Organization and evolution of the Cyp2 gene cluster on mouse chromosome 7, and comparison with the syntenic human cluster.

Wang, Haoyi; Donley, Kyle M; Keeney, Diane S.; Hoffman, Susan M.G.

doi:10.1289/ehp.6546

Cited by 30 publications

(36 citation statements)

References 18 publications

(33 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This is supported by the observation that hepatic expression of Cyp2f2, which is about 250 kb downstream of Cyp2a5 (Wang et al, 2003), was not affected. Although it is not clear at present which of the CYP2B proteins were detected in liver microsomes by the polyclonal anti-CYP2B antibody, the lack of alteration in the overall intensity of the detected CYP2B bands suggests that the expression of the Cyp2b genes, which are about 40 to 950 kb upstream of Cyp2g1 (Wang et al, 2003), was not affected either. The first identified gene downstream of Cyp2a5 seems to be a Cyp2a pseudogene (Cyp2a23p), about 65 kb away (Wang et al, 2003).…”

Section: Cyp2g1-null Mice 725mentioning

confidence: 79%

“…The genes are adjacent to one another on chromosome 7, with Cyp2g1 immediately (less than 20 kb) upstream of Cyp2a5 (Wang et al, 2003). The mechanism of Cyp2a5 suppression in the Cyp2g1-null mice has not been identified.…”

Section: Cyp2g1-null Mice 725mentioning

confidence: 99%

“…The structure of the mouse Cyp2g1 gene has been characterized; this gene contains nine exons, and the transcriptional initiation sites are located at 16 and 15 base pairs upstream of the translation start codon (Zhuo et al, 2001). The Cyp2g1 gene is located in a Cyp2 gene cluster on mouse chromosome 7, next to the Cyp2a5 gene (Wang et al, 2003). In this study, we have generated Cyp2g1-null mice by replacing exon 3 of the Cyp2g1 gene with the neo gene.…”

mentioning

confidence: 99%

See 2 more Smart Citations

Targeted Disruption of the Olfactory Mucosa-SpecificCyp2g1Gene: Impact on Acetaminophen Toxicity in the Lateral Nasal Gland, and Tissue-Selective Effects onCyp2a5Expression

Zhuo

Behr

et al. 2003

J Pharmacol Exp Ther

View full text Add to dashboard Cite

CYP2G1 is a cytochrome P450 monooxygenase expressed uniquely in the olfactory mucosa (OM). We have generated Cyp2g1-null mice to identify the roles of CYP2G1 in the biology and the tissue-specific toxicity of xenobiotic compounds in the nose. Homozygous Cyp2g1-null mice are viable and fertile; they show no evidence of embryonic lethality, morphological abnormality, or developmental deficits; and they seem to have normal olfactory ability. However, OM microsomes from Cyp2g1-null mice were found to have significantly lower activities than microsomes from wild-type mice in the metabolism of testosterone and progesterone (ϳ60% decrease) and in the metabolic activation of coumarin (Ͼ70% decrease). Unexpectedly, a significant reduction in the expression of the Cyp2a5 gene was found in the liver, the lateral nasal gland (LNG), and, to a lesser extent, the kidney of adult Cyp2g1-null mice. The loss of CYP2G1 expression, and the associated decrease in the hepatic expression of CYP2A5, did not decrease systemic clearance, extent of hepatotoxicity, or OM toxicity of acetaminophen (AP). However, the LNG was protected from AP (at 400 mg/kg) toxicity in the Cyp2g1-null mice. Paradoxically, the LNG did not have detectable CYP2G1, and the decrease in LNG CYP2A5 expression in the Cyp2g1-null mice was not accompanied by decreases in microsomal AP metabolism. We hypothesize that OM CYP2G1 (through a paracrine pathway) or LNG CYP2A5 may indirectly influence resistance of the LNG to chemical toxicity, possibly by regulating gene expression in the LNG through steroid hormones or other endogenous P450 substrates and their metabolites.The tissue-specific expression of CYP2G1 in the OM is highly conserved in mammals (for recent review, see Ding and Dahl, 2003). CYP2G1 is a major P450 enzyme in OM microsomes of rabbits and mice. In vitro metabolic assays with heterologously expressed mouse CYP2G1 or purified rabbit or bovine CYP2G1 revealed high activity with sex steroid hormones, including androstenedione, testosterone, 5␣-dihydrotestosterone, progesterone, and estradiol. CYP2G1 is also active toward arachidonic acid, producing both epoxy-and hydroxyeicosatrienoic acids. In addition, CYP2G1 is active in the metabolism of numerous exogenous compounds, including compounds known to cause tissue-selective toxicity in the nasal mucosa, such as coumarin, DCBN (an herbicide), and AP. The substrate specificities, combined with the tissue-selective expression pattern of this enzyme, suggest that CYP2G1 may be critical in target tissue metabolic activation and the consequent cytotoxicity of nasal toxicants and that it may have important biological functions in the olfactory chemosensory organ through its metabolic activities toward endogenous substrates. These intriguing possibilities were explored in the present study through development and characterization of a Cyp2g1-null mouse model. Unlike many of the multigene subfamilies in the mouse Cyp2 gene family, the Cyp2g subfamily contains only a single gene, Cyp2g1. The structure of the mo...

