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ORIGINAL ARTICLE
Year : 2009  |  Volume : 54  |  Issue : 1  |  Page : 13-16
Study of total antioxidant status and glutathione peroxidase activity in Tunisian vitiligo patients


Research Unit on the Antioxidant Compounds, Oxidative Stress, Trace Elements and Metabolic Diseases, Ecole Superieure des Sciences et Techniques de Tunis Health, Tunisia

Correspondence Address:
Akrem Jalel
Ecole Supérieure des Sciences et Techniques de la Santé de Tunis, BP 176 Bab-Souika 1006 Tunis
Tunisia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0019-5154.48978

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   Abstract 

Background: Vitiligo affects one to two percent of the word population. Its pathogenesis has not been clarified yet. Multiple mechanisms such as autoimmune, neuronal, endocrine and oxidative stress resulting from unbalanced antioxidant defense system have been proposed. Aims: Our purpose was to study the total antioxidant status and glutathione peroxidase activity in Tunisian vitiligo patients with or without diabetes or dysthyroidism. Materials and Methods: We studied 60 vitiligo patients and 62 healthy controls. The sex ratio male/female in vitiligo patients was (27/33 = 0.81). Patients with vitiligo were divided into three groups, according to the association with diabetes or dysthyroidism. The total antioxidant status (TAS), glutathione peroxidase activity (GPX activity) was evaluated by adaptable methods using Kits. Results and Conclusion: The generalized vitiligo was the most frequent type (35 patients versus 25 of focal ones). All patients having vitiligo showed low levels of TAS: 0.85 ± 0.7 and low GPX activity: 45 ± 0.6, as compared to the control group: 1.40 ± 0.12 mmol/L; 49 ± 1.8 U/L, (p < 0.01), for TAS and GPX, respectively. The association of low TAS and GPX activities was more pronounced in diabetic vitiligo patients than in dysthyroid vitiligo patients. This study demonstrated that antioxidant processes depletion (low TAS and low GPX activity) is clearly involved with vitiligo in Tunisian patients, regardless of the association of the disease with diabetes or dysthyroidism.


Keywords: Diabetes, dysthyroidism, glutathione peroxidase activity, total antioxidants status, vitiligo


How to cite this article:
Jalel A, Hamdaoui MH. Study of total antioxidant status and glutathione peroxidase activity in Tunisian vitiligo patients. Indian J Dermatol 2009;54:13-6

How to cite this URL:
Jalel A, Hamdaoui MH. Study of total antioxidant status and glutathione peroxidase activity in Tunisian vitiligo patients. Indian J Dermatol [serial online] 2009 [cited 2019 Jun 24];54:13-6. Available from: http://www.e-ijd.org/text.asp?2009/54/1/13/48978



   Introduction Top


Mammalian pigmentation results from the synthesis and accumulation of photoprotective epidermal melanins. Melanins are formed from the amino acid precursor L-tyrosine, within specialized cells, the melanocytes. The melanogenic pathway involves the formation and polymerization of reactive oquinones. [1] To date, systemic and epidermal oxidative stress via H 2 O 2 in the depigmentation disorder vitiligo has been suggested to be the initial pathogenesis event in melanocyte degeneration in the epidermis of patients with active disease. [2],[3],[4] Detailed in vitro and in vivo studies on various metabolic mechanisms have provided a new understanding of the physiological and physio-pathological events in this disease process, despite the fact that the precise step in the cascade for initiation of this peculiar disorder still remains unknown. [5],[6] Vitiligo has been also reported in association with several endocrinopathies and other disorders of autoimmune nature such as dysthyroidism and diabetes. Our purpose was to examine the total antioxidant status and glutathione peroxidase activity in Tunisian vitiligo patients with or without associated metabolic diseases.


   Materials and Methods Top


Patients

Sixty vitiligo patients and sixty two healthy volunteers aged from 11 to 67 years attending in Medenine Hospital (Medenine is a town in the south of Tunisia) participated in the present study. Local medical authority has approved the study and informed consent has been obtained from each subject. The total vitiligo patients (TVP, n = 60) were subdivided into three groups: vitiligo patients without associated pathologies (VP, n = 25), diabetic vitiligo patients (DVP, n = 20) and dysthyroid vitiligo patients (ThVP, n = 15). All subjects were interviewed according to a standard questionnaire for details of their age, demographic, clinical, anthropometrics (BMI, kg/m 2 ), family vitiligo, diabetes and dysthyroidism history, smoking habits, and their habits diet information, in particular type of foods, meals, desserts, snacks and drinks consumed including coffee and tea, site of onset, duration, and past treatment were taken. A complete clinical examination was done, and the site and pattern of the lesions were noted. The evolution of the disease, as evidenced by the appearance of new lesions and increase in the size of existing lesions over the past three months was also completed. Screening was done for autoimmune and endocrine disorders by history and clinical examination. These disorders included thyroid disease and diabetes mellitus. Investigations including thyroid hormones (TSH, T3), plasma glucose are determined for each patient.

