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 Table of Contents  
REVIEW ARTICLE
Year : 2021  |  Volume : 8  |  Issue : 3  |  Page : 144-152

Glutathione: The master antioxidant – Beyond skin lightening agent


1 Department of Dermatology, Venereology and Leprology, Government Medical College, Amritsar, Punjab, India
2 Punjab Institute of Medical Sciences, Jalandhar, Punjab, India

Date of Submission11-May-2021
Date of Decision18-Jun-2021
Date of Acceptance19-Sep-2021
Date of Web Publication24-Nov-2021

Correspondence Address:
Dr. S.K. Malhotra
Department of Dermatology, Venereology and Leprology, Government Medical College, Amritsar, Punjab, Postal Code:143001
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/pigmentinternational.pigmentinternational_

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  Abstract 


Glutathione is a thiol-containing tripeptide which is considered as a master antioxidant. Found naturally in fresh leafy vegetables, fruits, and nuts, commercially available preparations of glutathione have been found to be useful in number of medical conditions such as central nervous system disorders, autism, cardiovascular system disorders, peripheral vascular disorders, diabetes and its complications, liver disease, acquired immunodeficiency syndrome/human immunodeficiency virus, and chronic obstructive pulmonary diseases. With regards to the dermatologic disorders, some studies have highlighted the role of glutathione as a skin-lightening agent. The studies on use in other diseases such as psoriasis, pemphigus vulgaris, acne vulgaris, rosacea, etc., are limited and need to be explored more. Glutathione is available as oral preparations (pills, sublingual tablets, solutions, syrups, and sprays), parenteral forms (intravenous [IV] preparations), topical formulations (creams, soaps, and facewashes). The major drawback of oral form of glutathione is its low bioavailability in humans. To overcome this drawback, sublingual tablets and oral liposomal glutathione have been made available. However, the number of studies evaluating its efficacy and safety are less in number. This review article has been written to highlight the role of glutathione in various dermatologic disorders apart from skin-lightening agent.

Keywords: Antioxidant, glutathione, liposome


How to cite this article:
Gandhi G, Malhotra S, Kaur T, Tyagi S, Bassan R. Glutathione: The master antioxidant – Beyond skin lightening agent. Pigment Int 2021;8:144-52

How to cite this URL:
Gandhi G, Malhotra S, Kaur T, Tyagi S, Bassan R. Glutathione: The master antioxidant – Beyond skin lightening agent. Pigment Int [serial online] 2021 [cited 2021 Dec 5];8:144-52. Available from: https://www.pigmentinternational.com/text.asp?2021/8/3/144/330888




  Introduction Top


Reduced glutathione (GSH) is the main low-molecular-weight thiol-containing tripeptide present in almost all living cells ranging from bacteria to mammals. It was discovered 130 years ago in baker’s yeast (Saccharomyces cerevisiae). Initially named as “philothion,” many works have tried to establish and elucidate its pivotal role in aerobic life.[1] Glutathione exists in a reduced form (GSH) and an oxidized form (GSSG).


  Structure Top


Glutathione is a tripeptide consisting of three amino acids: glutamate, cysteine, and glycine, hence, described as γ-l-glutamyl-l-cysteinylglycine [Figure 1].[2]
Figure 1 Structure of glutathione.

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  Intracellular distribution of glutathione Top


Glutathione is synthesized from glutamate, cysteine, and glycine in the cytosol. It is a two ATP-requiring enzymatically catalyzed process.[3] After its synthesis, glutathione gets distributed in intracellular organelles, including endoplasmic reticulum (ER), nucleus, and mitochondria.[4]


  Nuclear glutathione Top


In the nucleus, GSH prevents the oxidation of sulfhydryl groups of several proteins to disulfide groups. This helps in maintaining the critical protein sulfhydryl level which is considered necessary for DNA repair and protein function. Glutathione also functions as a hydrogen donor in ribonucleotide reductase-catalyzed reduction of ribonucleotides to deoxyribonucleotides and thus plays a contributory role in DNA synthesis.


