The effect of fasting on leukocyte and plasma glutathione and sulfur amino acid concentrations

doi:10.1016/0026-0495(86)90110-1

Metabolism

Volume 35, Issue 2, February 1986, Pages 118-121

https://doi.org/10.1016/0026-0495(86)90110-1 Get rights and content

Abstract

Leukocyte and plasma concentrations of free glutathione, cysteine, methionine, and taurine, and total glutathione and cysteine concentrations were determined in healthy human subjects before and during a seven-day period of total energy deprivation. In leukocytes a progressive decline in total glutathione concentration was found during seven days of starvation due to a decrease in free glutathione content. An increased mixed protein-bound glutathione concentration was calculated, whereas the total cysteine level was unaltered. Fasting resulted in a decreased plasma concentration of free glutathione, whereas the total glutathione level remained unchanged. Free leukocyte concentrations of taurine and methionine were reduced, whereas plasma sulfur amino acid levels were essentially unaffected. These results probably reflect a limited availability of sulfur amino acids during fasting, when glutathione is used as cysteine reservoir for synthesis of other vital sulfur containing compounds. The potential use of leukocyte glutathione, methionine, and taurine concentrations as intracellular indicators of sulfur amino acid deficiency are stressed.

References (40)

ES Cho et al.
Tissue glutathione as a cyst(e)ine reservoir during fasting and refeeding of rats
J Nutr
(1981)
DJ Reed et al.
The role of methionine in glutathione biosynthesis by isolated hepatocytes
Biochem Biophys Res Commun
(1977)
G Lunn et al.
Transport accounts for glutathione turnover in human erythrocytes
Blood
(1979)
N Tateishi et al.
Rat liver glutathione: possible role as a reservoir of cysteine
J Nutr
(1977)
ME Anderson et al.
Dynamic state of glutathione in blood plasma
J Biol Chem
(1980)
AA Voetman et al.
Changes in the levels of glutathione in phagocytizing human neutrophils
Blood
(1980)
J Mårtensson
The effects of short-term fasting on the excretion of sulfur compounds in healthy subjects
Metabolism
(1982)
JT Isaacs et al.
Cyclic AMP-dependent control of the rat hepatic glutathione disulfide sulfhydryl ratio
Biochim Biophys Acta
(1977)
A Szewczuk et al.
The reaction of iodo-acetamide with the active center of γ-glutamyl transpeptidase
Biochim Biophys Acta
(1965)
F Tietze
Enzymic method for quantitative determination of nanogram amounts of total and oxidized glutathione
Anal Biochem
(1969)

L Hagenfeldt et al.

Glutathione and γ-glutamylcysteine in whole blood, plasma and erythrocytes

Clin Chim Acta

(1978)

DM Greenberg

Biosynthesis of cysteine and cystine

KM Daniels et al.

The effect of dietary cysteine level on cysteine metabolism in rats

J Nutr

(1982)

A Meister et al.

Glutathione

Ann Rev Biochem

(1983)

PG Richman et al.

Regulation of γ-glutamylcysteine synthetase by nonallosteric feedback inhibition by glutathione

J Biol Chem

(1974)

BH Lauterburg et al.

In vivo regulation of hepatic glutathione synthesis: Effects of food deprivation or glutathione depletion by electrophilic compounds

Adv Exp Med Biol

(1982)

BH Lauterburg et al.

Mechanism of action of N-acetylcysteine in the protection against the hepatotoxicity of acetaminophen in rats in vivo

J Clin Invest

(1983)

NS Kosower et al.

The glutathione status of cells

Int Rev Cytol

(1978)

R Hahn et al.

The fate of extracellular glutathione in the rat

Biochim Biophys Acta

(1978)

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^☆: Supported by grants from the Swedish Medical Research Council (project No 84-13X-05644-05), Tore Nilsson Research Fund, Åke Wibergs Foundation, County Council of Östergötland, and the Medical Society of Linköping.

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The effect of fasting on leukocyte and plasma glutathione and sulfur amino acid concentrations☆

Abstract

J Nutr

Biochem Biophys Res Commun

Blood

J Nutr

J Biol Chem

Blood

Metabolism

Biochim Biophys Acta

Biochim Biophys Acta

Anal Biochem

Clin Chim Acta

J Nutr

Glutathione

Ann Rev Biochem

Regulation of γ-glutamylcysteine synthetase by nonallosteric feedback inhibition by glutathione

J Biol Chem

In vivo regulation of hepatic glutathione synthesis: Effects of food deprivation or glutathione depletion by electrophilic compounds

Adv Exp Med Biol

Mechanism of action of N-acetylcysteine in the protection against the hepatotoxicity of acetaminophen in rats in vivo

J Clin Invest

The glutathione status of cells

Int Rev Cytol

The fate of extracellular glutathione in the rat

Biochim Biophys Acta