Biologic and pharmacologic regulation of mammalian glutathione synthesis

Griffith, Owen W.

doi:10.1016/s0891-5849(99)00176-8

Cited by 1,081 publications

(817 citation statements)

References 111 publications

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“…The GSH and GSSG contents of tissues are dependent upon a number of factors related to the biosynthesis of GSH and its catabolism by oxidation and degradation (Reed, 1986;Griffith, 1999;Bharath et al, 2002). Concentrations of GSH precursor molecules, such as cysteine, and activities of enzymes such as glutamate cysteine ligase, the rate limiting enzyme in GSH biosynthesis, and GSSG reductase, are thought to be critical factors in the augmentation of GSH.…”

Section: Discussionmentioning

confidence: 99%

Comparison of thiol redox state of mitochondria and homogenates of various tissues between two strains of mice with different longevities

Rebrin

Sohal

2004

Experimental Gerontology

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The main purpose of this study was to determine if differences in life spans of two different strains of mice are associated with the thiol redox state of their tissues and mitochondria. A comparison, based on amounts of reduced and oxidized glutathione (GSH, GSSG) and reactive protein thiols, was made between short-lived SAM (P8) mice and the longer-lived C57BL/6 mice at 13 months of age. The average life span of the latter mouse strain is approximately 48% longer than the former strain. Analyses of plasma, tissue homogenates and mitochondria of liver, kidney, heart, brain and skeletal muscle indicated that, in general, amounts of GSH and reactive protein sulfhydryls and GSH:GSSG ratios were lower and concentrations of GSSG were higher in the SAM than the C57BL/6 mice. Differences in the redox state between the two strains were more consistent and pronounced in skeletal muscle than in other tissues, and in mitochondria than in their respective tissue homogenates. Overall, the results support the view that the shorter-lived SAM mice exhibit a relatively higher level of oxidative stress than the longer-lived C57BL/6 mice, which is consistent with the predictions of the oxidative stress hypothesis of aging. Intra-species comparisons may be useful for the identification of biochemical characteristics associated with the variations in life spans.

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Section: Discussionmentioning

confidence: 99%

Comparison of thiol redox state of mitochondria and homogenates of various tissues between two strains of mice with different longevities

Rebrin

Sohal

2004

Experimental Gerontology

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“…Although much is known about the stimuli that increase or decrease ␥-GCS, the detailed mechanism of regulation is not completely understood [33]. Several studies have demonstrated the presence of AP-1, AP-2, antioxidant response elements (ARE)/electrophile response elements (EpRE), and SP-1 binding sites in 5Ј region upstream of the transcription start site of the two subunits of ␥-GCS [34,35].…”

Section: Discussionmentioning

confidence: 99%

“…While the heavy subunit possesses the catalytic activity and is subject to negative feedback inhibition by GSH, the kinetic properties are significantly influenced by light subunit binding [11]. The magnitude of the modulatory effect of ␥-GCS L is species and cell dependent, but in all studies to date, the availability of the light subunit enhances the catalytic activity of ␥-GCS H [11,33,43]. Gamma-GCS L enhances the binding of ␥-GCS H to its substrates, so the elevation in GSH may be as a result of increased association of the two subunits, thereby enabling more interaction with the increased cysteine made available through the conversion from cystine.…”

Section: Discussionmentioning

confidence: 99%

“…Similarly, Cai [45] observed activation of both subunits in rat hepatocytes treated with 0.1-5 mM BSO for 12 h. In our study, the BSO concentration was 10-fold lower and exposure was 10 d rather than 12 h. Vascular complications of diabetes are associated with long-term hyperglycemia-induced oxidative stress; therefore, a 10 d experimental period was used. It has been suggested that there is a threshold value below which the level of GSH must fall before activation of ␥-GCS occurs [33]. This may explain the reason for not observing any upregulation of the ␥-GCS subunits in BSO-treated HVSMC.…”

Section: Discussionmentioning

confidence: 99%

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Restoration of glutathione levels in vascular smooth muscle cells exposed to high glucose conditions

Powell

Nally

McMaster

et al. 2001

Free Radical Biology and Medicine

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Abstract-Hyperglycemia-induced oxidative stress may play a key role in the pathogenesis of diabetic vascular disease. The purpose of this study was to determine the effects of glucose on levels of glutathione (a major intracellular antioxidant), the expression of ␥-glutamylcysteine synthetase (the rate-limiting enzyme in glutathione de novo synthesis), and DNA damage in human vascular smooth muscle cells in vitro. High glucose conditions and buthionine sulphoximine, an inhibitor of ␥-glutamylcysteine synthetase, reduced intracellular glutathione levels in vascular smooth muscle cells. This reduction was accompanied by a decrease in the mRNA expression of both subunits of ␥-glutamylcysteine synthetase as well as an increase in DNA damage. In high glucose conditions, incubation of the vascular smooth muscle cells with ␣-lipoic acid and L-cystine restored glutathione levels. We suggest that the decrease in GSH levels seen in high glucose conditions is mediated by the availability of cysteine (rate-limiting substrate in de novo glutathione synthesis) and the gene expression of the ␥-glutamylcysteine synthetase enzyme. Glutathione depletion is associated with an increase in DNA damage, which can be reduced when glutathione levels are restored.

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“…To measure GPx activity, 10 µL of each sample were added to 240 µL of a working solution containing buffer A plus 4 mM sodium azide, 4 mM GSH, 0.2 mM NADPH and 0.5 U/mL GRd. After incubation for 4 min at 37 ºC , the reaction was started by adding 10 µL of cumene hydroperoxide (0.3%) and the GPx activity was determined following the oxidation of the NADPH for 3 min at 340 nm in an UV spectrophotometer (Shimadzu Deutschland GmBH, Duisburg, Germany) (Griffith, 1999). GRd activity was measured in samples (35 µL) added to 465 µL of a working solution containing buffer A plus 2 mM GSSG.…”

Section: Measurements Of Gpx and Grd Activitiesmentioning

confidence: 99%

Improved mitochondrial function and increased life span after chronic melatonin treatment in senescent prone mice

Rodríguez

Escames

López

et al. 2008

Experimental Gerontology

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Biologic and pharmacologic regulation of mammalian glutathione synthesis

Cited by 1,081 publications

References 111 publications

Comparison of thiol redox state of mitochondria and homogenates of various tissues between two strains of mice with different longevities

Comparison of thiol redox state of mitochondria and homogenates of various tissues between two strains of mice with different longevities

Restoration of glutathione levels in vascular smooth muscle cells exposed to high glucose conditions

Improved mitochondrial function and increased life span after chronic melatonin treatment in senescent prone mice

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