What Are the Uses of Glutathione?

What is Glutathione?

Glutathione is a tripeptide compound consisting of glycine, L-cysteine and L-glutamic acid, which is catalyzed by glutathione synthetase, and its active groups are sulfhydryl and γ-glutamyl[1-2]. The sulfhydryl group[3] (-SH) in glutathione has been shown to play a major role in scavenging free radicals and activating enzyme activities, and it also maintains the redox homeostasis of intracellular glutathione[4]. Glutathione is mainly synthesized in the cytoplasm, and the synthesized glutathione is transported from the cytoplasm to the organelles via specific transporter proteins[5-6].

1. Structure of Glutathione

The molecular formula of glutathione is C10H17O6SN3[7] and its chemical structure is shown in Figure 1.

Fig. 1.Chemical structure of glutathione

Glutathione is an intracellular antioxidant, which can act directly by scavenging reactive oxygen and nitrogen species, or indirectly by supporting enzyme activities as a cofactor[8-9]. Glutathione exists in two forms (glutathione and GSSH), of which glutathione plays a major physiological role and accounts for the majority of the total[10-11]. The ratio of glutathione to GSSG is often considered a marker of oxidative stress (OS)[12].

Figure 2. Functions of Glutathione and Enzymes that Maintain Redox Homeostasis

In addition to its role as a general antioxidant, glutathione is involved in the biosynthetic pathways of key metabolites, signaling processes, detoxification, storage and transport, and maintenance of the glutathione (GRX)-mediated reduction process[13]. Reductive stress (RS) is used to describe the reduction of chelated trivalent iron promoted by NADH when NADH concentrations are too high[14] , and oxidative stress (OS) is now known to be the counterpart of oxidative stress characterized by excessive levels of reduced bioequivalents by stimulating glutamate cysteine ligase (GCL) activity leading to an increase in glutathione production[15,16],[17]. The endogenous intracellular antioxidant glutathione was shown to be involved in several RS-related mechanisms [18].

Salvemini et al [19] showed that when HeLa cells were transfected with the glucose-6-phosphate dehydrogenase (G6PD) gene, which is responsible for the production of NADPH, an increase in glutathione levels and a decrease in the production of ROS were demonstrated. Heat shock proteins (HSP) have also been shown to protect against several stressful stimuli in mammalian cells.HSP helps to promote the glutathione-reduction cycle by increasing glutathione levels and thereby promoting a reducing state [20].

Brewer et al. [21] demonstrated that the activation of the regulatory protein Nrf2 by the enzyme NOX4 contributed to the expression of antioxidant-related genes, leading to an increase in the concentration of glutathione and a decrease in the production of ROS. This led to an increase in glutathione concentration and consequently an increase in the glutathione/GSSG ratio.

It has been observed that glutathione forms part of almost 85% of the mixed protein/non-protein disulfides [22]. The structural basis for this important physiological function relies primarily on the reactive sulfhydryl group on the cysteine side chain of glutathione, which serves as the basis for the binding of glutathione to free radicals in the body, which accelerates the excretion of free radicals into acid metabolites, thereby protecting organs from damage[23].

Glutathione performs a variety of physiological functions, including xenobiotic catabolism, glutathionylation of proteins, and the production of some steroids, lipids, and deoxyribonucleotides, as well as being an important source of cysteine[24]. Considering these characteristics of glutathione, it is not surprising that glutathione plays an important etiological role in the development of many diseases, such as cardiometabolic and cardiovascular diseases (CVD) [25,26].

2. Distribution of Glutathione

Glutathione is widely distributed in animal and plant cells and is abundant in the erythrocytes, liver, kidney of animals and wheat germ of plants[27]. Glutathione is also abundant in yeast cells, but less so in vegetables and other plants. Currently, yeast cells are mainly used for industrial production of glutathione, including Saccharomyces cerevisiae and Saccharomyces cerevisiae.

