Which oxidizes GSH
2 molecules of oxidized GSH become into GSH again.
Which oxidizes GSH
EXAMPLE OF A RATE-LIMITED, ANTIOXIDANT FREE RADICAL SCAVENGING PATHWAY
In general free radical scavenging occurs through complex metabolic pathways involving many steps which are rate-limited. Deficiencies of nutrients, vitamins and minerals, which make up the enzymes and coenzymes of these systems can slow down or halt certain pathways.
It is apposite to describe one of these rate-limited, free radical scavenging mechanisms, to give the impression of its complexity and why it is rate-limited. The example chosen involves the glutathione pathway which is possibly one of the most important pathways.
When, for example, a superoxide radical must be destroyed, superoxide dismutase can catalyze its conversion to O2 and H2O2 (11). Ascorbate, nonenzamatically, also converts superoxide to H202 but is oxidized in the process to the ascorbate free radical and dehydroascorbate. The ascorbate free radical and the dehydroascorbate are reduced back to ascorbate either by NADH (catalyzed by semidehydroascorbate reductase and forming NAD) or reduced glutathione (GSH) (catalyzed by dehydroascorbate reductase and forming oxidized glutathione (GSSG)) (12). Some of the peroxide can be converted to oxygen and water by catalase but most will be destroyed by a glutathione-requiring enzyme system. GSH (catalyzed by glutathione peroxidase) reduces the peroxide to water but in the process is oxidized to GSSG. The resulting GSSG is reduced by NAD(P)H (catalyzed by glutathione reductase). The resulting NAD is reduced back to NADH by way of the Krebs cycle or resulting NADP is reduced back to NADPH by the hexose monophosphate (HMP) pathway. It is thought that commonly the rate-limiting step in the last series of reactions is that catalyzed by glutathione peroxidase and its cofactor selenium, but other substances which could limit all this are the vitamin E, vitamin C, vitamin B2, vitamin B3, cysteine, etc. Note: the ascorbate used in this example is as in the vitamin C sense; the small amount available is oxidized to dehydroascorbate and then must be reduced back to ascorbate by the pathway described, to be reused as ascorbate. One can easily see how this mechanism and similar mechanisms could be overwhelmed by a toxic pathogen liberating free radicals or by an inflammatory cascade regardless of its cause.
Reduced glutathione (GSH) is a major tissue antioxidant that provides reducing equivalents for the glutathione peroxidase (GPx) catalyzed reduction of lipid hydroperoxides to their corresponding alcohols and hydrogen peroxide to water. In the GPx catalyzed reaction, the formation of a disulfide bond between two GSH molecules generates oxidized glutathione (GSSG). The enzyme glutathione reductase (GR) recycles GSSG to GSH with the simultaneous oxidation of β-nicotinamide adenine dinucleotide phosphate (β-NADPH2).
ofonorow wrote:Which oxidizes GSH. Nothing is for free, and again the only way that makes common sense - for vitamin C to be a "nonrate limited free radical scavenger" - is for it to enter cells mostly as ascorbate (not DHA).
No I haven't read Dr. Levy's book, but will put it on my list.
Administration of cysteine may increase cellular levels of GSH, but even moderate doses of L-cysteine are toxic.
This thiazolidine is readily transported; its administration to mice stimulates GSH synthesis and protects against acetaminophen tox-icity. Brain GSH levels are only slightly increased after giving the thiazolidine; cysteine levels increase about 3-fold.
Cysteine delivery systems are limited by feedback inhibition of y- glutamylcysteine synthetase by GSH, but this may be bypassed by administration of substrate of GSH synthetase.
Procedures that increase the levels of the synthetases are also of interest. Ultimately, one may consider
the idea of increasing enzyme levels by gene therapy.
Administration of GSH leads to small increases in GSH levels, which may be ascribed to extracellular GSH breakdown, transport of the products, and intracellular synthesis of GSH.
\Biochemical studies have elucidated the enzymatic bases of the functions of GSH. Of major importance has been the development of selective enzyme inhibitors which are potential therapeutic
agents. It is now possible to increase or to decrease cellular GSH levels and also to selectively inhibit
reactions involved in GSH metabolism.
The discovery that the lethal and other effects of GSH deficiency can be prevented by administration of
ascorbate was made in the course of studies on newborn rats (4); later research on guinea pigs(12), which also do not synthesize ascorbate, and on adult mice (10, 13, 14), which do, has shown that there are significant interrelationships between GSH and ascorbate (15).
When newborn rats are made GSH-deficient by administration of BSO, they develop cellular damage in
liver, kidney, lung, and brain. They die within a few days. Death and tissue damage can be prevented
by administration of ascorbate (but not of dehydroascorbate).
The tissue ascorbate levels of GSH-deficient animals were greatly increased by giving ascorbate, as
expected, but surprisingly, giving ascorbate also led to higher GSH levels.
Treatment of newborn rats with only two doses of BSO (on the 2nd and 3rd days of life) led to cataracts,
observed when the rats opened their eyes on days 14-16. The incidence of cataracts was 97% but was
only 9% in animals given both BSO and ascorbate (2mmol/kg/day).
GSH deficiency in adult mice is associated with decreased levels of phosphatidylcho-line in the lung and in the bronchoalveolar fluid; when ascorbate is given, lamellar body damage does not occur and the levels
of phosphatidylcholine increase by about 2-fold(13
Methods that increase cellular levels of GSH (10) include those based on administration of precursors
of substrates for y-glutamylcysteine synthetase and GSH synthetase, and of GSH derivatives such
as esters Cellular GSH levels may also be increased by increasing the levels of the synthetases; this has
been accomplished in microorganisms(70), and studies on animals are now feasible (see Refs. 71
and 72) and in progress.
Ascorbate Deficiency in Guinea Pigs; Sparing of Ascorbate by GSH
It is well known that guinea pigs given an ascorbate-deficient diet develop scurvy and die within 21-24 days. There is a marked loss of weight (after the first week), which is followed by the appearance of
characteristic bone changes and hematomas. Treatment of such animals with GSH ester significantly delayed the onset of scurvy; there were no signs of scurvy after 40 days (33).
When guinea pigs receiving a scorbutic diet were given GSH ester, the tissue ascorbate
levels (as well as the GSH levels) were higher than those of saline-treated controls. The loss of
ascorbate was slowed in the presence of higher levels of GSH, another in vivo result that supports
a role of GSH in the reduction of dehydroascorbate. The findings indicate that GSH, supplied as an ester, spares ascorbate.
Administration of L-cysteine precursors and other strategies allow GSH levels to be maintained under conditions that would otherwise result in GSH depletion and cytotoxicity.
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