Generation of a ‘humanized’ h CYP1A1_1A2_Cyp1a1/1a2(−/−)_Ahr d mouse line harboring the poor-affinity aryl hydrocarbon receptor

Abstract

Herein, we describe generation of the h CYP1A1_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 h CYP1A1_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 h CYP1A1_1A2_Cyp1a1/1a2(−/−)_Ahr d mice are shifted to the right of those in h CYP1A1_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.