| DNA adducts formation and induction of apoptosis in rat liver epithelial 'stem-like' cells exposed to carcinogenic polycyclic aromatic hydrocarbons. | |
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MedLine Citation:
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PMID: 17961608 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The bipotent liver progenitor cells, so called oval cells, may participate at the early stages of hepatocarcinogenesis induced by chemical carcinogens. Unlike in mature parenchymal cells, little is known about formation of DNA adducts and other genotoxic events in oval cells. In the present study, we employed spontaneously immortalized rat liver WB-F344 cell line, which is an established in vitro model of oval cells, in order to study genotoxic effects of selected carcinogenic polycyclic aromatic hydrocarbons (PAHs). With exception of dibenzo[a,l]pyrene, and partly also benzo[g]chrysene and benz[a]anthracene, all other PAHs under the study induced high levels of CYP1A1 and CYP1B1 mRNA. In contrast, we observed distinct genotoxic and cytotoxic potencies of PAHs. Dibenzo[a,l]pyrene, and to a lesser extent also benzo[a]pyrene, benzo[g]chrysene and dibenzo[a,e]pyrene, formed high levels of DNA adducts. This was accompanied with accumulation of Ser-15 phosphorylated form of p53 protein and induction of apoptosis. Contrary to that, benz[a]anthracene, chrysene, benzo[b]fluoranthene and dibenzo[a,h]anthracene induced only low amounts of DNA adducts formation and minimal apoptosis, without exerting significant effects on p53 phosphorylation. Finally, we studied effects of 2,4,3',5'-tetramethoxystilbene and fluoranthene, inhibitors of CYP1B1 activity, which plays a central role in metabolic activation of dibenzo[a,l]pyrene. In a dose-dependent manner, both compounds inhibited apoptosis induced by dibenzo[a,l]pyrene, suggesting that it interferes with the metabolic activation of the latter one. The present data show that in model cell line sharing phenotypic properties with oval cells, PAHs can be efficiently metabolized to form ultimate genotoxic metabolites. Liver progenitor cells could be thus susceptible to this type of genotoxic insult, which makes WB-F344 cell line a useful tool for studies of genotoxic effects of organic contaminants in liver cells. Our results also suggest that, unlike in mature hepatocytes, CYP1B1 might be a primary enzyme responsible for formation of DNA adducts in liver progenitor cells. |
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Authors:
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Jan Topinka; Sona Marvanová; Jan Vondrácek; Oksana Sevastyanova; Zuzana Nováková; Pavel Krcmár; Katerina Pencíková; Miroslav Machala |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2007-09-16 |
Journal Detail:
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Title: Mutation research Volume: 638 ISSN: 0027-5107 ISO Abbreviation: Mutat. Res. Publication Date: 2008 Feb |
Date Detail:
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Created Date: 2008-01-15 Completed Date: 2008-04-02 Revised Date: 2012-01-24 |
Medline Journal Info:
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Nlm Unique ID: 0400763 Medline TA: Mutat Res Country: Netherlands |
Other Details:
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Languages: eng Pagination: 122-32 Citation Subset: IM |
Affiliation:
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Laboratory of Genetic Ecotoxicology, Institute of Experimental Medicine, AS CR, 142 20 Prague, Czech Republic. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Apoptosis* Aryl Hydrocarbon Hydroxylases / genetics Cells, Cultured Cytochrome P-450 CYP1A1 / genetics DNA Adducts / metabolism* Liver / cytology* Polycyclic Hydrocarbons, Aromatic / pharmacology* RNA, Messenger / analysis Rats Rats, Inbred F344 Stem Cells / metabolism* |
| Chemical | |
Reg. No./Substance:
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0/DNA Adducts; 0/Polycyclic Hydrocarbons, Aromatic; 0/RNA, Messenger; EC 1.14.14.1/Aryl Hydrocarbon Hydroxylases; EC 1.14.14.1/Cytochrome P-450 CYP1A1; EC 1.14.14.1/cytochrome P450, family 1, subfamily B, polypeptide 1 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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