RGD Reference Report - Ethanol lowers glutathione in rat liver and brain and inhibits methionine synthase in a cobalamin-dependent manner. - Rat Genome Database

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Ethanol lowers glutathione in rat liver and brain and inhibits methionine synthase in a cobalamin-dependent manner.

Authors: Waly, MI  Kharbanda, KK  Deth, RC 
Citation: Waly MI, etal., Alcohol Clin Exp Res. 2011 Feb;35(2):277-83. doi: 10.1111/j.1530-0277.2010.01343.x. Epub 2010 Dec 1.
RGD ID: 7207080
Pubmed: PMID:21121936   (View Abstract at PubMed)
PMCID: PMC3058891   (View Article at PubMed Central)
DOI: DOI:10.1111/j.1530-0277.2010.01343.x   (Journal Full-text)

BACKGROUND: Methionine synthase (MS) is a ubiquitous enzyme that requires vitamin B12 (cobalamin) and 5-methyl-tetrahydrofolate for the methylation of homocysteine to methionine. Previous studies have shown that acute or chronic ethanol (ETOH) administration results in the inhibition of MS and depletion of glutathione (GSH), and it has been proposed that GSH is required for the synthesis of methylcobalamin (MeCbl). METHODS: We measured GSH levels and investigated the ability of different cobalamin cofactors [cyano- (CNCbl), glutathionyl- (GSCbl), hydroxo- (OHCbl), and MeCbl] to support MS activity in liver and brain cortex from control and ETOH-treated rats. RESULTS: In control animals, MS activity was higher in liver than in cortex for all cobalamins and MeCbl-based activity was higher than for other cofactors. S-adenosylmethionine (SAM) was required for OHCbl, CNCbl, and GSCbl-based activity, but not for MeCbl. Feeding an ETOH-containing diet for four weeks caused a significant decrease in liver MS activity, in a cobalamin-dependent manner (OHCbl >/= CNCbl > GSCbl > MeCbl). In brain cortex, OHCbl, CNCbl, and GSCbl-based activity was reduced by ETOH treatment, but MeCbl-based activity was unaffected. GSH levels were reduced by ETOH treatment in both liver and cortex homogenates, and addition of GSH restored OHCbl-based MS activity to control levels. Betaine administration had no significant effect on GSH levels or MS activity in either control or ETOH-fed groups. CONCLUSIONS: The ETOH-induced decrease in OHCbl-based MS activity is secondary to decreased GSH levels and a decreased ability to synthesize MeCbl. The ability of MeCbl to completely offset ETOH inhibition in brain cortex, but not liver, suggests tissue-specific differences in the GSH-dependent regulation of MS activity.



Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
MtrRathomocysteine metabolic process  IMP  RGD 
MtrRatmethionine metabolic process  IMP  RGD 
MtrRattetrahydrofolate metabolic process  IMP  RGD 

Molecular Function

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
MtrRatmethionine synthase activity  IMP  RGD 

Objects Annotated

Genes (Rattus norvegicus)
Mtr  (5-methyltetrahydrofolate-homocysteine methyltransferase)


Additional Information