Blood sampling

Fasting blood was collected and was subdivided in aliquots. One of them was used to analyze basal clinical parameters. Another was used to determine the whole blood GPX Activity (GPX). Remain of blood was centrifuged at 3,000 rpm for 10 min, and then the plasma was removed and frozen for analyses of total antioxidant status (TAS).


   Analysis of samples Top


Analyses of basal clinical parameters

Fasting blood glucose (FBG) was measured by routine Auto analyzer methods (Synchron CX 7, Beckman), using dedicated kits.T3 was measured by resin fixation and TSH by radioimmunology. [7]

Analyses of total antioxidant status, whole blood GPX activity

The TAS was determined in heparinized plasma samples by the method of Miller et al . [8] The whole blood GPX activity was determined by the method of Paglia and Valentine. Kits for analysis of TAS and GPX activities were purchased from Randox (United Kingdom).

Statistical analysis

Statistical analyses were carried out using ANOVA followed by Student's t-test for normally distributed data or by the Mann-Whitney U-test for non-normally distributed data. Associations between variables were examined using Spearman's rank correlation coefficient. All data are presented as mean ± SEM. Differences were considered significant at p < 0.05.


   Results Top


The vitiligo characteristics (type, age at onset and sex ratio) of Tunisian patients are given in [Table 1]. The sex ratio was (27/33 = 0.81) and the generalized vitiligo was the most frequent type (35 patients versus 25 of focal ones). Anthropometric characteristics of different groups (age, weight and BMI) are indicated in [Table 2] and [Table 3]. They revealed overweight as indicated by their BMI ≥27kg/m 2 . Fasting blood glucose was significantly higher in diabetics than in controls (p < 0.01). In dysthyroid vitiligo patients, the TSH significantly increased, while the T3 showed to be decreased. Values of TAS and GPX are given in [Table 3]. The total antioxidant defense system decreased in diabetics groups. The values of TAS were normal in the control group as compared to the reference values (between 1.3 and 1.7 mmol) given by RANDOX. However, values of the TAS were significantly lower the control group. The GPX activities decreased in all group of vitiligo by about 40% or more, in particular in DVP group (45%).


   Discussion Top


One of the major hypotheses in the pathogenesis of vitiligo is the oxidative stress induced by reactive oxygen species (ROS) which plays a major role in the production of free radicals. In spite of its key role in the regulation of proliferation and differentiation of many cell types, ROS usually causes several damages of different cell types. Epidermal melanocytes are concerned and the potential regulatory roles of ROS might be particularly important, as ROS are frequently generated in epidermal cells following UV irradiation (normal tanning stimulus but also the main etiological factor for skin cancer). In addition to this excessive production of ROS, there are other pathways conducting to oxidative stress like defective recycling of tetrahydrobiopterin which has been reported in vitiligo epidermis. [5],[9] The alteration in the antioxidant pattern, with a significant reduction of GPX and catalase activities has been demonstrated in both lesional and non lesional epidermis of patients. [10],[11] The antioxidant imbalance has been confirmed also in peripheral blood mononuclear cells of active vitiligo and was correlated to the increased intracellular production of reactive oxygen species and appeared to be a consequence of mitochondrial impairment. [9],[12] These findings support the concept of a possible systemic oxidative stress in vitiligo. The generation of ROS and/or the resulting increase in lipid peroxidation products have been proposed as etiological factors for depigmentary natural processes such as hair graying [13] and several pathological conditions, like vitiligo. [8],[14] Moreover, imbalances of the normal antioxidant mechanisms are common in human melanoma cells [15] and the autocytotoxic hypothesis suggests that melanocyte impairment could be related initially to an increased oxidative stress, [16],[17] with a consequent induction of H 2 O 2 accumulation in the epidermis of patients with active disease, [18] lower levels of GPX and catalase were demonstrated in the epidermis of both lesional and non lesional skin of vitiligo patients [19],[20] and during active phases of disease, an imbalance of antioxidants was found in both the epidermis [21] and peripheral blood mononuclear cells (PBMC), correlated to an increased intracellular ROS production. [22],[23] These data, in accord with our findings of decreased levels of GPX and TAS, suggest that the entire epidermis, and even PBMC, may be involved in vitiligo etiology. H 2 O 2 and other reactive oxygen species are key regulators of many intracellular pathways, within mammalian skin. The polymerization reactions involving quinonic melanogenic intermediates are spontaneous, and lead to H 2 O 2 production. In support of this view, several oxidative reactions of melanin precursors are inhibited by catalase. [1] In active vitiligo an increased oxidative stress of the entire epidermal compartment has been demonstrated. [16],[21] Recently, the activity of vitiligo has been associated with a systemic oxidative stress, evaluated by assessing the intracellular generation of ROS and the antioxidant pattern in PBMC. [24] In particular, TAS, GPX, glutathione and Vitamin E levels were decreased, and this imbalance of antioxidants was associated with hyperproduction of ROS. [25],[26],[27],[28] These aspects of oxidative stress are related to cytoplasmic events. In the B16 mouse melanoma model, this inhibition is not related to a severe cellular damage, as treatment conditions with a strong inhibitory action, are adequately withstood by the cells.