  Glutathione in endoplasmic reticulum Top


In ER, glutathione exists mainly as oxidized glutathione (GSSG). GSSG is the main source of oxidizing equivalents to provide the adequate environment necessary for favoring disulfide bond formation and proper folding of nascent proteins.


  Mitochondrial glutathione Top


The mitochondria is a major source of reactive oxygen species (ROS). Most of them originate from the mitochondrial respiratory chain. Partial reduction reactions occur even under physiologic conditions, causing release of superoxide radical (O2 · ) and hydrogen peroxide.[4]


  Natural sources of glutathione Top


Glutathione is available naturally in fresh leafy vegetables, broccoli, walnuts, chestnuts, oranges, whey protein, tomatoes, fresh fruits, avocados, asparagus, meat, and poultry.[5]


  Pharmaceutical formulations of glutathione Top


Glutathione is available as oral preparations (pills, sublingual tablets, solutions, syrups, and sprays) and parenteral forms (IV preparations). Formulations for topical, intranasal, and intrabronchial routes are also available.[6]


  Oral glutathione Top


Oral glutathione is derived from Candida utilis (Torula yeast). It is marketed either alone, or in combination with vitamin C, N-acetyl cysteine, grape seed extract, alpha lipoic acid, and other antioxidants.[6]

When taken orally, it can be absorbed as an intact tripeptide from the gastrointestinal tract; principally from the jejunum. However, even when large oral doses are administered, most of the absorbed glutathione remain within the gut luminal cells and only small and transient increase of glutathione occurs in the circulation. Circulating glutathione is cleared by the kidney.[7]

Sublingual lozenges and spray preparations of glutathione have also been made available. Substances that are absorbed through the buccal route go directly into the systemic circulation and this eliminates disadvantages imposed by oral intake, such as the decreased ability of GSH to pass through the gastrointestinal tract as an intact molecule. Bioavailability of sublingual route is better and this route requires lower doses and has been considered to be safe by Food and Drug Administration (FDA). The required dose is 20 to 40 mg/kg (i.e., 1–2 g in two divided doses) and significant effects are reported within a period of 3 months.[6]


  Adverse effects associated with oral preparations Top


Local side effects can be expected like soreness of the gums caused by sucking the lozenges. Transferring the lozenge from one side of the mouth to the other to prevent the onset of soreness can minimize these incidents. Another disadvantage may be related to the flavor or texture of the lozenge.[8]

Oral suspensions and solutions have not yet gained popularity due to their sulfurous taste. The major drawback of oral form of glutathione is its low bioavailability in humans.[8]


  Parenteral preparations Top


To achieve the anticipated therapeutic levels and rapid onset of action, IV glutathione has been made available. The recommended dose of glutathione is 600 to 1200 mg which is to be injected once weekly or twice weekly and there is no specified net duration of therapy. But this route has not been yet approved by FDA. Also, there is lack of literature evaluating its efficacy.[8] IV administered GSH is not directly utilized by cells but is cleaved into its component amino acids and is resynthesized to GSH intracellularly after transmembrane transport. Hong et al. demonstrated that after IV administration, most GSH was immediately oxidized and disappeared from the circulation with a half-life of 10 minutes. The rest is broken down into its three component amino acids. According to this study, after the administration of glutathione at a dose of 50 mg/kg, the mean concentration of glutathione in blood reached 1219.8 μM at 10 minutes. Meanwhile, the concentration of its three constituent amino acids: glutamate, glycine, and cysteine was 268 μM (21.97%), 477 μM (39.10%), and 264.7 μM (21.70%), respectively.[9]


