Document Detail


Alkyltransferase-mediated toxicity of bis-electrophiles in mammalian cells.
MedLine Citation:
PMID:  19941875     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The primary function of O(6)-alkylguanine-DNA alkyltransferase (AGT) is to maintain genomic integrity in the face of damage by both endogenous and exogenous alkylating agents. However, paradoxically, bacterial and mammalian AGTs have been shown to increase cytotoxicity and mutagenicity of dihaloalkanes and other bis-electrophiles when expressed in bacterial cells. We have extended these studies to mammalian cells using CHO cells that lack AGT expression and CHO cells stably transfected with a plasmid that expresses human AGT. The cytotoxicity of 1,2-dibromoethane, dibromomethane and epibromohydrin was significantly increased by the presence of AGT but cytotoxicity of butadiene diepoxide was not affected. Mutations caused by these agents were assessed using hypoxanthine-guanine phosphoribosyltransferase (HPRT) as a reporter gene. There was a small (c. 2-3-fold) but statistically significant AGT-mediated increase in mutations caused by 1,2-dibromoethane, dibromomethane and epibromohydrin. Analysis of the mutation spectrum induced by 1,2-dibromoethane showed that the presence of AGT also altered the types of mutations with an increase in total base substitution mutants due to a rise in transversions at both G:C and A:T sites. AGT expression also led to mutations arising from the transcribed strand, which were not seen in cells lacking AGT. Although the frequency of deletion mutations was decreased by AGT expression, the formation of large deletions (> or = 3 exons) was increased. This work demonstrates that interaction of AGT with some bis-electrophiles can cause mutagenicity and diminished cell survival in mammalian cells. It is consistent with the hypothesis that DNA-AGT cross-links, which have been characterized in experiments with purified AGT protein and such bis-electrophiles, can be formed in mammalian cells.
Authors:
Aley G Kalapila; Anthony E Pegg
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2009-11-24
Journal Detail:
Title:  Mutation research     Volume:  684     ISSN:  0027-5107     ISO Abbreviation:  Mutat. Res.     Publication Date:  2010 Feb 
Date Detail:
Created Date:  2010-01-28     Completed Date:  2010-04-27     Revised Date:  2014-09-14    
Medline Journal Info:
Nlm Unique ID:  0400763     Medline TA:  Mutat Res     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  35-42     Citation Subset:  IM    
Copyright Information:
Copyright 2009 Elsevier B.V. All rights reserved.
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MeSH Terms
Descriptor/Qualifier:
Alcohols / toxicity
Alkyl and Aryl Transferases / pharmacology*
Animals
CHO Cells
Cricetinae
Cricetulus
Epoxy Compounds / toxicity*
Humans
Hydrocarbons, Brominated / toxicity*
Mutagenicity Tests
Mutagens / toxicity*
Grant Support
ID/Acronym/Agency:
CA-018137/CA/NCI NIH HHS; CA-071976/CA/NCI NIH HHS; R01 CA018137/CA/NCI NIH HHS; R01 CA018137-35/CA/NCI NIH HHS; R01 CA071976/CA/NCI NIH HHS; R01 CA071976-13/CA/NCI NIH HHS; R01 CA071976-14/CA/NCI NIH HHS; R37 CA018137/CA/NCI NIH HHS; R37 CA018137-33/CA/NCI NIH HHS; R37 CA018137-34/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Alcohols; 0/Epoxy Compounds; 0/Hydrocarbons, Brominated; 0/Mutagens; 0/bromohydrins; 1464-53-5/erythritol anhydride; EC 2.5.-/Alkyl and Aryl Transferases; V69B659W01/methylene bromide
Comments/Corrections

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