Expression of cytochrome P450 2A5 in preneoplastic and neoplastic mouse liver lesions

Wastl, Ute; Rossmanith, Walter; Lang, Matti A.; Camus-Randon, Anne-Marie; Grasl‐Kraupp, Bettina; Bursch, Wilfried; Schulte‐Hermann, Rolf

doi:10.1002/(sici)1098-2744(199808)22:4<229::aid-mc4>3.0.co;2-e

Cited by 35 publications

(18 citation statements)

References 28 publications

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“…Examples include CYP2S1 in human lung squamous cell carcinoma (Saarikoski et al, 2005) and CYP2A5 in mouse liver tumors induced by chemical carcinogen (Wastl et al, 1998;Ulvila et al, 2004). A significant alteration in P450 expression profiling in tumors might be used as a prognostic biomarker (Downie et al, 2005;Kumarakulasingham et al, 2005) and could affect the efficacy of chemotherapeutic drugs if they are metabolized by the involved P450 enzymes (Lopes et al, 2004;Oberndorfer et al, 2005;Roy and Waxman, 2006).…”

Section: Discussionmentioning

confidence: 99%

“…Because some P450 enzymes were reported to be overexpressed in tumors (Wastl et al, 1998;Oyama et al, 2004;Downie et al, 2005;Wenzlaff et al, 2005), we also examined the expression of CYP2A13 protein in different types of human lung carcinomas. The tissue array used for immunohistochemical analysis included carcinoma tissue, margin of carcinoma tissue, and normal tissue from each patient (n ϭ 18).…”

Section: Immunohistochemical Study Of Cyp2a13 In Human Tissuesmentioning

confidence: 99%

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CYP2A13 in Human Respiratory Tissues and Lung Cancers: An Immunohistochemical Study with A New Peptide-Specific Antibody

Zhu¹,

Thomas²,

Lǚ³

et al. 2006

Drug Metabolism and Disposition

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ABSTRACT:Human cytochrome P450 2A13 (CYP2A13) is highly efficient in the metabolic activation of a tobacco-specific carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), and another potent carcinogen, aflatoxin B1 (AFB1). Although previous studies demonstrated that CYP2A13 mRNA is predominantly expressed in human respiratory tissues, expression of CYP2A13 protein in these tissues and the involved cell types have not been determined because of the lack of CYP2A13-specific antibodies. To explore the toxicological and physiological function of CYP2A13, it is important to understand the tissue/cellular distribution of CYP2A13 protein.In this study, we generated a peptide-specific antibody against human CYP2A13 and demonstrated by immunoblot analysis that this antibody does not cross-react with heterologously expressed human CYP2A6 and mouse CYP2A5 proteins, both sharing a high degree of amino acid sequence similarity with CYP2A13. Nor does the antibody cross-react with heterologously expressed human CYP3A4, CYP2S1, or any of the cytochrome P450 enzymes present in the human liver microsomes. Using this highly specific antibody for immunohistochemical staining, we detected a high level of CYP2A13 protein expression in the epithelial cells of human bronchus and trachea, but a rare distribution in the alveolar cells. There was little expression of CYP2A13 protein in different types of lung cancers. In consideration of the high efficiency of CYP2A13 in NNK metabolic activation, our result is consistent with the reported observations that most smoking-related human lung cancers are bronchogenic and supports that CYP2A13-catalyzed in situ activation may play a critical role in human lung carcinogenesis related to NNK and AFB1 exposure.

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Section: Discussionmentioning

confidence: 99%

Section: Immunohistochemical Study Of Cyp2a13 In Human Tissuesmentioning

confidence: 99%

CYP2A13 in Human Respiratory Tissues and Lung Cancers: An Immunohistochemical Study with A New Peptide-Specific Antibody

Zhu¹,

Thomas²,

Lǚ³

et al. 2006

Drug Metabolism and Disposition

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“…The gene product activates the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (Felicia et al, 2000) and is believed to play an important role in liver carcinogenesis (Wastl et al, 1998). The Cyp2a5 gene is upregulated by many compounds and agents causing liver injury (Kirby et al, 1994;Camus-Randon et al, 1996) and in certain liver tumors (Wastl et al, 1998), yet the mechanism of induction is not known. Some xenobiotics, such as the classic P450 inducer phenobarbital, up-regulate Cyp2a5 transcriptionally, whereas others, such as pyrazole, induce it by increasing the stability of the mRNA (Aida and Negishi, 1991;Hahnemann et al, 1992).…”

mentioning

confidence: 99%

Heterogeneous Nuclear Ribonucleoprotein A1 and Regulation of the Xenobiotic-Inducible GeneCyp2a5

