Role of MAP kinase signalling pathways in the mode of action of peroxisome proliferators.
Peroxisome proliferators (PPs) are a class of non-genotoxic chemicals that cause rodent liver enlargement and hepatocarcinogenesis. In primary rat hepatocytes, PPs cause cell proliferation, suppression of apoptosis and peroxisome proliferation. We have investigated the role of different families of mitogen-activated protein (MAP) kinases in the mode of action of PPs. Addition of 50 microM nafenopin to primary rat hepatocyte cultures caused weak activation of extracellular signal regulated kinases and p38 MAP kinase. However, incubation of primary hepatocytes with the p38 MAP kinase inhibitor SB203580 or the MAP kinase kinase (MEK) inhibitor PD098059 prevented the induction of DNA synthesis and the suppression of transforming growth factor beta(1)-induced apoptosis by the PP nafenopin. In contrast, in the presence of these MAP kinase inhibitors, nafenopin still induced palmitoyl CoA oxidation, a measure of peroxisome proliferation. We have shown previously that PPs such as nafenopin require tumour necrosis factor alpha (TNF-alpha) to exert their effects on cellular proliferation and apoptosis. Here we show that treatment of primary rat hepatocyte cultures with nafenopin causes an increase in bioactive TNF-alpha and that this process requires p38 MAP kinase activity.
Cosulich
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S
AstraZeneca Central Toxicology Laboratory, Alderley Park, Macclesfield, Cheshire SK10 4TJ and AstraZeneca Pharmaceuticals, 3G8 Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK. sabina.cosulich@astrazeneca.com
James
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N
Roberts
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R
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D007093:Imidazoles / Q000494:pharmacology; D020935:MAP Kinase Signaling System; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D009255:Nafenopin / Q000494:pharmacology*; D010171:Palmitoyl Coenzyme A / Q000378:metabolism; D020025:Peroxisome Proliferators / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D016196:S Phase / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D048051:p38 Mitogen-Activated Protein Kinases
D007093:Imidazoles; D020025:Peroxisome Proliferators; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha; D009255:Nafenopin; D010171:Palmitoyl Coenzyme A; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580