Heterogeneity of enzyme-altered foci in rat liver

Schwarz, Michael; Buchmann, Albrecht; Schulte, Martina; Pearson, Dale; Kunz, Werner

doi:10.1016/0378-4274(89)90039-8

Cited by 25 publications

(7 citation statements)

References 45 publications

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Section: Regulatory Genes and Signaling Pathways In The Livermentioning

confidence: 99%

“…In particular, a decrease in the expression of different CYP isoforms was observed (Schwarz et al 1989; Buchmann et al 1987). However, treatment with phenobarbital, a tumor promoter and CAR agonist was able to induce transiently the expression of CAR target CYPs in these liver foci (Schwarz et al 1989). Similarly, expression of different drug-metabolizing enzymes, especially CYP isoforms, was observed in murine liver tumors from phenobarbital-treated animals alongside a very low expression of these enzymes in tumors from animals which had not received phenobarbital (Loeppen et al 2005).…”

Section: Regulatory Genes and Signaling Pathways In The Livermentioning

confidence: 99%

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Recent advances in 2D and 3D in vitro systems using primary hepatocytes, alternative hepatocyte sources and non-parenchymal liver cells and their use in investigating mechanisms of hepatotoxicity, cell signaling and ADME

Hewitt²,

et al. 2013

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This review encompasses the most important advances in liver functions and hepatotoxicity and analyzes which mechanisms can be studied in vitro. In a complex architecture of nested, zonated lobules, the liver consists of approximately 80 % hepatocytes and 20 % non-parenchymal cells, the latter being involved in a secondary phase that may dramatically aggravate the initial damage. Hepatotoxicity, as well as hepatic metabolism, is controlled by a set of nuclear receptors (including PXR, CAR, HNF-4α, FXR, LXR, SHP, VDR and PPAR) and signaling pathways. When isolating liver cells, some pathways are activated, e.g., the RAS/MEK/ERK pathway, whereas others are silenced (e.g. HNF-4α), resulting in up- and downregulation of hundreds of genes. An understanding of these changes is crucial for a correct interpretation of in vitro data. The possibilities and limitations of the most useful liver in vitro systems are summarized, including three-dimensional culture techniques, co-cultures with non-parenchymal cells, hepatospheres, precision cut liver slices and the isolated perfused liver. Also discussed is how closely hepatoma, stem cell and iPS cell–derived hepatocyte-like-cells resemble real hepatocytes. Finally, a summary is given of the state of the art of liver in vitro and mathematical modeling systems that are currently used in the pharmaceutical industry with an emphasis on drug metabolism, prediction of clearance, drug interaction, transporter studies and hepatotoxicity. One key message is that despite our enthusiasm for in vitro systems, we must never lose sight of the in vivo situation. Although hepatocytes have been isolated for decades, the hunt for relevant alternative systems has only just begun.Electronic supplementary materialThe online version of this article (doi:10.1007/s00204-013-1078-5) contains supplementary material, which is available to authorized users.

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Section: Regulatory Genes and Signaling Pathways In The Livermentioning

confidence: 99%

Section: Regulatory Genes and Signaling Pathways In The Livermentioning

confidence: 99%

Recent advances in 2D and 3D in vitro systems using primary hepatocytes, alternative hepatocyte sources and non-parenchymal liver cells and their use in investigating mechanisms of hepatotoxicity, cell signaling and ADME

Hewitt²,

et al. 2013

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“…Frozen sections were taken from each liver and stained enzyme-histochemically for glucose-6-phosphatase (G-6-Pase) activity (32). G-6-Pase-altered lesions were quantified by means of a computer-assisted digitizer system (33). The volume fraction of enzyme-altered tissue in liver and the number of lesions per unit of liver were calculated using standard stereological techniques.…”

Section: /Ogg1mentioning

confidence: 99%

The Peroxisome Proliferator WY-14,643 Promotes Hepatocarcinogenesis Caused by Endogenously Generated Oxidative DNA Base Modifications in Repair-Deficient Csbm/m/Ogg1−/− Mice

Trapp

Schwarz²,

Epe³

2007

Cancer Research

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Basal levels of endogenously generated oxidative DNA modifications such as 7,8-dihydro-8-oxoguanine (8-oxoG) mice, which were f3-fold higher than in the repair-proficient mice, declined by 39% under the treatment, whereas the frequencies in the livers of the repair-proficient animals remained unchanged. Preneoplastic lesions (staining positive or negative for glucose-6-phoshatase) developed in the livers of both wild-type and Csb m/m /Ogg1 À/À mice after 30 weeks.Both the numbers and the total volumes of the lesions were f6-fold higher in the repair-deficient mice than in the wildtype mice. The results indicate that spontaneous mutations generated from endogenous oxidative DNA base damage efficiently translate into increased tumorigenesis when cell proliferation is stimulated. [Cancer Res 2007;67(11):5156-61]

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“…The microscopic pictures of the stained sections were projected onto a digitizer screen and the outlines of the sections and of transections from enzyme-altered lesions therein were traced manually with a cursor. 22 The digitized 2-dimensional data were then used for calculation of the number of lesions per cm 3 of liver, their volume fraction in liver, and their size distribution using the stereological procedures of Fulman and Saltykov. 23 Cell Proliferation.…”

Section: Methodsmentioning

confidence: 99%

Hepatocarcinogenesis in Female Mice With Mosaic Expression of Connexin32

Moennikes¹,

Buchmann²,

Willecke³

et al. 2000

Hepatology

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Mice deficient for connexin32 (Cx32), the major gap junction forming protein in liver, are highly susceptible to hepatocarcinogenesis. Because the Cx32 gene is located on the X-chromosome, heterozygous females show mosaicism with respect to Cx32 expression; this enables their use in studying the effect of Cx32-deficiency in a mixed Cx32-plus/ Cx32-minus environment in vivo. Connexins are subunits of gap junctional channels, through which directly neighboring cells exchange low molecular weight molecules such as ions, second messengers, and cellular metabolites. Intercellular communication mediated via gap junctions plays an important role in tissue homeostasis and cancer. [1][2][3][4][5][6] We could recently show that targeted disruption of the connexin32 (Cx32) gene is associated with strongly enhanced hepatocarcinogenesis in mice, demonstrating the tumor-suppressive role of this connexin in liver. 7,8

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Heterogeneity of enzyme-altered foci in rat liver

Cited by 25 publications

References 45 publications

Recent advances in 2D and 3D in vitro systems using primary hepatocytes, alternative hepatocyte sources and non-parenchymal liver cells and their use in investigating mechanisms of hepatotoxicity, cell signaling and ADME

Recent advances in 2D and 3D in vitro systems using primary hepatocytes, alternative hepatocyte sources and non-parenchymal liver cells and their use in investigating mechanisms of hepatotoxicity, cell signaling and ADME

The Peroxisome Proliferator WY-14,643 Promotes Hepatocarcinogenesis Caused by Endogenously Generated Oxidative DNA Base Modifications in Repair-Deficient Csbm/m/Ogg1−/− Mice

Hepatocarcinogenesis in Female Mice With Mosaic Expression of Connexin32

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