Glutathione’s Whitening Function, External Use or Oral use, Which One is Better?

21 Apr Glutathione’s Whitening Function, External Use or Oral use, Which One is Better?

In recent years, humans have used various natural and synthetic substances to whiten the skin, such as kojic acid, arbutin and its derivatives, vitamin C and its derivatives, fruit acids, and animal and plant extracts. It has become a research trend in the pharmaceutical and cosmetic industries to find effective tyrosinase inhibitors that have no toxic or side effects on the human body.

Glutathione, a powerful antioxidant with additional anti-melanogenic properties, acts as a low molecular weight thiol tripeptide and is essential for maintaining intracellular redox balance. In addition to being one of the most abundant antioxidants, with the discovery of its anti-melanogenic properties, glutathione has been widely used in skin lightening agents and swept the world in a short period of time, and has become the most popular in recent years The “systemic skin brightening molecule”.

Although glutathione exists in reduced (GSH) and oxidized (GSSG) forms, most of it in the body is in the reduced form. GSH exerts antioxidant activity as a free radical scavenger during the reductive detoxification of hydrogen peroxide and lipid peroxide. In mammalian cells, GSH is converted to GSSG by glutathione peroxidase, but it is reduced to GSH by glutathione reductase in the presence of nicotinamide adenine dinucleotide phosphate.

                                      ▲GSH

NO.1″Extrinsic aging” caused by ultraviolet rays

Skin aging is a complex biological phenomenon consisting of two independent clinically and biologically distinct processes, namely “intrinsic aging” and “extrinsic aging”. Extrinsic aging (including “photoaging”) is the result of exposure to outdoor elements, primarily ultraviolet (UV) radiation. Photoaged skin displays a variety of age-related clinical changes, including deep wrinkles, sallow discoloration, and irregular hyperpigmentation. Recently, studies have shown that excessive production of reactive oxygen species (ROS) in cells is involved in the skin aging process caused by UV exposure, ROS can enhance color and increase pigmentation.

Melanin in human skin is a polymer of various indole compounds synthesized from L-tyrosine. Two different types of melanin are found in human skin – black or brown eumelanin and yellow-red pheomelanin – and the ratio of these two complex polymers determines skin color. An increased proportion of pheomelanin is associated with lighter skin tone. Melanin production is induced upon exposure to UV radiation and plays a key role in protecting skin cells from UV radiation damage. However, melanin pigmentation in the epidermis can lead to skin changes such as tanning and mottled hyperpigmentation.

The mechanism by which GSH inhibits melanogenesis is by inhibiting tyrosinase activity; this is a well-known function of thiol compounds, including glutathione and cysteine. Tyrosinase, the rate-limiting enzyme controlling melanin production, catalyzes the conversion of L-tyrosine supplied in the blood into 3,4-dihydroxyphenylalanine and then into dopaquinone. Like glutathione, currently commonly used skin whitening kojic acid, arbutin, and hydroquinone have inhibitory effects on tyrosinase.

NO.2″Topical” VS “Oral”

Globally, glutathione skin disease treatment drugs are mostly tablets, capsules, topical preparations and parenteral preparations, and most of the experimental studies are oral experiments.

Two trials of oral GSH in a Thai population by Arjinpathana and Asawanonda, and a trial in Filipino women by Handog et al. Involved administering 500 mg/day of GSH to the study population in two divided doses, except that lozenges (rather than oral capsules) were used in the latter study to enhance systemic absorption of glutathione. The primary efficacy outcome of both trials was the assessment of melanin index before and after treatment. Both trials used the Mexameter MX 18 (Courage+Khazaka electronic GmbH, Cologne, Germany) to assess the primary efficacy outcome.

A randomized, double-blind, two-arm, placebo-controlled study by Arjinpathana and Asawanonda in 60 healthy medical students showed sustained, statistically significant reductions in melanin index at all six sites assessed in subjects in the GSH group The reduction was greater than that of placebo at both sites.

An open-label, single-arm pilot study by Handog et al. In 30 healthy Filipino women (aged 22-42 years) with Fitzpatrick type IV or V skin, using lozenges instead of GSH capsules, reported a significant reduction in melanin index in sun-exposed and sun-protected areas for all subjects, And in the global assessment, moderate skin lightening was observed in 90% of the subjects.

In both studies, GSH was very well tolerated.

Glutathione has a variety of physiological effects. It inhibits melanin production by inhibiting the activity of tyrosinase, and oral administration of GSH in humans can reduce the production of melanin in the skin. However, glutathione in aqueous solution is extremely unstable and easily decomposed. In contrast, GSSG is not easily decomposed in aqueous solution and is suitable for use in liquid form, so it is mostly used for external use.

A research team selected 30 healthy adult women between the ages of 30 and 50 to study the effect of topical oxidized glutathione on skin lightening and skin condition improvement. The study design is a randomized, double-blind, matched, placebo-controlled clinical trial. Subjects applied GSSG 2% (weight/weight [w/w]) lotion to one side of the face and a placebo lotion to the other side twice daily for 10 weeks. The study objectively measured changes in melanin index values, stratum corneum moisture content, smoothness, wrinkle formation, and skin elasticity. Studies have also investigated skin lightening, wrinkle reduction, and smoothness.

From the first few weeks after the start of the trial to the end of the study period, the GSSG-treated skin melanin index was significantly lower than that of placebo (P < 0.001 at 10 weeks). In addition, in the second half of the study, the moisture content of the stratum corneum in the GSSG-treated site was significantly increased, wrinkle formation was suppressed, and skin smoothness was improved. There were no apparent adverse effects of GSSG application. Research has proven that topical GSSG is safe and effective for skin lightening and improving skin condition in healthy women.

▲Changes in melanin index values after GSSG treatment

Of course, there are also studies proving that a combination of topical and oral glutathione may be superior to monotherapy.

[1] Sonthalia S, Jha AK, Lallas A, Jain G, Jakhar D. Glutathione for skin lightening: a regnant myth or evidence-based verity? Dermatol Pract Concept. 2018 Jan 31;8(1):15-21. doi: 10.5826/dpc.0801a04. PMID: 29445569; PMCID: PMC5808366.

[2] Watanabe F, Hashizume E, Chan GP, Kamimura A. Skin-whitening and skin-condition-improving effects of topical oxidized glutathione: a double-blind and placebo-controlled clinical trial in healthy women. Clin Cosmet Investig Dermatol. 2014 Oct 17;7:267-74. doi: 10.2147/CCID.S68424. PMID: 25378941; PMCID: PMC4207440.

[3] Wahab S, Anwar AI, Zainuddin AN, Hutabarat EN, Anwar AA, Kurniadi I. Combination of topical and oral glutathione as a skin-whitening agent: a double-blind randomized controlled clinical trial. Int J Dermatol. 2021 Aug;60(8):1013-1018. doi: 10.1111/ijd.15573. Epub 2021 Apr 19. PMID: 33871071.

[4] Handog EB, Datuin MS, Singzon IA. An open-label, single-arm trial of the safety and efficacy of a novel preparation of glutathione as a skin-lightening agent in Filipino women. Int J Dermatol. 2016;55:153–157.