3. What Are the Uses of Glutathione?

3.1 Glutathione Uses in Cardiovascular Diseases

Inhibition of glutathione synthesis precedes OS and atherosclerosis[28], and the ability of cells to synthesize glutathione during atherogenesis, particularly in macrophages, is inversely related to the onset and progression of atherosclerosis in ApoE mice[29]. Lp(a), apoB, LDL-c and total plasma cholesterol have been reported to be reduced in transgenic mice with atherogenic lipid metabolism after administration of ribosylcysteine, which increases the activity levels of glutathione and GPx.30 Shimizu et al.[31] examined plasma and erythrocyte levels of total glutathione in 134 patients with stroke and myocardial infarction. The results showed that elevated glutathione levels resulted in lower systolic and diastolic blood pressure values, and elevated glutathione levels also resulted in a lower incidence of diabetes. In addition, the same authors reported that glutathione levels were lower in patients with CVD compared to controls with no prior history of CVD. Dami et al [32] evaluated the results of glutathione levels in 76 patients undergoing some form of cardiac surgery. Glutathione levels were 21% and 40% lower in asymptomatic and symptomatic CVD patients, respectively, compared to healthy controls. Based on these results, the authors concluded that reduced glutathione levels are strongly associated with cardiac abnormalities in patients with CVD.

3.2 Glutathione Uses in Kidney Diseases

Glutathione can effectively activate various enzymes, promote fat, protein and sugar metabolism, and play an important role in protecting renal tubules and effectively treating kidney diseases. Relevant studies have shown that glutathione is effective in treating patients with nephrotic syndrome, lowering the level of triglycerides and significantly increasing the level of serum proteins[33] . Overseas studies have shown that the metabolic pathway of glutathione may be a bioactivation pathway, which is related to the nephrotoxicity of a variety of drugs and chemicals [34].

3.3 Glutathione Uses in Organophosphorus Poisoning

Organophosphorus pesticide poisoning produces a large number of oxygen free radicals, which exacerbate the damage to various tissues and organs. If the treatment is not timely, it will lead to organic failure or even death, which will bring serious threat to the life and health of patients[35] . Glutathione can activate the activity of various enzymes in the body and thus have a certain protective effect on tissues and organs.

In a study of 86 cases of organophosphorus pesticide poisoning, it was shown that the application of reduced glutathione in the first aid treatment of organophosphorus pesticide poisoning achieved satisfactory results, effectively reducing the damage to various tissue functions and controlling them. It is worthwhile to promote its application in clinical practice[36] . Reduced glutathione combined with atropine and chlorophosphamide can effectively treat patients with acute organophosphorus pesticide poisoning, alleviate the symptoms, with remarkable effect, effectively regulate serum cardiac troponin Ⅰ (cTn Ⅰ) and serum cholinesterase (CHE) levels, and promote liver function recovery [37].

3.4 Glutathione Uses in Liver Disease

When liver cells are attacked by viruses or harmful substances, a large amount of erythrocytes will be synthesized in the body, which is involved in the repair process of liver cell membranes[38] . Glutathione can combine with free radicals to produce low-toxicity metabolites, thus reducing liver damage. Short-term intravenous infusion of glutathione after hepatic artery chemoembolization in patients with intermediate to advanced PLC can improve clinical outcomes, alleviate liver function problems, and improve patients' quality of life[39] . Studies have shown that treatment with glutathione in patients with intermediate and advanced PLC treated with TACE has a significant hepatoprotective effect and can maintain normal serum liver enzyme levels[40] . Changes in hepatic glutathione are the cause or consequence of a variety of pathologies.

 In humans, regular dietary intake of precursor sulfur-containing amino acids will maintain hepatocyte glutathione levels in the range of 5 mM to 10 mM. Inherited disorders of glutathione synthesis and metabolism can severely disrupt liver function and, in some cases, may lead to death.41 In alcoholic liver disease, nematocytes are the most common cause of liver disease. In alcoholic liver disease, mitochondrial reduced glutathione, whose primary function is to maintain competitive functional organelles, is depleted by alcohol intake, and glutathione depletion in hepatocyte mitochondria has been revealed to be an important mechanism of hepatic sensitivity to alcohol-induced injury [42].