  Adverse effects of iv glutathione Top


Intravenous doses have been known to show more adverse effects due to the chances of overdose or due to the additives which are present in glutathione injection. The common adverse effects include mild, transient headaches, and skin eruptions ranging from mild to severe drug reactions such as fatal Stevens–Johnson syndrome and toxic epidermal necrolysis, kidney and liver dysfunction, thyroid dysfunction, severe abdominal pain, and fatal complications such as air embolism or sepsis due to incorrect method of IV administration.[8]


  Topical formulations Top


Topical formulations of glutathione are also available in the form of cream, facewash, soap, and lotion. Topical glutathione in the form of lotion is not efficiently absorbed by the skin cells as the thiol group undergoes rapid formation of disulfide.[5] Also, apart from the poor permeability and absorption, foul odor limits its use. More recently, glutathione-based chemical peel has also gained popularity.[6]


  Glutathione as a mesotherapy Top


Though there is lack of literature regarding the efficacy and methodology of use of glutathione as mesotherapy solution, it is widely being practiced by the dermatologists for treatment of melasma either as monotherapy or along with ascorbic acid, pyruvic acid, vitamin E, etc.[6]


  Transdermal delivery Top


To enhance the permeability and reduce the foul odor associated with the topical applications of glutathione, Lee et al. demonstrated the use of transdermal delivery of glutathione by loading it into the hyaluronic acid microneedles.[10]


  Glutathione polymer films Top


Recent research focuses on the use of GSH responsive linkers to prepare polymers which degrade upon the exposure to millimolar concentrations of GSH, and the use of these polymers to prepare particles that disassemble at these concentrations. GSH responsive polymers have been used in the controlled delivery of the chemotherapeutic agents and genetic material.[11]


  Biologic effects of glutathione Top


Glutathione is considered as a master antioxidant. It plays a key role in the detoxification of drugs and xenobiotics. Furthermore, glutathione in its reduced form (GSH) acts as a hydrogen donor in the detoxification process of hydrogen peroxide. Glutathione plays a key role in energy production as it protects mitochondria from the oxidative damage. The factors that lead to depletion of glutathione includes natural ageing process, or the external stressors that include chronic exposure to chemical toxins, cadmium exposure, alcohol use, smoking, pollution, strenuous aerobic activities, dietary factors, ultraviolet (UV) radiation exposure, tissue injury as from burns, ischemia, septic shock, surgery, drugs (such as acetaminophen and adriamycin). Glutathione levels are also found to be decreased in central nervous system disorders (such as Alzheimer disease and Parkinson disease), autism, cardiovascular system disorders (atherosclerosis), peripheral vascular disorders, diabetes and its complications, liver disease, acquired immunodeficiency syndrome/human immunodeficiency virus, and chronic obstructive pulmonary diseases. Supplementation of glutathione in all these systemic disorders has shown to have a therapeutic effect.[12]


  Glutathione in dermatologic disorders Top


Glutathione is a key antioxidant and role of its reduced form as a skin lightening agent has been well studied. Oxidative stress and the imbalance between oxidant and antioxidant system in the body have been implicated in the pathogenesis of various dermatologic disorders. The skin is chronically exposed to both endogenous and environmental pro-oxidants leading to the production of ROS.[13] ROS leads to lipid peroxidation, which is considered as the hallmark of oxidative stress in body.[14] Malondialdehyde (MDA) is considered as the end product of lipid peroxidation and MDA levels is directly proportional to the oxidative stress.[15]

The most important antioxidants present in human body include superoxide dismutase, glutathione peroxidase, and catalase.[16] Glutathione which is considered a master antioxidant can help keep the balance between the oxidant and antioxidant system in the body and prove to be an effective therapy but studies proving its efficacy are limited. Glutathione has been considered as a wonder drug for the treatment of hyperpigmentation. The studies on use in other diseases such as psoriasis, pemphigus vulgaris, acne vulgaris, rosacea, etc. are limited and need to be explored more and brought into practice.


