Glutathione Delivery via Iontophoresis Increases Gluthathione Levels in Blood Samples

Glutathione is a mitochondrial antioxidant, and additional antioxidant capacity in mitochondria appears to be beneficial to long-term health, improving mitochondrial function and overall health. Mitochondria conduct the energetic process of producing ATP, used to power the cell, with a flux of oxidative molecules as a side-effect. With age, mitochondria tend to become less efficient and produce more oxidizing molecules, harmful to the cell. Glutathione levels decline with age, which may contribute to this age-related mitochondrial dysfunction.

Oral supplementation with gluthatione doesn't have any effect, unfortunately, but researchers recently published a small study of supplementation with large amounts of glutathione precursors. This caused increased gluthatione manufacture, increased glutathione in blood samples, and measurable benefits to health in old individuals. Here, researchers provide evidence for an iontophoresis approach for the delivery of glutathione through the skin via an electrical field, an intriguing option to be compared against intravenous administration when considering relative costs and benefits.

Glutathione (GSH) is the most abundant antioxidant in human cells. Reactive oxygen species (ROS) produced in the body can promote oxidative damage to cells and may cause genomic instability and mitochondrial dysfunction, two hallmarks of aging. The concentration of GSH has been shown to decrease with aging, resulting in reduced antioxidant activity in cells. Consequently, lower GSH levels have been associated with an increased risk of aging-associated diseases. Relatively higher blood levels of GSH, on the other hand, are associated with improved physical and mental health in older individuals. Supplementation of GSH may, therefore, protect against age-related morbidity and mortality.

In recent years, intravenous supplementation has become a popular method to restore GSH levels. It is an effective method but has its limitations as it is only accessible in a specialty clinic setting and is expensive and inconvenient for patients. Two aging patients with low serum GSH levels were supplemented with GSH in our clinic using a non-invasive drug delivery device, the IontoPatch, to deliver GSH through the skin. The IontoPatch technology uses bipolar electric fields, iontophoresis, to deliver molecules across the skin into the underlying tissue. Iontophoresis is widely used in physical therapy for localized treatment of pain and inflammation.

A 1 mL dose of a 200 mg/mL saline solution of GSH was added to the patch's negative electrode for each treatment. The patch was applied on the upper arm's skin and was worn for six consecutive days for at least four hours each day. Serum levels of GSH were assessed at baseline and days 7 and 23 after treatment was initiated. In both cases, serum GSH levels increased after seven days of treatment (64.4% and 21.8%). Serum GSH levels then decreased between days 7 and 23 to 44.5% and 17.2% above baseline. There were no adverse events reported in either case. More extensive studies should be conducted to determine the pharmacokinetics, safety of long-term supplementation, and supplementation health benefits.



'Oral supplementation with gluthatione doesn't have any effect, unfortunately,...'?
In vitro and ex vivo uptake of glutathione (GSH) across the intestinal epithelium and fate of oral GSH after in vivo supplementation PMID: 25198144 DOI: 10.1021/jf503257w
'Previously, it has been reported that dietary GSH does
not increase serum GSH level after ingestion and its bioavailability
is low, but increases only liver cysteine originating from the
breakdown of ingested GSH in the gut.14-16 This is in line with
orally ingested GSH not altering plasma total, GSSG, and reduced
GSH level from the current work as reported previously. However,
the previous study overlooked analyzing GSH or GSSG level from
red cells and liver. In this study, we found mostly orally ingested
GSH was immediately converted into GSSG and deposited into
red cells and predominantly carried into liver tissues. We speculate
some of the ingested 13C-GSH could be degraded during the
circulation of intact GSH into γ-glutamyl amino acid, cysteine, and
glycine or γ-glutamyl cysteine by endogenous enzymes. However,
the current LC-MS/MS technique could not detect notable
degradation of ingested GSH. This must be further clarified in the
future by developing a more sensitive method. Our recent smallscale work on human subjects indicated that there was no significant change of plasma GSH after ingestion of GSH. However,
the GSH contents in the protein-bound fraction of plasma
significantly (P < 0.01) increased from 15 to 120 min after GSH
supplementation.26 This is a very unique biological system
because reduced GSH has a free thiol group (-SH) in cysteine,
and an excess presence of reduced GSH in the plasma or tissues
might have some harmful effects for the body due to the
potential risk of reactive oxygen species (ROS) generation.
If ingested GSH is deposited in circulating red cells or liver tissue
as a GSSG form, it could be safer and used for detoxification in
the body or liver.'

Posted by: Jones at November 3rd, 2021 6:37 AM

Randomized controlled trial of oral glutathione supplementation on body stores of glutathione

'Results: GSH levels in blood increased after 1, 3 and 6 months versus baseline at both doses. At 6 months, mean GSH levels increased 30-35 % in erythrocytes, plasma and lymphocytes and 260 % in buccal cells in the high-dose group (P < 0.05). GSH levels increased 17 and 29 % in blood and erythrocytes, respectively, in the low-dose group (P twofold in the high-dose group versus placebo (P < 0.05) at 3 months.

Conclusions: These findings show, for the first time, that daily consumption of GSH supplements was effective at increasing body compartment stores of GSH.'

Posted by: Jones at November 3rd, 2021 7:08 AM

"Conflict of interest: JPR received research support for this study and travel funds to present previous research findings from Kyowa Hakko Bio Co., Ltd. Kyowa Hakko Bio Co., Ltd is a biotechnology and fermentation company that provides glutathione (SetriaÒ). None of the other authors have any conflicts of interest to disclose."

On a logical level glutathione is a peptide, and will be cut by peptidases in the stomach/intestine. B it maybe these now created precursors help to boost glutathione levels a bit?

Posted by: jimofoz at November 3rd, 2021 6:05 PM

Back when I looked into oral glutathione supplementation studies I came to the conclusion that GSH is well buffered in blood.
If sufficent glutathione levels are present GSH does not easily raise levels above baseline by oral supplementation. It converts to GSSG and is stored for later use in the liver to make new GSH if needed.
If glutathione levels are depleted oral GSH supplementation repletes levels rather reliably.

Posted by: Jones at November 4th, 2021 4:51 AM

Thx Jones.
This iontopatch commentary was motivated by a whole 2 person trial, and the results are not extraordinary

Posted by: JohnD at November 4th, 2021 1:11 PM

Can you please comment the sentence
"The concentration of GSH has been shown to decrease with aging"
and give relevant references?

Thank you,

Silvio De Flora,
Professor emeritus,
University of Genoa, Italy

Posted by: Silvio De Flora, University of Genoa, Italy at December 12th, 2021 9:57 AM
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