   Conclusion Top


The results of the present investigation provide the first evidence for an important role of oxidative stress in the physiopathology of vitiligo.

 
   References Top

1.d'Ischia M, Napolitano A, Prota G. Peroxidase as an alternative to tyrosinase in the oxidative polymerization of 5, 6-dihydroxyindoles to melanin(s). Biochim Biophys Acta 1991;1073:423-30.  Back to cited text no. 1    
2.Dell'Anna M, Maresca V, Briganti S, Camera E, Falchi M, Picardo M. Mitochondrial impairment in peripheral blood mononuclear cells during the active phase of vitiligo. J Invest Dermatol 2001;117:908-13.  Back to cited text no. 2    
3.Halliwell B, Aruoma OI. DNA damage by oxygen-derived species. FEBS Lett 1991;281:9-19.  Back to cited text no. 3    
4.Hemesath TJ, Price ER, Takemoto C, Badalian T, Fisher D. MAP kinase links the transcription factor microphthalmia to c-kit signaling in melanocytes. Nature 1998;391:298-301.  Back to cited text no. 4    
5.Hornyak T, Hayes D, Ziff E. Cell-density-dependent regulation of expression and glycosylation od dopachrome tautomerase/tyrosinase-related protein-2. J Invest Dermatol 2000;115:106-12.  Back to cited text no. 5    
6.Jimιnez-Cervantes C, Solano F, Kobayashi T, Urabe K, Hearing VJ, Lozano JA, et al . A new enzymatic function in the melanogenic pathway: The 5,6-dihydroxyindole-2-carboxylic acid oxidase activity of tyrosinase-related protein-1 (TRP-1). J Biol Chem 1994;269:17993-8000.  Back to cited text no. 6    
7.Abe J, Berk BC. Fyn and JAK2 mediate Ras activation by reactive oxygen species. J Biol Chem 1999;274:21003-10.  Back to cited text no. 7    
8.Wood JM, Schallreuter-Wood KU, Lindsey NJ, Callaghan S, Gardner ML. A specific tetrahydrobiopterin binding domain on tyrosinase controls melanogenesis. Biochem Biophys Res Commun 1995;206:480-5.  Back to cited text no. 8    
9.Jimιnez-Cervantes C, Martνnez-Esparza M, Solano F, Lozano JA, Garcνa-Borron JC. Molecular interactions within the melanogenic complex: Formation of heterodimers of tyrosinase and TRP1 from B16 mouse melanoma. Biochem Biophys Res Commun 1998;253:761-7.  Back to cited text no. 9    
10.Jara R, Solano F, Lozano A. Assays for mammalian tyrosinase: A comparative study. Pigment Cell Res 1988;1:332-9.  Back to cited text no. 10    
11.Shang F, Gong X, Taylor A. Activity of ubiquitin-dependent pathway in response to oxidative stress: Ubiquitin-activating enzyme is transiently upregulated. J Biol Chem 1997;272:23086-93.  Back to cited text no. 11    
12.Sundaresan M, Yu Z, Ferrans V, Irani, K, Finkel T. Requirement for generation of H 2 O 2 for platelet-derived growth factor signal transduction. Science 1995;270:296-9.  Back to cited text no. 12    
13.Nappi J, Vass E. Hydrogen peroxide generation associated with the oxidations of the eumelanogenic precursors 5,6-dihydroxyindole and 5,6-dihydroxyindole-2-carboxylic acid. Melanoma Res 1996;6:341-9.  Back to cited text no. 13    
14.Paglia DE, Valentine WN. Studies on the quantitative and qualitative characterization of erythrocyte gluthatione peroxidase. J Lab Clin Med 1967;70:158-69.  Back to cited text no. 14    
15.Passi S, Grandinetti M, Maggio F, Stancato A, De Luca C. Epidermal oxidative stress in vitiligo. Pigment Cell Res 1998;11:81-5.  Back to cited text no. 15    
