RT Journal Article SR Electronic T1 Generation and Characterization of a Novel Cyp2a(4/5)bgs-null Mouse Model JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP dmd.112.048736 DO 10.1124/dmd.112.048736 A1 Yuan Wei A1 Lei Li A1 Xin Zhou A1 Qing-Yu Zhang A1 Anwar Dunbar A1 Fang Liu A1 Kerri Kluetzman A1 Weizhu Yang A1 Xinxin Ding YR 2012 UL http://dmd.aspetjournals.org/content/early/2012/10/16/dmd.112.048736.abstract AB Knockout mouse models targeting various cytochrome P450 (P450 or CYP) genes are valuable for determining P450s' biological functions, including roles in drug metabolism and chemical toxicity. In this study, a novel Cyp2a(4/5)bgs-null mouse model was generated, in which a 1.2-megabase pair genomic fragment containing nine Cyp genes in mouse chromosome 7 (including, sequentially, Cyp2a5, 2g1, 2b19, 2b23, 2a4, 2b9, 2b13, 2b10, and 2s1) are deleted, through Cre-mediated recombination in vivo. The resultant mouse strain was viable and fertile, without any developmental deficits or morphological abnormalities. Deletion of the constitutive genes in the cluster was confirmed by PCR analysis of the genes and the mRNAs in tissues known to express each gene. The loss of this gene cluster led to significant decreases in microsomal activities toward testosterone hydroxylation in various tissues examined, including olfactory mucosa, lung, liver, and brain. In addition, systemic clearance of pentobarbital was decreased in Cyp2a(4/5)bgs-null mice, as indicated by >60% increases in pentobarbital-induced sleeping time, compared to wild-type mice. This novel Cyp2a(4/5)bgs-null mouse model will be valuable for in vivo studies of drug metabolism and chemical toxicities in various tissues, including the liver, lung, brain, intestine, kidney, skin, and nasal mucosa, where one or more of the targeted Cyp genes are known to be expressed in wild-type mice. The model will also be valuable for preparation of humanized mice that express human CYP2A6, CYP2A13, CYP2B6, or CYP2S1, and as a knockout mouse model for five non-P450 genes (Vmn1r184, Nalp9c, Nalp4a, Nalp9a, and Vmn1r185) that were also deleted.