Peroxisome proliferators do not increase DNA synthesis in purified rat hepatocytes

Parzefall, Wolfram; Berger, Walter; Kainzbauer, Eveline; Teufelhofer, Olga; Schulte‐Hermann, Rolf; Thurman, Ronald G.

doi:10.1093/carcin/22.3.519

Cited by 46 publications

(35 citation statements)

References 29 publications

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“…2. reported that acceleration of proliferation in rat hepatocytes by WY-14643 was attenuated by the reduction of TNFα via inactivation of Kupffer cells. It was also reported that WY-14643 failed to cause cell proliferation in hepatic parenchymal cells cultured under the condition where non-parenchymal cells had been eliminated, and that its proliferative effect was recovered when Kupffer cells were added to the culture (Parzefall et al, 2001). As for the attenuation of apoptosis, it was reported that a high concentration of TNFα inhibited spontaneous TGFβ1-induced apoptosis in primary cultured hepatocytes (Rolfe et al, 1997).…”

Section: Discussionmentioning

confidence: 98%

Profiling of Gene Expression in Rat Liver and Rat Primary Cultured Hepatocytes Treated With Peroxisome Proliferators

et al. 2006

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-The Toxicogenomics project has been constructing a large-scale database of about 150 compounds exposed to rat (single dose, 3, 6, 9, 24 hrs and repeated dose for 3, 7, 14 28 days with 3 dose levels) and rat hepatocytes (2, 8, 24 hr with 3 concentrations) and data of transcriptome in liver using GeneChip, and the related toxicological measures are being accumulated. In the present study, the data of three ligands of peroxisome proliferator activated receptor α (PPARα), i.e., clofibrate, WY-14643 and gemfibrozil in our database were analyzed. Many of the β-oxidation-related genes were commonly induced in vivo and in vitro, whereas expression changes in genes related to cell proliferation, apoptosis, were detected in vivo (single and repeated dose) but not in vitro. Changes in those related to the immune response, coagulation and the stress response were also detectable exclusively in vivo. Using the genes mobilized in two or three PPARα agonists, hierarchical clustering was performed on 32 compounds stored in our database. In the profiling of an in vivo single dose, benzbromarone and aspirin were located in the same cluster of the three PPARα agonists. The clustering of in vitro data revealed that benzbromarone, three NSAIDs (aspirin, indomethacin and diclofenac sodium) and valproic acid belonged to the same cluster of PPARα agonists, supporting the reports that benzbromarone,valproic acid and some NSAIDs were reported to be PPARα agonists. Using the genes commonly up-regulated both in vivo and in vitro, principal component analysis was performed in 32 compounds, and principal component 1 was found to be the convenient parameter to extract PPARα agonist-like compounds from the database.

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Section: Discussionmentioning

confidence: 98%

Profiling of Gene Expression in Rat Liver and Rat Primary Cultured Hepatocytes Treated With Peroxisome Proliferators

et al. 2006

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“…Most interestingly, in highly purified rodent hepatocytes, PPs fail to further increase DNA synthesis [112,110,157]. The possible explanation of this difference is the involvement of nonparenchymal cell(s) in whole liver that is lost in isolated cultured hepatocytes.…”

Section: Proposed Modes Of Action For Dehp In Kupffer Cellsmentioning

confidence: 99%

Modes of Action and Species-Specific Effects of Di-(2-ethylhexyl)Phthalate in the Liver