  SKIN-LIGHTENING EFFECT Top


The role of glutathione as a skin-lightening agent was accidentally discovered as a side effect during treatment of chronic diseases with glutathione.[17] Various mechanisms have been proposed; the most important of which is through tyrosinase inhibition. The thiol group of glutathione chelates copper ions on the active site of enzyme tyrosinase thus inhibiting it. The second mechanism by which glutathione causes lightening of skin is inhibition of transfer of tyrosinase to premelanosomes for melanin synthesis.[17],[18],[19] The third mechanism of tyrosinase inhibition is through its antioxidant effect as it scavenges the free radicals generated in the epidermis following UV light irradiation. Glutathione shifts the process of melanogenesis from eumelanin to pheomelanin through the reaction between thiol and dopaquinone groups causing formation of sulfhydryl-dopa conjugates[20] [Figure 2].
Figure 2 Flowchart showing mechanism of glutathione as a skin-lightening agent.

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According to study by Shuja et al.,[21] Jing et al.,[22] and Hamadi et al.,[23] levels of plasma GSH levels were found to be significantly decreased in cases of melasma when compared with controls. Several other studies of glutathione have been conducted in relation to melasma. Most of the studies have shown its therapeutic role in melasma, whereas some studies have contradicted this fact[17],[24],[25],[26],[27] [Table 1].
Table 1 Studies conducted on glutathione in relation to its skin-lightening effect

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  Antiageing effect Top


Skin ageing can be “extrinsic” or “intrinsic.” UV irradiation results in extrinsic ageing. The changes observed in photoaged skin include deep wrinkles, sallow discoloration, and irregular pigmentation. The process of skin aging is advanced by the intracellular and extracellular oxidative stress. Glutathione, because of its antioxidant effect, is effective in reducing the photo-induced aging of the skin. According to a randomized, double-blind, placebo-controlled, matched-pair study by Watanabe et al. on 30 healthy Filipino women with baseline facial melanin index value of 200 to 350, topical application of GSSG lotion effectively reduces wrinkle formation and increases the level of skin moisture levels.[2] A study by Weschawalit et al. found that skin elasticity improved and wrinkling reduced when given glutathione at a dose of 250 mg/day for a period of 10 weeks.[27] Being a natural detoxifier, glutathione improves the health of cells of the body and reverses the process of ageing.


  Vitiligo Top


It has been postulated that the oxidant–antioxidant imbalance may play a role in the pathogenesis of vitiligo. A study by Yildirim et al. on 24 patients with generalized vitiligo and 20 healthy controls found statistically significant higher levels of superoxide dismutase activity in erythrocytes, serum MDA, and nitric oxide (NO) and statistically significant lower levels of glutathione and glutathione peroxidase in the patients of vitiligo compared to the controls.[28] Secondary to the oxidative stress, the polyunsaturated fatty acids undergo peroxidation resulting in formation of free radicals. MDA is an end product of a lipid peroxidation reaction and an indicator of oxidative stress. This free radical-mediated damage is considered as the initial pathogenic event in degeneration of melanocyte in generalized vitiligo and supplementing glutathione, which is a potent antioxidant, in vitiligo patients may prove to have therapeutic effect.


  Acne vulgaris Top


It has been reported that oxidative stress contributes to pathogenesis and progression of acne vulgaris. According to a study by Ottaviani et al., peroxidated squalene induces the inflammatory mediators, which may play a role in pathogenesis of acne vulgaris. It has also been found that antioxidants are effective in the treatment of acne vulgaris.[29]A trial on 40 patients and 19 healthy subjects by Ikeno et al. measured the GSH levels in the stratum corneum of the subjects and found that GSH in stratum corneum in acne patients was significantly lower than that of healthy controls.[30]


