Phenotype of the Cyp1a1/1a2/1b1(-/-) Triple-Knockout Mouse
- 1 June 2008
- journal article
- research article
- Published by Elsevier in Molecular Pharmacology
- Vol. 73 (6) , 1844-1856
- https://doi.org/10.1124/mol.108.045658
Abstract
Crossing the Cyp1a1/1a2(-/-) double-knockout mouse with the Cyp1b1(-/-) single-knockout mouse, we generated the Cyp1a1/1a2/1b1(-/-) triple-knockout mouse. In this triple-knockout mouse, statistically significant phenotypes (with incomplete penetrance) included slower weight gain and greater risk of embryolethality before gestational day 11, hydrocephalus, hermaphroditism, and cystic ovaries. Oral benzo[a]pyrene (BaP) daily for 18 days in the Cyp1a1/1a2(-/-) produced the same degree of marked immunosuppression as seen in the Cyp1a1(-/-) mouse; we believe this reflects the absence of intestinal CYP1A1. Oral BaP-treated Cyp1a1/1a2/1b1(-/-) mice showed the same “rescued” response as that seen in the Cyp1a1/1b1(-/-) mouse; we believe this reflects the absence of CYP1B1 in immune tissues. Urinary metabolite profiles were dramatically different between untreated triple-knockout and wild-type; principal components analysis showed that the shifts in urinary metabolite patterns in oral BaP-treated triple-knockout and wild-type mice were also strikingly different. Liver microarray cDNA differential expression (comparing triple-knockout with wild-type) revealed at least 89 genes up- and 62 genes down-regulated (P-value ≤0.00086). Gene Ontology “classes of genes” most perturbed in the untreated triple-knockout (compared with wild-type) include lipid, steroid, and cholesterol biosynthesis and metabolism; nucleosome and chromatin assembly; carboxylic and organic acid metabolism; metal-ion binding; and ion homeostasis. In the triple-knockout compared with the wild-type mice, response to zymosan-induced peritonitis was strikingly exaggerated, which may well reflect down-regulation of Socs2 expression. If a single common molecular pathway is responsible for all of these phenotypes, we suggest that functional effects of the loss of all three Cyp1 genes could be explained by perturbations in CYP1-mediated eicosanoid production, catabolism and activities.Keywords
This publication has 70 references indexed in Scilit:
- Basal and inducible CYP1 mRNA quantitation and protein localization throughout the mouse gastrointestinal tractFree Radical Biology & Medicine, 2007
- Epoxyeicosatrienoic acids affect electrolyte transport in renal tubular epithelial cells: dependence on cyclooxygenase and cell polarityAmerican Journal of Physiology-Renal Physiology, 2007
- Generation of ‘humanized’ hCYP1A1_1A2_Cyp1a1/1a2(−/−) mouse lineBiochemical and Biophysical Research Communications, 2007
- Physiologic and pathophysiologic roles of lipid mediators in the kidneyKidney International, 2007
- Eicosanoid regulation of pulmonary innate immunity post-hematopoietic stem cell transplantationArchivum Immunologiae et Therapiae Experimentalis, 2007
- TCDD decreases ATP levels and increases reactive oxygen production through changes in mitochondrial F0F1-ATP synthase and ubiquinoneToxicology and Applied Pharmacology, 2006
- Mutual repression between steroid and xenobiotic receptor and NF- B signaling pathways links xenobiotic metabolism and inflammationJournal of Clinical Investigation, 2006
- Role of epoxyeicosatrienoic acids in protecting the myocardium following ischemia/reperfusion injuryProstaglandins & Other Lipid Mediators, 2006
- Soluble epoxide hydrolase inhibition reveals novel biological functions of epoxyeicosatrienoic acids (EETs)Prostaglandins & Other Lipid Mediators, 2006
- Linear Models and Empirical Bayes Methods for Assessing Differential Expression in Microarray ExperimentsStatistical Applications in Genetics and Molecular Biology, 2004