These "humanized" hCYP1A1_1A2_Cyp1a1/1a2(-/-)_Ahrd mice carry the human CYP1A1 and CYP1A2 genes in the absence of functional mouse Cyp1a1 and Cyp1a2 orthologs, and also mimic the human poor-affinity aryl hydrocarbon receptor (AHR) by carrying the poor-affinity Ahrd allele derived from DBA/2J mice. These may be useful in drug or carcinogen metabolism research; specifically as a model for human risk assessment studies involving drug or environmental toxicants that may be substrates for the aryl hydrocarbon receptor (AHR) or cytochrome P450 family 1 members.
Daniel W Nebert, University of Cincinnati Medical Center
Genetic Background | Generation |
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Allele Type | Gene Symbol | Gene Name |
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Not Applicable | Ahr | aryl-hydrocarbon receptor |
Allele Type | Gene Symbol | Gene Name |
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Targeted (Null/Knockout) | Del(9Cyp1a2-Cyp1a1)1Dwn | deletion, Chr 9, Daniel W Nebert 1 |
Allele Type |
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Transgenic (Inserted expressed sequence, Humanized sequence) |
These "humanized" hCYP1A1_1A2_Cyp1a1/1a2(-/-)_Ahrd mice carry the human CYP1A1 and CYP1A2 genes in the absence of functional mouse Cyp1a1 and Cyp1a2 orthologs, and also mimic the human poor-affinity aryl hydrocarbon receptor (AHR) by carrying the poor-affinity Ahrd allele derived from DBA/2J mice (rather than the high-affinity Ahrb1 allele normally present on a C57BL/6J genetic background); all on a C57BL/6J (reported >99.8%) genetic background.
Mice homozygous for the Cyp1a2/Cyp1a1 targeted allele [Cyp1a1/1a2(-/-)], homozygous for the Ahrd allele, and carrying the hCYP1A1_1A2 transgene are viable and fertile with normal lifespan. As the Cyp1a2/Cyp1a1(-) targeted allele lacks the coding regions of both Cyp1a1 and Cyp1a2 genes, no mouse CYP1A1 or CYP1A2 mRNA expression is observed in liver, lung or kidney. Transgene expression of the orthologous human genes is observed in the same tissues. Because expression of the hCYP1A1_1A2 transgene is controlled by the mouse AHR, the low-affinity Ahrd allele results in diminished CYP1A responses following exposure to AHR inducers (such as dioxin) when compared to hCYP1A1_1A2_Cyp1a1/1a2(-/-) mice harboring a high-affinity Ahr allele. These humanized hCYP1A1_1A2_Cyp1a2/Cyp1a1(-/-)_Ahrd mice may be useful in drug or carcinogen metabolism research; specifically as a model for human risk assessment studies involving drug or environmental toxicants that may be substrates for the aryl hydrocarbon receptor (AHR) or cytochrome P450 family 1 members.
These "humanized" hCYP1A1_1A2_Cyp1a1/1a2(-/-)_Ahrd mutant mice were generated in the laboratory of Dr. Daniel W. Nebert (University of Cincinnati Medical Center). These mice were generated by breeding hCYP1A1_1A2_Cyp1a1/1a2(-/-) mice (see Stock No. 007580, but reportedly maintained on a >99.8% C57BL/6J genetic background) to B6.D2-Ahrd mice (Stock No. 002921). The resulting mice were subsequently bred with B6.D2-Ahrd mice for at least 2 generations to fix the Ahrd allele to homozygosity. Mice homozygous for the Cyp1a1/1a2 mutation, homozygous for the Ahrd allele, and carrying the hCYP1A1_1A2 transgene were sent to The Jackson Laboratory. Upon arrival, mice were bred with B6.D2-Ahrd mice (Stock No. 002921) for at least one generation to establish this colony.
Upon rederivation of these mice at The Jackson Laboratory, we will perform a genetic background analysis using a single nucleotide polymorphism (SNP) analysis. The results of this analysis have not yet been completed (December 2008).