  Rosacea Top


The UV radiation is a very well-known triggering and aggravating factor for rosacea.[31] It is a potent inducer of ROS generation in the skin.[32] In patients of rosacea, there is an increased ratio of oxidized to reduced glutathione compared with healthy subjects.[33] A pilot, prospective, two-center, assessor-blinded study by Dall’Oglio et al. on 30 patients postulated that capability of exogenous GSH to cross cell membrane is very low; hence making it an ineffective treatment option. It supported the use of a synthetic and patented modified GSH molecule (GSH-C4) which is a butanoyl derivative of GSH. It had significant anti-inflammatory action and demonstrated a significant reduction of erythema score and the lesion count.[34]


  Warts Top


Several studies are available suggesting the increase of oxidative stress in the patients of warts and that the use of antioxidants may play a valuable role in the treatment of warts. Arican et al. evaluated the role of oxidative stress by measuring MDA levels which were significantly higher in the lesional skin areas than the nonlesional areas in patients with plantar warts.[35] Similar cross-sectional studies performed by Sasmaz et al.[36] and Cokluk et al.[37] found significant increase in catalase activity and MDA levels in patients with nongenital and genital warts, respectively, when compared with the control group. Therefore, glutathione being a potent antioxidant can be proposed as a treatment option for warts.


  Psoriasis Top


A trial carried out by Kokcam and Nazıroglu on 34 patients having moderate to severe psoriasis and healthy age-matched controls found increased MDA levels in plasma and red blood cells (RBCs) in patients of psoriasis when compared with controls. Antioxidant treatments tend to decrease the epidermal inflammation by inactivating the free radicals and stabilize the membrane and prevent new epidermal destruction.[38]


  Pemphigus vulgaris Top


In pemphigus vulgaris, increased production of ROS from activated neutrophils has been found to decrease the concentrations of antioxidants in plasma and RBCs, resulting in oxidative stress. Apart from inducing oxidative stress, ROS molecules attack almost every component of the cell and cause further nonspecific damage to surrounding tissues. ROS together with immunoglobulin G-related proteinase damages the basement membrane and causes the separation of the dermal–epidermal junction. A study by Naziroglu et al. on 18 patients with PV (12 males, 6 females) and 18 healthy volunteers found a significant reduction in plasma and RBC GSH-Px and catalase activity and GSH value and increase in plasma MDA level in patients with pemphigus vulgaris.[39]


  Erectile dysfunction Top


The reduced form of glutathione is essential cofactor for NO synthase that catalyzes synthesis of NO from L-arginine in the endothelium. Decreased levels of glutathione therefore interfere with the endothelial function. NO functions as a principal neural mediator of erection during the sexual stimulation. Therefore, it is postulated that supplementation of glutathione in patients of erectile dysfunction can prove to have a therapeutic effect but number of studies highlighting this fact is limited and this needs to be explored.[40]


  Alopecia areata Top


Several studies have found an increased oxidative stress in patients with alopecia areata (AA) by measuring the levels of MDA in serum, erythrocytes, and scalp biopsy samples. Koca et al. found higher levels of serum MDA in patients with AA compared to the controls subjects.[41] Abdel Fattah et al. found increased levels of MDA in plasma and tissues and also noted increased levels of MDA with increasing severity and duration of the disease.[42]


  Allergic contact dermatitis Top


An experimental study on 18 chromium allergic subjects, Lejding et al. found that application of barrier creams containing glutathione resulted in a significant reduction in reactivity to chromium and cement extract when compared with the untreated skin.[43]


  Systemic sclerosis Top


Recently, cellular redox state has been observed to play a significant role in the progression of systemic sclerosis. Oxidative stress may directly or indirectly stimulate the accumulation of extracellular matrix proteins. On the other hand, fibrosis may contribute to oxidative stress or both of them may be triggered by an independent mechanism. Therefore, it can be postulated that glutathione can prove to be beneficial in systemic sclerosis by targeting the oxidative stress and hence halting the process of fibrosis.[44]


