Document Detail


Folate deficiency alters hepatic and colon MGMT and OGG-1 DNA repair protein expression in rats but has no effect on genome-wide DNA methylation.
MedLine Citation:
PMID:  20051376     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Folate deficiency is implicated in human colon cancer. The effects of feeding rats a folate-deficient diet for 24 weeks on DNA damage (8-oxo-7,8-dihydroguanine), DNA repair [O(6)-methylguanine-DNA methyltransferase (MGMT) and 8-oxoguanine-DNA glycosylase (OGG-1) activity], and epigenetic parameters (genome-wide cytosine methylation and indices of cellular methylation status) were investigated. Relative to control diet, the folate-deficient diet resulted in significantly reduced levels of serum ( approximately 80%; P < 0.0001), whole blood ( approximately 40%; P < 0.0001), and tissue folate (between 25% and 60% depending on the tissue sampled; P < 0.05); increased plasma total homocysteine ( approximately 35%; P < 0.05); and decreased S-adenosylmethionine to S-adenosylhomocysteine concentrations ( approximately 11%; P < 0.05). There was no significant change in the levels of 5-methyldeoxycytidine in liver or colon DNA, nor in the activity of liver DNA cytosine methyltransferase. However, there were significant increases in 8-oxo-7,8-dihydroguanine (P < 0.001) in lymphocyte DNA and in levels of the DNA repair proteins OGG-1 ( approximately 27%; P < 0.03) and MGMT ( approximately 25%; P < 0.003) in the liver, but not in the colon. This may reflect the ability of the liver, but not the colon, to upregulate DNA repair enzymes in response to either elevated DNA damage or an imbalance in the nucleotide precursor pool. These results show that folate deficiency can significantly modulate DNA damage and DNA repair, providing mechanisms by which it plays a role in the etiology of human cancer. We speculate that the inability of colon tissue to respond to folate deficiency occurs in humans and may increase the potential for malignant transformation.
Authors:
Susan J Duthie; George Grant; Lynn P Pirie; Amanda J Watson; Geoffrey P Margison
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Cancer prevention research (Philadelphia, Pa.)     Volume:  3     ISSN:  1940-6215     ISO Abbreviation:  Cancer Prev Res (Phila)     Publication Date:  2010 Jan 
Date Detail:
Created Date:  2010-01-06     Completed Date:  2010-03-03     Revised Date:  2013-03-27    
Medline Journal Info:
Nlm Unique ID:  101479409     Medline TA:  Cancer Prev Res (Phila)     Country:  United States    
Other Details:
Languages:  eng     Pagination:  92-100     Citation Subset:  IM    
Affiliation:
Rowett Institute of Nutrition and Health, University of Aberdeen, United Kingdom. s.duthie@abdn.ac.uk
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MeSH Terms
Descriptor/Qualifier:
Animals
Colon / metabolism*
DNA Damage / physiology
DNA Glycosylases / biosynthesis*
DNA Methylation / physiology*
DNA Repair / physiology
Folic Acid Deficiency / metabolism*
Liver / metabolism*
Male
O(6)-Methylguanine-DNA Methyltransferase / biosynthesis*
Rats
Grant Support
ID/Acronym/Agency:
A6058//Cancer Research UK; //Cancer Research UK
Chemical
Reg. No./Substance:
EC 2.1.1.63/O(6)-Methylguanine-DNA Methyltransferase; EC 3.2.2.-/DNA Glycosylases; EC 3.2.2.-/OGG1 protein, rat
Comments/Corrections

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