show abstract

Section: Cyp2g1-null Mice 725mentioning

confidence: 79%

Section: Cyp2g1-null Mice 725mentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Targeted Disruption of the Olfactory Mucosa-SpecificCyp2g1Gene: Impact on Acetaminophen Toxicity in the Lateral Nasal Gland, and Tissue-Selective Effects onCyp2a5Expression

Zhuo

Behr

et al. 2003

J Pharmacol Exp Ther

View full text Add to dashboard Cite

show abstract

“…The human CYP2ABFGST gene cluster on chromosome 19 contains several functional CYP genes, which encode five cytochrome P450 (P450) enzymes (CYP2A6, CYP2A13, CYP2B6, CYP2F1, and CYP2S1), as well as several CYP pseudogenes (Wang et al, 2003). The five CYP genes are all expressed in the respiratory tract, but their contributions to xenobiotic metabolism and target tissue bioactivation remain poorly defined.…”

Section: Introductionmentioning

confidence: 99%

Generation and Characterization of aCYP2A13/2B6/2F1-Transgenic Mouse Model

Wei

Lei

et al. 2012

Drug Metab Dispos

View full text Add to dashboard Cite

ABSTRACT:CYP2A13, CYP2B6, and CYP2F1, which are encoded by neighboring cytochrome P450 genes on human chromosome 19, are active in the metabolic activation of many drugs, respiratory toxicants, and chemical carcinogens. To facilitate studies on the regulation and function of these human genes, we have generated a CYP2A13/2B6/2F1-transgenic (TG) mouse model (all *1 alleles). Homozygous transgenic mice are normal with respect to gross morphological features, development, and fertility. The tissue distribution of transgenic mRNA expression agreed well with the known respiratory tract-selective expression of CYP2A13 and CYP2F1 and hepatic expression of CYP2B6 in humans. CYP2A13 protein was detected through immunoblot analyses in the nasal mucosa (NM) (ϳ100 pmol/mg of microsomal protein; similar to the level of mouse CYP2A5) and the lung (ϳ0.2 pmol/mg of microsomal protein) but not in the liver of the TG mice. CYP2F1 protein, which could not be separated from mouse CYP2F2 in immunoblot analyses, was readily detected in the NM and lung but not the liver of TG/Cyp2f2-null mice, at levels 10-and 40-fold, respectively, lower than that of mouse CYP2F2 in the TG mice. CYP2B6 protein was detected in the liver (ϳ0.2 pmol/mg of microsomal protein) but not the NM or lung (with a detection limit of 0.04 pmol/mg of microsomal protein) of the TG mice. At least one transgenic protein (CYP2A13) seems to be active, because the NM of the TG mice had greater in vitro and in vivo activities in bioactivation of a CYP2A13 substrate, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (a lung carcinogen), than did the NM of wild-type mice.

show abstract

“…The corresponding gene subfamilies (Cyp2a,2b,2f,2g,2s,and 2t) are also clustered in the mouse genome (Wang et al, 2003), on chromosome 7, which is known to be syntenic to human chromosome 19. These various Cyp2 genes are preferentially expressed in the respiratory tract, although some Cyp2a and Cyp2b genes are also expressed in the liver and elsewhere.…”

Section: Introductionmentioning

confidence: 99%

Generation and Characterization of a Novel Cyp2a(4/5)bgs-Null Mouse Model

Wei

Zhou

et al. 2012

Drug Metab Dispos

View full text Add to dashboard Cite

Knockout mouse models targeting various cytochrome P450 (P450 or CYP) genes are valuable for determining P450's biologic 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 morphologic abnormalities. Deletion of the constitutive genes in the cluster was confirmed by polymerase chain reaction 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 (OM), 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 with wild-type (WT) 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 OM, where one or more of the targeted Cyp genes are known to be expressed in WT 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.

show abstract

Organization and evolution of the Cyp2 gene cluster on mouse chromosome 7, and comparison with the syntenic human cluster.

Cited by 30 publications

References 18 publications

Targeted Disruption of the Olfactory Mucosa-SpecificCyp2g1Gene: Impact on Acetaminophen Toxicity in the Lateral Nasal Gland, and Tissue-Selective Effects onCyp2a5Expression

Targeted Disruption of the Olfactory Mucosa-SpecificCyp2g1Gene: Impact on Acetaminophen Toxicity in the Lateral Nasal Gland, and Tissue-Selective Effects onCyp2a5Expression

Generation and Characterization of aCYP2A13/2B6/2F1-Transgenic Mouse Model

Generation and Characterization of a Novel Cyp2a(4/5)bgs-Null Mouse Model

Contact Info

Product

Resources

About