Rusyn

Peters

Cunningham

2006

Critical Reviews in Toxicology

245

141

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The industrial plasticizer di-(2-ethylhexyl)phthalate (DEHP) is used in manufacturing of a wide variety of polyvinyl chloride (PVC)-containing medical and consumer products. The biological action of DEHP is very similar to chemicals that are collectively known as peroxisome proliferators (PPs). PPs are a structurally diverse group of compounds characterized as nongenotoxic rodent carcinogens. This review focuses on the effect of DEHP in liver, a primary target organ for the pleiotropic effects of DEHP and other PPs. Specifically, liver parenchymal cells, identified herein as hepatocytes, are a major cell type that are responsive to exposure to PPs, including DEHP; however, other cell types in the liver may also play a role. The PP-induced increase in the number and size of peroxisomes in hepatocytes, so called 'peroxisome proliferation' that results in elevation of fatty acid metabolism, is a hallmark response to these compounds in the liver. A link between peroxisome proliferation and tumor formation has been a predominant, albeit questioned, theory to explain the cause of a hepatocarcinogenic effect of PPs. Other molecular events, such as induction of cell proliferation, decreased apoptosis, oxidative DNA damage, and selective clonal expansion of the initiated cells have been also been proposed to be critically involved in PP-induced carcinogenesis in liver. Considerable differences in the metabolism and molecular changes induced by DEHP in the liver, most predominantly the activation of the nuclear receptor peroxisome proliferator-activated receptor (PPAR)α, have been identified between species. Both sexes of rats and mice develop adenomas and carcinomas after prolonged feeding with DEHP; however, limited DEHP-specific human data are available, even though exposure to DEHP and other phthalates is common in the general population. This likely constitutes the largest gap in our knowledge on the potential for DEHP to cause liver cancer in humans. Overall, it is believed that the sequence of key events that are relevant to DEHP-induced liver carcinogenesis in rodents involves the following events whereby the combination of the molecular signals and multiple pathways, rather than a single hallmark event (such as induction of PPARα and peroxisomal genes, or cell proliferation) contribute to the formation of tumors: (i) rapid metabolism of the parental compound to primary and secondary bioactive metabolites that are readily absorbed and distributed throughout the body; (ii) receptor-independent activation of hepatic macrophages and production of oxidants; (iii) activation of PPARα in hepatocytes and sustained increase in expression of peroxisomal and non-peroxisomal metabolismrelated genes; (iv) enlargement of many hepatocellular organelles (peroxisomes, mitochondria, etc.); (v) rapid, but transient increase in cell proliferation, and a decrease in apoptosis; (vi) sustained

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“…There are conflicting reports with regards to the effects of peroxisome proliferators on cytokine production, and their importance to hepatocarcinogenesis. A number of studies suggested that cytokines may play a critical role in cell proliferation and apoptosis by peroxisome proliferators (Bojes et al, 1997;Hasmall et al, 2000a;Parzefall et al, 2001). At the same time, many reports questioned that cytokines are a requisite for altered cell turnover by peroxisome proliferators (Ledda-Columbano et al, 1998;Anderson et al, 2001).…”

Section: Gene Expression Profiling Reveals Pparα-mediated Immunosupprmentioning

confidence: 99%

Time course investigation of PPARα- and Kupffer cell-dependent effects of WY-14,643 in mouse liver using microarray gene expression

Woods

Kosyk

Bradford

et al. 2007

Toxicology and Applied Pharmacology

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Administration of peroxisome proliferators to rodents causes proliferation of peroxisomes, induction of β-oxidation enzymes, hepatocelluar hypertrophy and hyperplasia, with chronic exposure ultimately leading to hepatocellular carcinomas. Many responses associated with peroxisome proliferators are nuclear receptor-mediated events involving peroxisome proliferators-activated receptor alpha (PPARα). A role for nuclear receptor-independent events has also been shown, with evidence of Kupffer cell-mediated free radical production, presumably through NAPDH oxidase, induction of redox-sensitive transcription factors involved in cytokine production and cytokinemediated cell replication following acute treatment with peroxisome proliferators in rodents. Recent studies have demonstrated, by using p47 phox -null mice which are deficient in NADPH oxidase, that this enzyme is not related to the phenotypic events caused by prolonged administration of peroxisome proliferators. In an effort to determine the timing of the transition from Kupffer cell-to PPARα-dependent modulation of peroxisome proliferator effects, gene expression was assessed in liver from Pparα-null, p47 phox -null and corresponding wild-type mice following treatment with 4-chloro-6-(2,3-xylidino)-pyrimidynylthioacetic acid (WY-14,643) for 8 h, 24 h, 72 h, 1 wk, or 4 wks. WY-14,643-induced gene expression in p47 phox -null mouse liver differed substantially from wildtype mice at acute doses and striking differences in baseline expression of immune related genes were evident. Pathway mapping of genes that respond to WY-14,643 in a time-and dose-dependent manner demonstrates suppression of immune response, cell death and signal transduction and promotion of lipid metabolism, cell cycle and DNA repair. Furthermore, these pathways were largely dependent on PPARα, not NADPH oxidase demonstrating a temporal shift in response to peroxisome proliferators. Overall, this study shows that NADPH oxidase-dependent events, while detectable following acute treatment, are transient and short-lived. To the contrary, a strong PPARα-specific gene signature was evident in mice that were continually exposed to WY-14,643.

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Peroxisome proliferators do not increase DNA synthesis in purified rat hepatocytes

Cited by 46 publications

References 29 publications

Profiling of Gene Expression in Rat Liver and Rat Primary Cultured Hepatocytes Treated With Peroxisome Proliferators

Profiling of Gene Expression in Rat Liver and Rat Primary Cultured Hepatocytes Treated With Peroxisome Proliferators

Modes of Action and Species-Specific Effects of Di-(2-ethylhexyl)Phthalate in the Liver

Time course investigation of PPARα- and Kupffer cell-dependent effects of WY-14,643 in mouse liver using microarray gene expression

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