Comparative expression profiling of 40 mouse cytochrome P450 genes in embryonic and adult tissues

Choudhary, Dharamainder; Jansson, Ingela; Schenkman, John B.; Sarfarazi, Mansoor; Stoilov, Ivaylo

doi:10.1016/s0003-9861(03)00174-7

Cited by 227 publications

(192 citation statements)

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“…Cyp2s1 exhibits a ubiquitous temporal and tissue distribution throughout embryogenesis in the mouse. Among the 40 mouse cytochrome P450s studied, Cyp2s1 was one of six expressed in all of the four fetal stages (11). During the earlier stages of development, the mouse embryo is in a hypoxic state, and hypoxic induction of Cyp2s1 could help explain why the enzyme is expressed at high levels in the embryo.…”

Section: Discussionmentioning

confidence: 99%

“…The flanking sequence of the three XREs in the trimeric XRE segment conforms to the optimal sequence for function, except at the nucleotide at the Ϫ3-position upstream of the core sequence (11). In each XRE in the trimeric segment, this is an adenine (5Ј-A*(C/T)GCACG-CAC-3Ј).…”

Section: Modification Of the Flanking Sequences Of The Xres In The Trmentioning

confidence: 99%

“…The facts that all other previously well characterized dioxininducible cytochrome P450s (CYP1A1, CYP1A2, and CYP1B1) contribute significantly to the activation of a variety of procarcinogens in mammals, that CYP2S1 is highly expressed in epithelial tissues exposed to the environment, that its expression pattern is similar to that of the procarcinogen-metabolizing enzyme CYP1B1 (8,11), and that the Cyp2s1 gene is located in a cluster with other CYP2 family members that metabolize xenobiotics, including procarcinogens, suggest that Cyp2s1 may play a role in metabolic activation or deactivation of procarcinogens present in the environment. The enzyme may also play a role in the metabolism of endogenous compounds (such as retinoic acid) involved in the differentiation and/or mainte-nance of epithelial issues and conceivably in the metabolism of pharmaceutical drugs.…”

mentioning

confidence: 99%

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A Novel Promoter Element Containing Multiple Overlapping Xenobiotic and Hypoxia Response Elements Mediates Induction of Cytochrome P4502S1 by Both Dioxin and Hypoxia

Rivera¹,

Wang²,

Saarikoski

et al. 2007

Journal of Biological Chemistry

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Cytochrome P4502S1 (CYP2S1) is expressed at high levels in epithelial tissues and is inducible by 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin) via the aryl hydrocarbon receptor (AHR). Transcriptional initiation of mouse Cyp2s1 was found to occur at three regions, ϳ198, 102, and 22 nucleotides from the translational initiation codon. Approximately 400 nucleotides upstream of its translational initiation codon, mouse Cyp2s1 contains three overlapping xenobiotic-responsive element (XRE) sequences, which make a major contribution toward dioxin inducibility. Each XRE sequence in this trimeric XRE can bind the AHR/aryl hydrocarbon receptor nuclear translocator (ARNT) dimer in a dioxin-dependent fashion in vitro and can mediate dioxin-dependent transcription. Cyp2s1 is also markedly inducible by hypoxia. Induction is dependent on hypoxiainducible factor-1 (HIF-1) and is mediated in large part by three overlapping hypoxia response elements (HREs) embedded within the trimeric XRE segment. Although each HRE within this segment can bind HIF-1␣/ARNT in vitro, the most 3 HRE contributes the most toward hypoxia inducibility. AHR/ARNT and HIF-1␣/ARNT dimers bind to the region containing the trimeric XRE segment of the endogenous Cyp2s1 gene in vivo in a dioxin-dependent fashion and hypoxia-dependent fashion, respectively. These observations identify a novel regulatory cassette that mediates changes in Cyp2s1 expression.The cytochrome P450 superfamily consists of at least 57 genes in humans and 102 genes in mice (1). In general, mammalian cytochrome P450s in families 1-4 metabolize foreign compounds (xenobiotics), although they also frequently metabolize endogenous molecules, such as steroids and fatty acids. Families 1-4 are often also inducible by xenobiotics. Members of family 1 are inducible by the potent tumor promoter, 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin), 6 and carcinogenic polycyclic aromatic hydrocarbons via the aryl hydrocarbon receptor (AHR) (2). Rylander et al. (3) identified human CYP2S1 by performing a homology search in a sequence data base, whereas we cloned mouse Cyp2s1 as a dioxin-inducible transcript in the mouse hepatoma cell line, Hepa-1, in which cells it is maximally induced about 10-fold (4). CYP2S1 is unusual for a non-CYP1 family member in being inducible by dioxin (although another Cyp2 family member, Cyp2a5, has recently been shown also to be dioxin-inducible (5)). Human CYP2S1 has also been shown to be inducible in skin by coal tar, which contains high concentrations of polycyclic aromatic hydrocarbon ligands for AHR. Human CYP2S1 can convert alltrans-retinoic acid to the catabolic products, 4-hydroxyretinoic acid and 5,6-epoxyretinoic acid (6), and it has been reported that the enzyme can metabolize naphthalene to two products (7). Both mouse and human CYP2S1 are expressed robustly in most epithelial surfaces and tissues, including the lung and intestinal tract and at all stages of embryogenesis (3, 8 -10).The facts that all other previously well characterized dioxininducible cytochrome P45...

