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Molecular Pharmacology

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Research ArticleArticle

Phenotype of the Cyp1a1/1a2/1b1(-/-) Triple-Knockout Mouse

Nadine Dragin, Zhanquan Shi, Rajat Madan, Christopher L. Karp, Maureen A. Sartor, Chi Chen, Frank J. Gonzalez and Daniel W. Nebert
Molecular Pharmacology June 2008, 73 (6) 1844-1856; DOI: https://doi.org/10.1124/mol.108.045658
Nadine Dragin
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Zhanquan Shi
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Rajat Madan
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Christopher L. Karp
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Maureen A. Sartor
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Chi Chen
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Frank J. Gonzalez
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Daniel W. Nebert
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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.

Footnotes

  • Supported in part by National Institutes of Health grants R01-ES08147 (D.W.N.), R01-ES014403 (D.W.N.), and P30-ES06096 (M.L.M., C.L.K., and D.W.N.).

  • N.D. and Z.S. contributed equally to this study.

  • These data were presented at the 27th Annual Meeting of the Society of Toxicology; 27 March 2007, Charlotte, NC.

  • ABBREVIATIONS: CYP, P450, cytochrome P450; AHR, aryl hydrocarbon receptor; BaP, benzo[a]pyrene; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; GD, gestational day; LC-MS, liquid chromatography-mass spectrometry; ALT, alanine aminotransferase; AST, aspartate aminotransferase; UPLC, ultra-performance liquid chromatography; QTOF, quantitative time-of-flight; FDR, false discovery rate; GO, gene ontology; Q-PCR, quantitative polymerase chain reaction; XME, xenobiotic-metabolizing enzyme; SOCS2, suppressor of cytokine-signaling-2.

  • ↵ Embedded Image The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.

    • Received January 24, 2008.
    • Accepted March 26, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 73 (6)
Molecular Pharmacology
Vol. 73, Issue 6
1 Jun 2008
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Research ArticleArticle

Phenotype of the Cyp1a1/1a2/1b1(-/-) Triple-Knockout Mouse

Nadine Dragin, Zhanquan Shi, Rajat Madan, Christopher L. Karp, Maureen A. Sartor, Chi Chen, Frank J. Gonzalez and Daniel W. Nebert
Molecular Pharmacology June 1, 2008, 73 (6) 1844-1856; DOI: https://doi.org/10.1124/mol.108.045658

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Research ArticleArticle

Phenotype of the Cyp1a1/1a2/1b1(-/-) Triple-Knockout Mouse

Nadine Dragin, Zhanquan Shi, Rajat Madan, Christopher L. Karp, Maureen A. Sartor, Chi Chen, Frank J. Gonzalez and Daniel W. Nebert
Molecular Pharmacology June 1, 2008, 73 (6) 1844-1856; DOI: https://doi.org/10.1124/mol.108.045658
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