|Year : 2022 | Volume
| Issue : 3 | Page : 252-257
|Desloratadine efficacy in relation to GSTM1 and GSTT1 polymorphic genes in chronic spontaneous urticaria
Amal Maouia1, Nadia Leban2, Monia Youssef3, Ahmed Noureddine Helal1, Asma Kassab2
1 Laboratory of Bioressources, Integrative Biology and Valorization, Higher Institute of Biotechnology of Monastir, Monastir, Tunisia
2 Biochemistry and Molecular Biology Laboratory, Faculty of Pharmacy, University of Monastir, Monastir, Tunisia
3 Department of Dermatology, CHU Fattouma Bourguiba, Monastir, Tunisia
|Date of Web Publication||22-Sep-2022|
Laboratory of Bioressources, Integrative Biology and Valorization Higher Institute of Biotechnology of Monastir, University of Monastir Avenue Tahar Haded - B.P. n° 74-5000 Monastir
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Background: The etiopathogeny of chronic spontaneous urticaria (CSU) is not well defined. Allelism in glutathione S-transferase GSTM1 and GSTT1 has been suggested as a risk factor. Desloratadine is the first-line treatment for this disease. Objective: This study aimed to investigate the efficacy of a first-line treatment: desloratadine 5 mg/day on antioxidant status and clinical assessment in Tunisian patients with CSU and to identify possible associations between GSTT1 and GSTM1 genotypes and susceptibility to CSU. Methods: Sixty patients with CSU and 60 age- and gender-matched healthy controls were included in the study. We calculated the urticaria activity score (UAS) and assessed the antioxidant parameters (total antioxidant status [TAS], glutathione S-transferase [GST], SOD, CAT, GPx]). Multiplex PCR was performed to find the relationship between GSTM1 and GSTT1 polymorphisms with CSU susceptibility. Results: At baseline, GST, GPx, CAT, SOD activities, and TAS were significantly lower in CSU patients compared to healthy controls (P < 0.05). After treatment, GST, GPx, CAT, SOD activities and TAS were significantly increased in patients compared to those before treatment (P < 0.001). We observed a significant association in null alleles of GSTM1. Before treatment, GST activity was significantly lower in patients having GSTM1+ genotype than those having GSTM1- genotype (P = 0.001). After treatment, TAS and antioxidant enzymes GST, GPx, SOD, and CAT were significantly elevated in patients having GSTM1- genotype than those having GSTM1+ genotype (P < 0.05). Conclusion: These results suggest the impact of GSTM1 and GSTT1 on CSU susceptibility and desloratadine efficacy in Tunisian patients.
Keywords: Chronic spontaneous urticaria, desloratadine, Glutathione S-transferase, oxidative stress, polymorphism
|How to cite this article:|
Maouia A, Leban N, Youssef M, Helal AN, Kassab A. Desloratadine efficacy in relation to GSTM1 and GSTT1 polymorphic genes in chronic spontaneous urticaria. Indian J Dermatol 2022;67:252-7
|How to cite this URL:|
Maouia A, Leban N, Youssef M, Helal AN, Kassab A. Desloratadine efficacy in relation to GSTM1 and GSTT1 polymorphic genes in chronic spontaneous urticaria. Indian J Dermatol [serial online] 2022 [cited 2022 Sep 30];67:252-7. Available from: https://www.e-ijd.org/text.asp?2022/67/3/252/356742
| Introduction|| |
Chronic spontaneous urticaria (CSU) is a mast cell-cutaneous disorder symptomized by the recurrence of daily wheals, angioedema, or both for at least 6 weeks due to known or unknown causes. In the world, 0.5%–1% of the population suffer from CSU. The disease has a large impact on the quality of life, since more than 30% of patients with moderate to severe symptoms continue to exhibit CSU sequel after 5 years.
Skin is often exposed to the harmful action of many chemical and physical toxicants. Exogenous toxicants generate endogenous metabolites that can lead to the generation of a wide variety of reactive oxygen species. Its hyper-production is identified as oxidative stress that overwhelms skin antioxidant defense systems, biological molecules damage, and inflammatory cytokine release.
The skin shows an antioxidant system consisted of the additive outcome of enzymatic and nonenzymatic substances such as glutathione peroxidase, catalase, superoxide dismutase, and glutathione S transferase (GST). GST consists of multifunctional enzymes, which catalyze the conjugation of reduced glutathione with various electrophilic compounds and play a key role in cellular detoxification. These enzymes are involved in the protection against inflammation, mutagenicity, and genotoxicity because of oxidative stress GST enzymes are involved in the synthesis of inflammatory mediators, leukotrienes and prostaglandins, and act in cell signaling as potential regulators of apoptosis. Cytosolic human GST exhibits genetic polymorphisms, and this variation can increase susceptibility to carcinogens and inflammatory diseases. Polymorphisms of specific subtypes of this enzyme family may lead to an imbalance in pro- and antioxidant systems with ensuing increased production of reactive oxygen species. GST isoenzymes, including but not limited to glutathione S-transferase Mu-1 (GSTM1) and glutathione S-transferase theta-1 (GSTT1), were shown to be polymorphically distributed in the population. The presence of null genotypes of these enzymes was associated with increased susceptibility to a number of autoimmune diseases such as type 2 diabetes and vitiligo.,
The GSTM1 gene, coding for cytosolic GST class mu enzyme, is located on chromosome 1p13.3. GSTM1 expression catalyzes the conjugation of glutathione to epoxide derivatives of polycyclic aromatic hydrocarbons. A partial deletion of GSTM1 polymorphism in the homozygous state (GSTM1 null) leads to a total absence of a functional gene product and a complete absence of GSTM1 enzyme activity.