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Section: Discussionmentioning

confidence: 99%

Section: Modification Of the Flanking Sequences Of The Xres In The Trmentioning

confidence: 99%

mentioning

confidence: 99%

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A Novel Promoter Element Containing Multiple Overlapping Xenobiotic and Hypoxia Response Elements Mediates Induction of Cytochrome P4502S1 by Both Dioxin and Hypoxia

Rivera¹,

Wang²,

Saarikoski

et al. 2007

Journal of Biological Chemistry

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“…If feasible, to more reliably characterize potential on developmental variation in rate-limiting metabolic activities governing naphthalene activation and deactivation pathways, remaining questions concerning the ontogeny of CYP2F enzymes should also be investigated (Choudhary et al, 2003(Choudhary et al, ,2005. Additional studies may be required to characterize other enzymes associated with the production and clearance of the key metabolites of naphthalene, including naphthalene-oxide (both enantiomers) and 1,2-naphthoquinone, as indicated by the evidence regarding the most appropriate measure of BED.…”

Section: Uncertainties Quintessential For Human Cancer Risk Assessmenmentioning

confidence: 99%

Naphthalene metabolism in relation to target tissue anatomy, physiology, cytotoxicity and tumorigenic mechanism of action

Bogen

Benson

Yost

et al. 2008

Regulatory Toxicology and Pharmacology

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This report provides a summary of deliberations conducted under the charge for members of Module C Panel participating in the Naphthalene State-of-the-Science Symposium (NS 3 ), Monterey, CA, October 9-12, 2006. The panel was charged with reviewing the current state of knowledge and uncertainty about naphthalene metabolism in relation to anatomy, physiology and cytotoxicity in tissues observed to have elevated tumor incidence in these rodent bioassays. Major conclusions reached concerning scientific claims of high confidence were that: (1) rat nasal tumor occurrence was greatly enhanced, if not enabled, by adjacent, histologically related focal cellular proliferation; (2) elevated incidence of mouse lung tumors occurred at a concentration (30 ppm) cytotoxic to the same lung region at which tumors occurred, but not at a lower and less cytotoxic concentration (tumorigenesis NOAEL = 10 ppm); (3) naphthalene cytotoxicity requires metabolic activation (unmetabolized naphthalene is not a proximate cause of observed toxicity or tumors); (4) there are clear regional and species differences in naphthalene bioactivation; and (5) target tissue anatomy and physiology is sufficiently well understood for rodents, non-human primates and humans to parameterize species-specific physiologically based pharmacokinetic (PBPK) models for nasal and lung effects. Critical areas of uncertainty requiring resolution to enable improved human cancer risk assessment were considered to be that: (1) cytotoxic naphthalene metabolites, their modes of cytotoxic action, and detailed low-dose dose-response need to be clarified, including in primate and human tissues, and neonatal tissues; (2) mouse, rat, and monkey © 2007 Elsevier Inc. All rights reserved. * Corresponding author. Fax: +1 510 286 5099. ktbogen@exponent.com (K.T. Bogen). Conflict of interest disclosureThe authors declare that they have no conflicts of interest. Each received an honorarium from Regulatory Checkbook, PO Box 319, Mt. Vernon, VA 22121, for service as set forward in Belzer et al. (2008). NIH Public Access Author ManuscriptRegul Toxicol Pharmacol. Author manuscript; available in PMC 2014 May 22. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript inhalation studies are needed to better define in vivo naphthalene uptake and metabolism in the upper respiratory tract; (3) in vivo validation studies are needed for a PBPK model for monkeys exposed to naphthalene by inhalation, coupled to cytotoxicity studies referred to above; and (4) in vivo studies are needed to validate a human PBPK model for naphthalene. To address these uncertainties, the Panel proposed specific research studies that should be feasible to complete relatively promptly. Concerning residual uncertainty far less easy to resolve, the Panel concluded that environmental, non-cytotoxic exposure levels of naphthalene do not induce tumors at rates that can be predicted meaningfully by simple linear extrapolation from those observed in rodents chronically exposed to far greater, cytotox...