16.Peinado P, Martνnez-Liarte J H, del Marmol V, Solano F, Lozano JA. Glutathione depletion in mouse melanoma cells increases their sensitivity to oxidative lysis. Cancer J 1992;5:348-53.  Back to cited text no. 16    
17.Tassabehji M, Newton VE, Read AP. Waardenburg syndrome type 2 caused by mutations in the human microphthalmia (MITF) gene. Nat Genet 1994;8:251-5.  Back to cited text no. 17    
18.Bentley NJ, Eisen T, Goding CR. Melanocyte-specific expression of the human tyrosinase promoter: Activation by the microphthalmia gene product and role of the initiator. Mol Cell Biol 1994;14:7996-8006.  Back to cited text no. 18    
19.Schallreuter KU, Wood JM, Pittelkow MR, Gutlich M, Lemke K, Rodl W, et al . Regulation of melanin biosynthesis in the human epidermis by tetrahydrobiopterin. Science 1994;263:1444-6.  Back to cited text no. 19    
20.Thannickal VJ, Hassoun PM, White AC, Fanburg BL. Enhanced rate of H 2 O 2 release from bovine pulmonary artery endothelial cells induced by TGF-α 1. Am J Physiol 1993;265:L622-6.  Back to cited text no. 20    
21.Maresca V, Roccella M, Roccella F, Camera E, Del Porto G, Passi S. Increased sensitivity to peroxidative agents as a possibile pathogenic factor of melanocyte damage in vitiligo. J Invest Dermatol 1997;109:1081-5.  Back to cited text no. 21    
22.Schallreuter KU, Moore J, Wood JM, Beazley WD, Gaze DC, Tobin J, et al . In vivo and in vitro evidence for hydrogen peroxide (H 2 O 2 ) accumulation in the epidermis of patients with vitiligo and its successful removal by a UVB-activated pseudocatalase. J Investig Dermatol Symp Proc 1999;4:91-6.  Back to cited text no. 22    
23.Thannickal VJ, Fanburg BL. Activation of an H 2 O 2 - generating NADH oxidase in human lung fibroblasts by transforming growth factor-1 J Biol Chem 1995;270:30334-8.  Back to cited text no. 23    
24.Pezzuto J, Shieh H, Saughnessy E, Beattie C. Approaches for drug development in treatment of advanced melanoma. Semin Oncol 1988;l5:578-88.  Back to cited text no. 24    
25.Milller NJ, Rice-Evans C, Davies MJ, Gopinathan V, Milner A. Total antioxidant status. Clin Sci (Lond) 1993;84:407-12.  Back to cited text no. 25    
26.Nordlund JJ, Abdel-Malek Z. Mechanisms for postinflammatory hyperpigmentation and hypopigmentation. Prog Clin Biol Res 1988;256:219-36.  Back to cited text no. 26    
27.Schallreuter KU, Moore J, Wood J, Beazley W, Peters E, Marles LK. Epidermal H 2 O 2 accumulation alters tetrahydrobiopterin (6BH4) recycling in vitiligo: Identification of a general mechanism in regulation of all 6BH4-dependent processes? J Invest Dermatol 2001;116:167-74.  Back to cited text no. 27    
28.Schreck R, Rieber P, Baeuerle PA. Reactive oxygen intermediates as apparently widely used messengers in the activation of the NF-kB transcription factor and HIV-1. EMBO J 1991;10:2247-58.  Back to cited text no. 28    



 
 
    Tables

  [Table 1], [Table 2], [Table 3]

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    Materials and Me...
    Results
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    Conclusion
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