymology; Liver/enzymology; Lung/enzymology; Mice; Mice, Transgenic/genetics*; Mice, Transgenic/metabolism; Receptors, Aryl Hydrocarbon/genetics*; Receptors, Aryl Hydrocarbon/metabolism