Oral Benzo[<i>a</i>]pyrene in<i>Cyp1</i>Knockout Mouse Lines: CYP1A1 Important in Detoxication, CYP1B1 Metabolism Required for Immune Damage Independent of Total-Body Burden and Clearance Rate

Uno, Shigeyuki; Dalton, Timothy P.; Dragin, Nadine; Curran, Chris; Derkenne, Sandrine; Miller, Marian L.; Shertzer, Howard G.; Gonzalez, Frank J.; Nebert, Daniel W.

doi:10.1124/mol.105.021501

Cited by 208 publications

(244 citation statements)

References 45 publications

(60 reference statements)

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“…Cyp1b1 mRNA primers specific for Cyp1b1 À/À mice were designed as described. 24 All samples were analyzed in triplicate. The relative mRNA levels were normalized to the reference gene mRNA in the same sample of cDNA.…”

Section: Real-time Pcr Analysismentioning

confidence: 99%

Cytochrome P450 1B1 Contributes to the Development of Angiotensin II–Induced Aortic Aneurysm in Male Apoe−/− Mice

Thirunavukkarasu

Khan

Song

et al. 2016

The American Journal of Pathology

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Cytochrome P450 (CYP) 1B1 is implicated in vascular smooth muscle cell migration, proliferation, and hypertension. We assessed the contribution of CYP1B1 to angiotensin (Ang) IIeinduced abdominal aortic aneurysm (AAA). Male Apoe À/À /Cyp1b1 þ/þ and Apoe À/À /Cyp1b1 À/À mice were infused with Ang II or its vehicle for 4 weeks; another group of Apoe À/À /Cyp1b1 þ/þ mice was coadministered the CYP1B1 inhibitor 2,3 0 ,4,5 0 -tetramethoxystilbene (TMS) every third day for 4 weeks. On day 28 of Ang II infusion, AAAs were analyzed by ultrasound and ex vivo by Vernier calipers, mice were euthanized, and tissues were harvested. Ang II produced AAAs in Apoe À/À /Cyp1b1 þ/þ mice; mice treated with TMS or Apoe À/À /Cyp1b1 À/À mice had reduced AAAs. Ang II enhanced infiltration of macrophages, T cells, and platelets and increased plateletderived growth factor D, Pdgfrb, Itga2, and matrix metalloproteinases 2 and 9 expression in aortic lesions; these changes were inhibited in mice treated with TMS and in Apoe À/À /Cyp1b1 À/À mice. Oxidative stress resulted in cyclooxygenase-2 expression in aortic lesions. These effects were minimized in Apoe À/À / Cyp1b1 þ/þ mice treated with TMS and in Apoe À/À /Cyp1b1 À/À mice and by concurrent treatment with the superoxide scavenger 4-hydroxyl-2,2,6,6-tetramethylpiperidine-1-oxyl. CYP1B1 contributed to the development of Ang IIeinduced AAA and associated pathogenic events in mice, likely by enhancing oxidative stress and associated signaling events. Thus, CYP1B1 may serve as a target for therapeutic agents for AAA in males. (Am J Pathol 2016 http://dx

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Section: Real-time Pcr Analysismentioning

confidence: 99%

Cytochrome P450 1B1 Contributes to the Development of Angiotensin II–Induced Aortic Aneurysm in Male Apoe−/− Mice

Thirunavukkarasu

Khan

Song

et al. 2016

The American Journal of Pathology

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“…In contrast, Cyp1a1(−/−) mice become sickly and die between 28 and 34 days--due to severe immunosuppression as well as toxic chemical depression of the bone marrow [10,18]. …”

Section: Oral Bap Toxicity Studiesmentioning

confidence: 99%

“…Benzo[a]pyrene (BaP), dissolved in corn oil, was given daily in normal rodent chow at a dose calculated to be 125 mg/kg/day [10,17,18]. Mice of five genotypes were sacrificed after 18 days on this diet.…”

Section: Treatment Of the Micementioning

confidence: 99%

“…Daily treatment of mice with oral BaP for 18 days, TCDD or corn oil treatment for 48 h, total RNA preparation, reverse transcription, Q-PCR analysis, microsomal protein immunoblots, determinations of the alanine aminotransferase (ALT) and aspartate aminotransferase (AST) plasma enzymes, and histology of peripheral blood were performed-as described previously [10,18]. …”

Section: Real-time Quantitative Pcr (Q-pcr) Western Immunoblot and mentioning

confidence: 99%

“…[7], Cyp1a2(−/−) [8], and Cyp1b1(−/−) [9] knockout mouse lines have previously been generated. Because of location on different chromosomes for the Cyp1a1_Cyp1a2 locus and the Cyp1b1 gene, the Cyp1a1/1b1(−/−) and Cyp1a2/1b1(−/−) double-knockout lines were easy to produce, and have been used in toxicity studies [10]. This lab discovered a recombination "hot spot" in the human CYP1A1_CYP1A2 spacer region [5].…”

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Generation of ‘humanized’ hCYP1A1_1A2_Cyp1a1/1a2(−/−) mouse line