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“…Cyp1b1 is expressed at relatively high levels in both fetal thymus and lung (15,16). The finding that fetal thymus in humans exhibits the highest CYP1B1 expression of any tissue (16) highlights the relevance of this model for human exposures.…”

mentioning

confidence: 91%

Fetal MouseCyp1b1and Transplacental Carcinogenesis from Maternal Exposure to Dibenzo(a,l)pyrene

Castro

Baird

Pereira

et al. 2008

Cancer Prevention Research

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Dibenzo(a,l)pyrene (DBP) is among the most potent carcinogenic polycyclic aromatic hydrocarbons. Previously, we showed that DBP administration to pregnant mice resulted in high mortality of offspring from an aggressive T-cell lymphoma. All mice that survive to 10 months of age exhibit lung tumors with high multiplicity. Recombinant cytochrome P450 (cyp) 1b1 from mice and the homologue 1B1 in humans exhibit high activity toward the metabolic activation of DBP. Targeted disruption of the cyp1b1 gene protects against most DBP-dependent cancers. Mice heterozygous for the disrupted cyp1b1 allele were used to examine the effect of cyp1b1 gene dosage on DBP transplacental carcinogenesis. Dams were treated with 1 or 15 mg/kg of DBP or 50 mg/kg of benzo(a)pyrene. Cyp1b1-null offspring did not develop lymphoma, whereas wild-type and heterozygous siblings, born to dams given the high dose of DBP, exhibited significant mortalities between 10 and 30 weeks of age. At 10 months, all groups had lung adenomas or carcinomas [9.5%, 40.3%, 25.6%, and 100% incidences for controls, benzo(a)pyrene, 1 and 15 mg/kg DBP, respectively]. Cyp1b1 status did not alter benzo(a)pyrene-dependent carcinogenesis. At 1 mg/kg DBP, cyp1b1 status altered the incidence of lung tumors (19.0, 27.8, and 28.6% for nulls, heterozygous, and wild-type, respectively). At 15 mg/kg, tumor multiplicities in cyp1b1 wild-type (9.3) and heterozygous (9.5) offspring were nearly twice that of cyp1b1-null siblings (5.0). These data confirm that cyp1b1 bioactivation of DBP occurs in fetal target tissues, following transplacental exposure, with the thymus and lung as primary and secondary targets, respectively.

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Comparative expression profiling of 40 mouse cytochrome P450 genes in embryonic and adult tissues

Cited by 227 publications

References 40 publications

A Novel Promoter Element Containing Multiple Overlapping Xenobiotic and Hypoxia Response Elements Mediates Induction of Cytochrome P4502S1 by Both Dioxin and Hypoxia

A Novel Promoter Element Containing Multiple Overlapping Xenobiotic and Hypoxia Response Elements Mediates Induction of Cytochrome P4502S1 by Both Dioxin and Hypoxia

Naphthalene metabolism in relation to target tissue anatomy, physiology, cytotoxicity and tumorigenic mechanism of action

Fetal MouseCyp1b1and Transplacental Carcinogenesis from Maternal Exposure to Dibenzo(a,l)pyrene

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