Targeted knockout of Cyp1a1 gene does not alter hepatic constitutive expression of other genes in the mouse [Ah] battery

Using the Cre-Lox system, we have generated a cytochrome P450 1A1 Cyp1a1(-/ -) knockout mouse by deletion of the translated portions of the Cyp1a1 gene . These mice are viable and demonstrate no obvious phenotype, compared with wild-type littermates. As a first step toward characterizing genes that mi ght be expected to compensate for loss of CYP1A1, constitutive expression o f [Ah] gene battery members was examined. In a cultured hepatoma CYP1A1 met abolism-deficient mutant line that does not express Cyp1a2, we have previou sly shown that constitutive transcriptional up-regulation of other [Ah] gen e battery members occurs; these results are consistent with the elevation o f a putative endogenous ligand (EL) for the Ah receptor that is a substrate for CYP1A1. The [Ah] battery includes Cyp1a2, NAD(P)H:quinone oxidoreducta se (Nqo1), and three other Phase II genes. Examining mRNA, protein, and enz yme activity, we demonstrate that the absence of CYP1A1 has no effect on th e hepatic constitutive expression of Cyp1a2 or Nqo1, We postulate that CYP1 A1 and CYP1A2 might have overlapping substrate specificity for metabolism o f the EL, such that basal CYP1A2 in the liver can compensate for the loss o f CYP1A1. (C) 2000 Academic Press.