Ethanol Lowers Glutathione in Rat Liver and Brain and Inhibits Methionine Synthase in a Cobalamin-Dependent Manner

Mostafa I. Waly, Kusum Kharbanda, Richard C. Deth

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)277-283
Number of pages7
JournalAlcoholism: Clinical and Experimental Research
Volume35
Issue number2
DOIs
StatePublished - Jan 1 2011

Fingerprint

5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase
Vitamin B 12
Liver
Glutathione
Rats
Brain
Ethanol
S-Adenosylmethionine
Betaine
Methylation
mecobalamin
Level control
Homocysteine
Nutrition
Methionine
Animals
Tissue
Diet

Keywords

  • Alcoholism
  • Betaine
  • Cirrhosis
  • Methylation
  • Vitamin B12

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Toxicology
  • Psychiatry and Mental health

Cite this

Ethanol Lowers Glutathione in Rat Liver and Brain and Inhibits Methionine Synthase in a Cobalamin-Dependent Manner. / Waly, Mostafa I.; Kharbanda, Kusum; Deth, Richard C.

In: Alcoholism: Clinical and Experimental Research, Vol. 35, No. 2, 01.01.2011, p. 277-283.

Research output: Contribution to journalArticle

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T1 - Ethanol Lowers Glutathione in Rat Liver and Brain and Inhibits Methionine Synthase in a Cobalamin-Dependent Manner

AU - Waly, Mostafa I.

AU - Kharbanda, Kusum

AU - Deth, Richard C.

PY - 2011/1/1

Y1 - 2011/1/1

N2 - 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.

AB - 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.

KW - Alcoholism

KW - Betaine

KW - Cirrhosis

KW - Methylation

KW - Vitamin B12

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JO - Alcoholism: Clinical and Experimental Research

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