Expressed Gene | CYP1A2, cytochrome P450 family 1 subfamily A member 2, human |
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Expressed Gene | CYP1A1, cytochrome P450 family 1 subfamily A member 1, human |
Site of Expression |
Allele Name | d variant |
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Allele Type | Not Applicable |
Allele Synonym(s) | ah; Ahd; Ahk; Ahhn; AhRd; in |
Gene Symbol and Name | Ahr, aryl-hydrocarbon receptor |
Gene Synonym(s) | |
Strain of Origin | Not Applicable |
Chromosome | 12 |
General Note | Strain of origin - this allele was found in DBA/2J, AKR/J, 129, SWR, RF, NZB strains |
Molecular Note | This allele encodes a 104 kDa receptor that is stabilized by molybdate and has an affinity for ligand 10-100 fold lower than that of the receptor produced by the C57BL/6J allele. PCR sequencing of cDNA revealed ten nucleotide differences between the coding sequences of the DBA/2J and C57BL/6J receptors. Five of the ten differences would cause amino acid changes. One of these, an apparent T to C transition replaces the opal termination codon in the C57BL/6J allele with an arginine codon in the DBA/2J allele. This change would extend translation of the DBA/2J mRNA by 43 amino acids, accounting for the larger size of the peptide produced by this allele (104 kDa vs 95 kDa for the C57BL/6J allele). A second T to C transition changes a leucine codon in the C57BL/6J allele to a proline codon in the DBA/2J allele, and would likely change secondary structure of the peptide and thus ligand affinity. |
Allele Name | targeted mutation 1, Daniel W Nebert |
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Allele Type | Targeted (Null/Knockout) |
Allele Synonym(s) | Cyp1a1/1a2-; Cyp1a2/Cyp1a1tm2Dwn; Del(9Cyp1a2-Cyp1a1)1Dwn |
Gene Symbol and Name | Del(9Cyp1a2-Cyp1a1)1Dwn, deletion, Chr 9, Daniel W Nebert 1 |
Gene Synonym(s) | |
Strain of Origin | 129P2/OlaHsd or 129S6/SvEvTac |
Chromosome | 9 |
Molecular Note | The Cyp1a2(t) targeted allele (J:122409) was generated using a targeting vector designed to insert a loxP-flanked PGK-NEO cassette 350 bp downstream of the endogenous stop codon (about 60 bp 3' of exon 7). The construct was electroporated into 129S6/SvEvTac-derived embryonic stem (ES) cells which were microinjection into C57BL/6 blastocysts. The chimeras were bred with C57BL/6 to generate Cyp1a2(t) mutant mice. To create the Cyp1a1 targeted allele (J:59398), a targeting vector was designed to insert a loxP-flanked hypoxanthine phosphoribosyltransferase (HPRT) minigene in intron 1 and a loxP site downstream of the termination codon in exon 7. Following electroporation into E14TG2a (HPRT-) ES cells and ES cell microinjection into the blastocoele cavity of C57BL/6J embryos, chimeric males were bred with C57BL/6J females. As described in J:86748, these Cyp1a1(t) mutant mice were then bred to a Cre-deleter strain (CAGGS-CRE, mixed C57BL/6J and FVB/NJ genetic background). The resulting transgenic mice found to be heterozygous for the floxed null Cyp1a1(-) allele (containing only exon 1, a portion of intron 1, and one remaining loxP site in the 3' UTR) were bred to mice heterozygous for the Cyp1a2(t) allele (as described in J:122409). Mutant mice (Cyp1a2(t), Cyp1a1(-), CAGGS-CRE) were bred to C57BL/6. Because of the close genomic position of these two genes, offspring having undergone Cre recombinase-mediated interchromosomal recombination between the loxP sites 3' beyond the stop codons of the Cyp1a2 and Cyp1a1 genes could be selected. Such mice were backcrossed to C57BL/6 for 10 generations (while selecting against the Cre-deleter transgene) to generate Cyp1a1/1a2 mutant mice. |
Allele Name | transgene insertion 1, Daniel W Nebert |
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Allele Type | Transgenic (Inserted expressed sequence, Humanized sequence) |
Allele Synonym(s) | hCYP1A1_1A2, BAC-H |
Gene Symbol and Name | Tg(CYP1A1,CYP1A2)1Dwn, transgene insertion 1, Daniel W Nebert |
Gene Synonym(s) | |
Promoter | CYP1A2, cytochrome P450 family 1 subfamily A member 2, human |
Promoter | CYP1A1, cytochrome P450 family 1 subfamily A member 1, human |
Expressed Gene | CYP1A2, cytochrome P450 family 1 subfamily A member 2, human |
Expressed Gene | CYP1A1, cytochrome P450 family 1 subfamily A member 1, human |
Strain of Origin | (C57BL/6J x DBA/2J)F1 |
Chromosome | UN |
Molecular Note | To create "humanized" CYP1A1 and CYP1A2 transgenic mice (hCYP1A1_1A2), a single copy of the 180-kb human CYP1A1_CYP1A2 locus-containing BAC-H (BAC Human CTB clone 31H21: including the 23.3 kb spacer region, 90 kb of CYP1A2 3'-flanking region and 53 kb of CYP1A1 3' flanking region) was microinjected into (C57BL/6J x DBA/2J)F1 oocytes. Founder mice having a single copy of BAC-H were identified and then backcrossed for 10 generations to C57BL/6 mice. |
When maintaining a live colony, mice homozygous for the Cyp1a1/1a2 targeted allele, homozygous for the Ahrd allele, and hemizygous for the hCYP1A1_1A2 transgene may be bred together.
When using the B6.Cg-Cyp1tm1Dwn Ahrd Tg(CYP1A1,CYP1A2)1Dwn/DwnJ mouse strain in a publication, please cite the originating article(s) and include JAX stock #008599 in your Materials and Methods section.
Facility Barrier Level Descriptions
Service/Product | Description | Price |
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Homozygous for Cyp1a2/Cyp1a1<tm2Dwn> Ahr<d>, Hemizygous or Non carrier for Tg(CYP1A1,CYP1A2)1Dwn |
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The Jackson Laboratory has rigorous genetic quality control and mutant gene genotyping programs to ensure the genetic background of JAX® Mice strains as well as the genotypes of strains with identified molecular mutations. JAX® Mice strains are only made available to researchers after meeting our standards. However, the phenotype of each strain may not be fully characterized and/or captured in the strain data sheets. Therefore, we cannot guarantee a strain's phenotype will meet all expectations. To ensure that JAX® Mice will meet the needs of individual research projects or when requesting a strain that is new to your research, we suggest ordering and performing tests on a small number of mice to determine suitability for your particular project. We do not guarantee breeding performance and therefore suggest that investigators order more than one breeding pair to avoid delays in their research.
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