Dragin

Uno

Wang

et al. 2007

Biochemical and Biophysical Research Communications

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Human/rodent CYP1A1 and CYP1A2 orthologs are well known to exhibit species-specific differences in substrate preferences and rates of metabolism. This lab previously characterized a BAC-transgenic mouse carrying the human CYP1A1_CYP1A2 locus; in this line, human dioxininducible CYP1A1 and basal vs dioxin-inducible CYP1A2 have been shown to be expressed normally (with regard to mRNAs, proteins and three enzyme activities) in every one of nine mouse tissues studied. The mouse Cyp1a1 and Cyp1a2 genes are oriented head-to-head and share a bidirectional promoter region of 13,954 bp. Using Cre recombinase and loxP sites inserted 3′ of the stop codons of both genes, we show here a successful interchromosomal excision of 26,173 bp that ablated both genes on the same allele. The Cyp1a1/1a2(−) double-knockout allele was bred with the "humanized" line; the final product is the hCYP1A1_1A2_Cyp1a1/1a2(−/−) line on a theoretically >99.8% C57BL/6J genetic background-having both human genes replacing the mouse orthologs. This line will be valuable for human risk assessment studies involving any environmental toxicant or drug that is a substrate for CYP1A1 or CYP1A2. KeywordsHumanized mouse line; Human CYP1A1_1A2 locus; Mouse Cyp1a1_1a2 locus; loxP; Cre recombinase; Interchromosomal excision; Benzo [a]pyrene; DioxinThe human and mouse cytochrome P450 (CYP) gene superfamilies contain 57 and 102 proteincoding genes, respectively; one of the 18 mammalian CYP families is CYP1, having three members in both human and mouse-CYP1A1, CYP1A2, and CYP1B1 [1][2][3]. The CYP1A and CYP1B subfamily ancestors diverged from one another probably more than 500 million years ago; CYP1A2 arose as a gene duplication event from CYP1A1 about 450 million years ago. Thus, land animals (including fowl) carry both CYP1A1 and CYP1A2; sea animals do not have the CYP1A2 gene [4]. Accordingly, the CYP1A1 and CYP1A2 genes are located at human chromosome 15q24.1, in head-to-head orientation, 23,306 bases from one transcription initiation start-site to the other [5]. Of three mammalian genomes studied, estimates are that about 10% of gene duplication pairs share bidirectional promoters [6]. The latest data from the UCSC browser assembled by NCBI and the Mouse Genome Sequencing Consortium puts the Cyp1a1 and Cyp1a2 genes on mouse chromosome 9 at cM 31.0, also in a head-to-head orientation, 13,954 bases from one transcription start-site to the other. In contrast, CYP1B1 is located on human chromosome 2p22.2, and Cyp1b1 (syntenic with human CYP1B1) is located on mouse chromosome 17. Using bacterial artificial chromosomes (BACs), we and others have been able to generate "humanized" hCYP1A1_1A2 BAC-transgenic lines [5,14]. Studies have been carried out with the hCYP1A1_1A2_Cyp1a1(−/−) line vs the hCYP1A1_1A2_Cyp1a2(−/−) line; for example, these lines were used both for theophylline [15] and for the food mutagen 2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP) [14]. In both cases, human CYP1A2 was shown to be responsible for the "human metabolite profile...

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Species Differences of Drug‐Metabolizing Enzymes

DeKeyser

Shou

2012

Encyclopedia of Drug Metabolism and Interactions

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The prediction of human pharmacokinetics, efficacy, and toxicity from preclinical data remains an important goal in the drug discovery and development process to minimize risk to participants during first in human studies. Animal models are commonly used in the preclinical development of new drugs; however, significant differences exist between species. These are due largely to alterations in isoform composition, regulation, expression, and catalytic activities of drug‐metabolizing enzymes (DMEs), particularly cytochromes P450 (CYPs), which play a critical role in numerous oxidative reactions of drugs. Although the reliability of animal testing to predict concentration‐dependent efficacy and toxicity in humans has been questioned; it is generally believed that data from animal studies can be reasonably extrapolated to humans using appropriate drug metabolism and pharmacokinetic principles. In this chapter, the authors describe the similarities and differences of major CYPs and other enzymes in their gene and protein structure, catalytic activity, enzyme kinetics and inhibition, and induction response between the various preclinical species and humans. These comparisons help to better understand underlying mechanisms responsible for the differences and address the question of whether animal data can be extrapolated to humans with regard to drug absorption, distribution, metabolism, and excretion. In conclusion, the DMEs show appreciable interspecies differences from structure to function, and caution must be taken when extrapolating metabolism data from animal models to humans.

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Oral Benzo[a]pyrene inCyp1Knockout Mouse Lines: CYP1A1 Important in Detoxication, CYP1B1 Metabolism Required for Immune Damage Independent of Total-Body Burden and Clearance Rate

Abstract: CYP1A1 and CYP1B1 metabolically activate many polycyclic aromatic hydrocarbons (PAHs), including benzo[a]pyrene, to reactive intermediates associated with toxicity, mutagenesis, and carcinogenesis. Paradoxically, however, Cyp1a1

Cited by 208 publications

References 45 publications

Cytochrome P450 1B1 Contributes to the Development of Angiotensin II–Induced Aortic Aneurysm in Male Apoe−/− Mice

Cytochrome P450 1B1 Contributes to the Development of Angiotensin II–Induced Aortic Aneurysm in Male Apoe−/− Mice

Generation of ‘humanized’ hCYP1A1_1A2_Cyp1a1/1a2(−/−) mouse line

Species Differences of Drug‐Metabolizing Enzymes

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