Raffalli-Mathieu

Glisovic²,

Ben‐David³

et al. 2002

Mol Pharmacol

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The heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) functions in the packaging of nascent RNA polymerase II transcripts and participates in a variety of nuclear and cytoplasmic processes that modulate gene expression. The RNA binding characteristics of hnRNP A1 suggest that it can modulate the expression of specific genes, but little is known about its possible targets in vivo. In this article, we show that hnRNP A1 interacts with the transcript of a cytochrome P450 gene, Cyp2a5, induced by xenobiotics and during liver damage. Binding of the hnRNP A1 to CYP2A5 mRNA was demonstrated by immunoprecipitation of the xenobiotic-stimulated (37/39 kDa) CYP2A5 mRNA-protein complex with a monoclonal antihnRNP A1 antibody, by partial trypsin digestion of the complex, and by showing that the RNA-protein complex is not formed with protein extracts from cells lacking the hnRNP A1. We also show that a specific hepatotoxic inducer of the Cyp2a5 gene, pyrazole, increases the cytoplasmic levels of hnRNP A1 in vivo. Finally, we show that hnRNP A1 can be overexpressed in mouse primary hepatocytes, leading to an accumulation of the CYP2A5 mRNA. Collectively, these results indicate that the hnRNP A1 is an important regulator of the Cyp2a5 gene.

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“…The increased expression of Cyp2a4 observed here may be a cross hybridiation with Cyp2a5 known to be increased in expression during the development of liver injury and hepatocarcinomas (Camus-Randon et al 1996;Knasmuller et al 1997;Salonpaa et al 1995;Wastl et al 1998) and is also induced directly by porphyrinogenic agents (Salonpaa et al 1995). The most highly upregulated Cyp genes in this set, Cyp2b9, Cyp2b10, and Cyp2b13, were increased in expression up to 100-fold.…”

Section: Toxicogenomics | Gant Et Almentioning

confidence: 50%

“…These data suggest that these particular Cyp genes may therefore be very sensitive indicators of a liver suffering toxicity. The expression of Cyp2a5 (coumarin-7-hydroxylase) was induced in both C57BL/6J and BALB/c mice ( Figure 3B) and has been associated with development of the neoplastic process (Wastl et al 1998). This was accompanied by a very marked increase in expression of Gadd45b ( Figure 3B), a gene associated with DNA damage, which has been previously associated with griseofulvin exposure (Knasmuller et al 1997).…”

Section: Discussionmentioning

confidence: 99%

Gene expression profiles associated with inflammation, fibrosis and cholestasis in mouse liver after griseofulvin

Gant¹,

Baus²,

Clothier³

et al. 2002

Environ. Health Perspect. Toxicogenomics

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Erythropoietic protoporphyria patients can develop cholestasis, severe hepatic damage, fibrosis, and cirrhosis. We modeled this hepatic pathology in C57BL/6J and BALB/c mice using griseofulvin and analyzed 3,127 genes for alteration of expression in the liver before and during the onset of protoporphyria, cholestasis, inflammation, and hepatic fibrosis. The two mouse strains developed different levels of pathologic damage in response to the griseofulvin. Characteristic gene expression profiles could be associated with griseofulvin-induced gene expression, disruption of lipid metabolism, and the pathologic states of inflammation, early fibrosis, and cholestasis. Additionally, some genes individually indicated an alteration of homeostasis or pathologic state; for example, fibroblast proliferation was potentially indicated by increased calcyclin (SA100a6) expression. Changes in cytochrome P450 (Cyp) gene expression were particularly pronounced, with increased expression of the Cyp2a, Cyp2b, and Cyp3a families. Decreased Cyp4a10 and Cyp4a14 expression was observed that could be associated with early pathologic change. A potential decrease in bile acid and steroid biosynthesis was indicated by the decreased expression of Cyp7b1 and Hsd3b4, respectively. DNA damage was indicated by induction of GADD45. This study illustrates how transcriptional programs can be associated with different stimuli in the same experiment. The time course of change in the gene expression profile compared with changes in pathology and clinical chemistry shows the potential of this approach for modeling causative, predictive, and adaptive changes in gene expression during pathologic change.

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Expression of cytochrome P450 2A5 in preneoplastic and neoplastic mouse liver lesions

Cited by 35 publications

References 28 publications

CYP2A13 in Human Respiratory Tissues and Lung Cancers: An Immunohistochemical Study with A New Peptide-Specific Antibody

CYP2A13 in Human Respiratory Tissues and Lung Cancers: An Immunohistochemical Study with A New Peptide-Specific Antibody

Heterogeneous Nuclear Ribonucleoprotein A1 and Regulation of the Xenobiotic-Inducible GeneCyp2a5

Gene expression profiles associated with inflammation, fibrosis and cholestasis in mouse liver after griseofulvin

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