Document Detail


Activation of P53 in HepG2 cells as surrogate to detect mutagens and promutagens in vitro.
MedLine Citation:
PMID:  20655369     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The current genotoxicity tests of the standard in vitro battery, especially those using mammalian cells, are limited by their low specificity and highlight the importance of new in vitro tools. This study aimed to evaluate the suitability of HepG2 cells for assaying mutagens and promutagens. We determined P53 activity as surrogate genotoxicity endpoint in HepG2 cells. Our results revealed a significant P53-induction by actinomycin D, methyl methanesulfonate and etoposide. Prior to the investigation of promutagens we characterized HepG2 cells by analyzing the expression of 45 genes involved in xenobiotic metabolism and measuring the activity of selected Cytochrome-P450 (CYP) enzymes. We determined a limited metabolic capacity prompting us to employ a co-treatment with rat liver S9 as metabolic activation system (MAS) for promutagens. While cyclophosphamide showed an elevation of activated P53 in the presence of S9, 7,12-dimethylbenz[a]anthracene and aflatoxin B(1) responded without the MAS. Inhibition of cellular CYP3A4 or CYP1A/1B suppressed the aflatoxin B(1)- and dimethylbenz[a]anthracene-mediated P53 response, respectively, indicating that HepG2 cells are capable of metabolizing these compounds in a CYP1A/B/3A4-dependent manner. In summary, our results indicate that P53 activation in HepG2 cells combined with a MAS can be used for the identification of new (pro)genotoxicants.
Authors:
Kathleen Boehme; Yasmin Dietz; Philip Hewitt; Stefan O Mueller
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Publication Detail:
Type:  Journal Article     Date:  2010-07-22
Journal Detail:
Title:  Toxicology letters     Volume:  198     ISSN:  1879-3169     ISO Abbreviation:  Toxicol. Lett.     Publication Date:  2010 Oct 
Date Detail:
Created Date:  2010-08-24     Completed Date:  2010-09-10     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  7709027     Medline TA:  Toxicol Lett     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  272-81     Citation Subset:  IM    
Copyright Information:
Copyright 2010 Elsevier Ireland Ltd. All rights reserved.
Affiliation:
Merck KGaA, Merck Serono, Toxicology, 64293 Darmstadt, Germany.
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MeSH Terms
Descriptor/Qualifier:
Animals
Biological Markers / metabolism
Cell Survival / drug effects
Cytochrome P-450 CYP1A1 / antagonists & inhibitors,  biosynthesis,  genetics
Cytochrome P-450 CYP3A / antagonists & inhibitors,  biosynthesis,  genetics
DNA Damage*
Gene Expression Profiling
Hep G2 Cells
Humans
Metabolic Detoxication, Drug / genetics
Mutagenicity Tests / methods
Mutagens / toxicity*
Rats
Tumor Suppressor Protein p53 / metabolism*
Chemical
Reg. No./Substance:
0/Biological Markers; 0/Mutagens; 0/Tumor Suppressor Protein p53; EC 1.14.13.67/CYP3A4 protein, human; EC 1.14.14.1/Cytochrome P-450 CYP1A1; EC 1.14.14.1/Cytochrome P-450 CYP3A

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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