3.5 Glutathione Uses in Food Field

In the food industry, glutathione can be used as a nutritional modifier, not only to enhance the flavor of meat but also to increase the appetite for meat[43] . Glutathione can also be used as a flavoring agent and added to monosodium glutamate (MSG) to maintain its freshness. In addition, glutathione has been added to infant foods and dairy products, which is equivalent to the effect of vitamin C. The addition of glutathione to canned fruits and vegetables helps to maintain the original nutrients and attractive colors and flavors and prevents pigmentation and browning [44].

3.6 Glutathione Used as an Antioxidant

Intracellular glutathione is an important antioxidant that scavenges free radicals, detoxifies electrophilic reagents and maintains the thiol status of proteins. Glutathione captures aldehydes and forms glutathione-aldehyde adducts to detoxify reactive lipid peroxidation products[45]. Glutathione and GSSG ratios are important indicators of OS, which contribute to the molecular mechanisms of cell proliferation, differentiation, or death by apoptosis, and reduced glutathione levels lead to oxidative stress associated with aging and many pathologies, including neurodegeneration, inflammation, and infections[46].

References:

[1] Douglas KT. Mechanism of action of glutathione-dependent enzymes. Adv Enzymol Relat Areas Mol Biol. 1987; 59: 67-103.

[2] Meister A. Glutathione metabolism and its selective modification. J Biol Chem.  1988 Nov; 263(33): 8-17.

[3] Jefferies H, Coster J, Khalil A, Bot J, McCauley RD, Hall JC. Glutathione. ANZ J Surg. 2003 Jul; 73(7): 22-45.

[4] Nishizawa S, Araki H, Ishikawa Y, et al. Low tumor glutathione level as a sensitivity marker for glutamate-cysteine ligase inhibitors. Oncol Lett. 2018 Jun; 15(6): 8735-8743.

[5] Wu G, Fang YZ, Yang S, et al. Glutathione metabolism and its implications for health. J Nutr.

2004 Mar; 134(3): 89-92.

[6] Mårtensson J, Lai JC, Meister A. High-affinity transport of glutathione is part of a multi com- ponent system essential for mitochondrial function. Proc Natl Acad Sci U S A.  1990 Sep; 87(18): 71-85.

[7] Sies H. Glutathione and its role in cellular functions. Free Radic Biol Med. 1999 Nov; 27(9- 10): 16-21.

[8] Gaucher C, Boudier A, Bonetti J, Clarot I, Leroy P, Parent M. Glutathione: Antioxidant Prope -rties Dedicated to Nanotechnologies. Antioxidants (Basel). 2018 Apr; 7(5): 62.

[9] Monostori P, Wittmann G, Karg E, Túri S. Determination of glutathione and glutathione disul- fide in biological samples: an in-depth review. J Chromatogr B Analyt Technol Biomed Life Sci. 2009 Oct 15; 877(28): 31-46.

[10]  Deponte M.  The  Incomplete  Glutathione  Puzzle:  Just  Guessing  at Numbers  and  Figures Antioxid Redox Signal. 2017 Nov ; 27(15): 1130-1161.

[11] Dai Pangcong, Wu Hui. Exploring the progress of glutathione application research[J]. Modern Food, 2020, 21: 47-50.

[12] Rebrin I, Sohal R S. Comparison of thiol redox state of mitochondria and homogenates of various tissues between two strains of mice with different longevities. Exp Gerontol. 2004 Oct; 39(10): 9-15.

[13] Liu Y, Hyde A S, Simpson MA, et al. Emerging regulatory paradigms in glutathione metabo- lism. Adv Cancer Res. 2014; 122: 69-101.