  Wound healing Top


Low levels of ROS are essential for initiation and progression of proper wound healing. On the other hand, high levels of ROS accelerate the cell death and impair the wound healing by derailing the cell and molecular mechanisms. It is the imbalance between the oxidants and antioxidants that result in delayed wound healing. Chronic wounds in humans have high levels of oxygen species. Therefore, it can be postulated that treatment of human chronic wounds with glutathione both systemically and locally after debridement can be effective in resolving chronicity.[45]


  Antiviral role Top


Although yet not fully elucidated, the role of glutathione as an antiviral has been studied. It has been reported to inhibit the expression of specific virus proteins, inhibiting the replication of viruses. Also glutathione blocks the oxidative stress. The endogenous levels of GSH and other antioxidants have been found to be altered in experimental infections in vitro and in vivo. Glutathione has been found to be active against human immunodeficiency virus, parainfluenza virus, and herpes simplex virus type 1 infections.[46]


  ROLE OF GLUTATHIONE IN CORONAVIRUS DISEASE 2019 Top


Based on the literature search, low levels of glutathione and accumulation of ROS have been associated with the severe symptoms of coronavirus disease 2019 (COVID-19). High levels of ROS are responsible for the recruitment of neutrophils at the site of inflammation, thus causing endothelial damage and tissue injury. Glutathione, apart from being a master antioxidant, also helps in the metabolism and excretion of the xenobiotics.

The COVID-19 virus utilizes angiotensin-converting enzyme 2 (ACE2) receptor for entry into the cells. ACE2 and ACE together take part in renin angiotensin system (RAS). ACE2 counters the action of ACE and causes decrease in angiotensin II and increase in angiotensin (1–7). ACE2 has antioxidative, anti-inflammatory, and antiapoptotic effects. The infection by COVID-19 downregulates ACE2. This imbalance between ACE/ACE2 has been known to increase the oxidative stress. It has been postulated that glutathione can counter this oxidative stress and help alleviate the cytokine storm associated with COVID-19 [Table 2].[47]
Table 2 Summary of indications of glutathione, route of administration, and mechanism of action

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  Glutathione supplementation in pregnancy and lactation Top


As per the data available, there is no conclusive evidence of use of glutathione in pregnancy and lactation.


  Drug interactions Top


There is no data available depicting any major drug interactions of glutathione.


  FUTURE DEVELOPMENTS: LIPOSOMAL GLUTATHIONE Top


Liposomes are considered as an effective mode of drug delivery. Oral liposomal glutathione has been commercially available in the market. Evading the acidic environment of the stomach, the absorption of glutathione has become more efficient. Till date, there are only few reports on efficacy of liposomal glutathione and more needs to be explored.[48]


  Conclusion Top


As of now, no conclusive evidence can be drawn in favor of glutathione for the treatment of dermatologic disorders. Glutathione is a master antioxidant and the role of oxidative stress in the pathomechanism of the dermatologic disorders favors its use. There are only limited number of studies regarding the efficacy and safety of glutathione in dermatologic disorders. The need of the hour is to conduct large scale studies to elucidate the role of glutathione in skin diseases.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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  In this article
Abstract
Introduction
Structure
Intracellular di...
Nuclear glutathione
Glutathione in e...
Mitochondrial gl...
Natural sources ...
Pharmaceutical f...
Oral glutathione
Adverse effects ...
Parenteral prepa...
Adverse effects ...
Topical formulations
Glutathione as a...
Transdermal delivery
Glutathione poly...
Biologic effects...
Glutathione in d...
SKIN-LIGHTENING ...
Antiageing effect
Vitiligo
Acne vulgaris
Rosacea
Warts
Psoriasis
Pemphigus vulgaris
Erectile dysfunction
Alopecia areata
Allergic contact...
Systemic sclerosis
Wound healing
Antiviral role
ROLE OF GLUTATHI...
Glutathione supp...
Drug interactions
FUTURE DEVELOPME...
Conclusion
References
Article Figures
Article Tables

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