[14] Wendel A. Measurement of in vivo lipid peroxidation and toxicological significance. Free Radic Biol Med. 1987; 3(5): 8-35.

[15] Lian G, Gnanaprakasam J R, Wang T, et al. Glutathione de novo synthesis but not recycling process  coordinates  with  glutamine  catabolism  to  control  redox  homeostasis  and  directs murine T cell differentiation. Elife. 2018 Sep; 7: 58-61.

[16] Krejsa C M, Franklin C C, White C C, et al. Rapid activation of glutamate cysteine ligase cardiovascular disease in a defined population: the Hisayama study. Stroke. 2004 Sep; 35(9): 7-25.

[32] Damy T, Kirsch M, Khouzami L, et al. Glutathione deficiency in cardiac patients is related to the functional status and structural cardiac abnormalities. PLoS One. 2009; 4(3): 48-71.

[33] Zhang Wanquan. Application value of reduced glutathione in the clinical treatment of nephrotic syndrome[J]. China Modern Drug Application,2017, 11(11): 119-120

[34] Morel G, Bonnet P, Cossec B, et al. The role of glutathione and cysteine conjugates in the nephrotoxicity of o-xylene in rats. Arch Toxicol. 1998 Sep; 72(9): 8-15.

[35]  Tigges  J, Worek  F, Thiermann  H,  et  al.  Organophosphorus  pesticides  exhibit  compound specific  effects  in  rat  precision-cut  lung  slices  (PCLS):  mechanisms  involved  in  airway response, cytotoxicity, inflammatory activation and antioxidative defense. Arch Toxicol. 2022 Jan; 96(1): 321-334.

[36] Xie JQ. Analysis of the efficacy of reduced glutathione in the emergency treatment of organophosphorus pesticide poisoning[J]. World Composite Medicine, 2021, 7(4): 18-20.

[37] JI Youren. Application value of reduced glutathione in the treatment of acute organophosphorus pesticide poisoning[J]. Primary Medicine Forum, 2019, 23(7): 965-967.

[38] Yang Z, Pan FY. Application value of hepatitis B virus nucleic acid testing in antiviral therapy[J]. Practical Examiner's Journal, 2021, 13(1): 3. [39] ZHAO Xiaoguang, ZHOU Xiaoguang, ZHOU Xiaoguang.

[39] ZHAO Xiaoguang, SHI Yujie. Effects of reduced glutathione prophylaxis on liver function in patients with middle- to late-stage primary hepatocellular carcinoma treated with TACE[J]. Journal of Practical Liver Diseases, 2019, 22(3): 128-131.

[40] Anderton  B,  Camarda  R,  Balakrishnan  S,  et  al.  MYC‐driven  inhibition  of the  glutama- te‐cysteine ligase promotes glutathione depletion in liver cancer. Embo Reports, 2017, 18(4): 569-585.

[41] Townsend D M , Tew K D , Tapiero H . The importance of glutathione in human disease. Bio- med Pharmacother, 2003 May, 57(3-4): 145-155.

[42] Fernández-Checa JC, ColellA, García-Ruiz C. S-Adenosyl-L-methionine and mitochondrial reduced glutathione depletion in alcoholic liver disease. Alcohol. 2002 Jul; 27(3): 79-83.

[43] Miao Q. Q. Q. Physiological functions of glutathione and its application prospects in food processing[J]. Science and Technology Wind, 2010, 8: 247.

[44] JIANG Jie, SAN Lifeng. Production of glutathione and its application in the food industry[J]. China Flavorings, 2009, 34(2):40- 44.

[45] Li Q, Tomcik K, Zhang S, Puchowicz MA, et al. Dietary regulation of catabolic dispos- al of 4-hydroxynonenal analogs in rat liver. Free Radic Biol Med. 2012 Mar; 52(6): 43-53.

[46] Aquilano K, Baldelli S, Ciriolo MR. Glutathione: new roles in redox signaling for an old antioxidant. Front Pharmacol. 2014 Aug; 26(5): 196.