The GSTT1 gene is located on chromosome 22q11.2. GSTT1 expression is important in the detoxification of naturally occurring monohalomethanes, dichloromethanes, and ethylene oxides. The inactivating homozygous deletion polymorphism in this gene was also described.
H1-antihistamines are the CSU treatment mainstay. These are usually classified as first- or second-generation according to their chemical structure and properties. Desloratadine is a selective and peripheral histamine H1-receptor antagonist that is widely used to treat CSU in a large, multicenter, double-blind, randomized, placebo-controlled trials and has an antioxidant activity in vitro. Patients with CSU show different responses to desloratadine as a first-line treatment.
In this context, we aimed to elucidate the impact of GSTM1 and GSTT1 on CSU susceptibility and desloratadine efficacy in Tunisian patients.
| Materials and Methods|| |
Sixty patients with CSU were enrolled from the Department of Dermatology, Fattouma Bourguiba Hospital, Monastir, Tunisia. The current study was approved by the hospital ethics committee. All patients provided informed written consent. We included patients who had only CSU disease and were symptomatic for more than six weeks. The patients with physical and cholinergic urticarias, urticarial vasculitis, and hereditary angioedema were excluded. Then they were under desloratadine 5 mg/day for 30 days. A first check-up before treatment and a second one after 1 month of treatment were assessed. Sixty controls sex- and age-matched were collected.
The venous blood was drawn into the tube containing EDTA and another containing heparin of lithium. The plasma of heparin tubes was used for measuring antioxidant parameters and the tubes containing EDTA served for DNA extraction. The samples were separated and stored at –80°C until use.
Urticaria activity score
Urticaria activity score (UAS) is frequently used in routine clinical practice to evaluate chronic urticaria severity and treatment efficacy. The EAACI/GA2LEN/EDF/WAO guideline recommends the use of a straightforward and well-established symptom UAS.
Antioxidant enzyme analysis
Glutathione S-transferase (GST) activity of heparinized plasma was determined using spectrophotometer following to the method of Habig et al. 1 mM 1-chloro-2,4-dinitrobenzene (CDNB) was added to potassium phosphate buffer pH 7.5 containing 1 mM GSH 1% absolute ethanol, the change in absorbance at 340 nm was measured in function of time. Results were expressed as μM of GSH-CDNB conjugate formed/min/ml.
Total antioxidant status
Total antioxidant stress (TAS) of heparinized plasma was measured using the colorimetric method, which is based on the bleaching of the characteristic color of a more stable ABTS [2,2′-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid)] radical action by antioxidants. TAS concentrations were performed using commercial tests manufactured by Randox Laboratories (UK, Antrium).
Superoxide dismutase activity
Superoxide dismutase (SOD) activity in erythrocytes was measured according to procedure by Asada et al. Nitroblue tetrazolium salt (NBT), a superoxide radical scavenger, is reduced by superoxide to form blue formazan whose absorption was measured at 560 nm. One unit of SOD is defined as the amount of enzyme required to give 50% inhibition of the NBT reduction reaction compared with enzyme control. The SOD activity was expressed in U/mg protein.
Glutathione peroxidase activity
Glutathione peroxidase (GPx) activity in erythrocytes was measured according to spectrophotometric procedure by Paglia. Phosphate-buffered saline (PBS) (pH 7.4) containing ethylenediaminetetraacetic acid (EDTA), reduced α-nicotinamide adenine dinucleotide phosphate (NADPH), glutathione (GSH), and sodium azide (NaN3). A change in absorbance at 340 NM was monitored for 1 min. The specific activity was calculated in U/mg protein.
Catalase (CAT) activity in erythrocytes was determined according to the spectrophotometric procedure by Aebi's method. CAT activity was measured at 25°C by recording H2O2 decomposition at 240 nm. The amount of H2O2 converted into H2O and ½ O2 in 1 min under standard conditions is accepted as the enzyme reaction rate.
Multiplex polymerase chain reaction for polymorphic GSTM1 and GSTT1 analysis
To examine the genetic polymorphism analysis for GSTM1 and GSTT1, a simultaneous amplification of genes of interest in the same reaction was performed using a multiplex polymerase chain reaction (PCR) as described in the procedure of Arand et al. Briefly, genomic DNA was extracted from venous blood samples using a “salting out” method. The multiplex PCR method was used to detect the presence or absence of the GSTM1, GSTT1 and albumin genes in the genomic DNA samples, simultaneously in the same tube. Both polymorphisms are due to gene deletions that result in complete absence of the respective enzyme activities. The primers amplify DNA fragments that are located in the deleted regions. The gene primers and the fragment length were indicated in [Table 1].
PCRs were carried out with a Mastercycler personal thermal cycler (Eppendorf, Germany). Isolated DNA (50 ng) was amplified in a 50-μL reaction mixture containing 30 pmol of GSTM1 and GSTT1 primers. As an internal control, albumin genes were coamplified in the presence of 200 μmol dNTP (deoxynucleoside triphosphate), 5 μL 10 × PCR buffer, 1.5 mM MgCl2, and 2 U Taq polymerase. The PCR conditions consisted of an initial melting temperature of 94°C (5 min) followed by 35 cycles of melting (94°C, 2 min) and annealing (59°C, 1 min), and the extension step (72°C) of 10 min terminated the process. The PCR products were separated by electrophoresis on 2% agarose gel stained with ethidium bromide and visualized by ultraviolet detection.
SPSS V 20.0 was used for Statistical analysis. Testing of antioxidant parameters was done by using Student's t test. The association between the GSTM1 and GSTT1 genotypes and the development of CSU were examined by use of the Chi-squared test (χ2). Genotype frequencies were compared using the odds ratios and their 95% confidence intervals (CIs). A value of P < 0.05 was considered statistically significant.
| Results|| |
At baseline, GST, GPx, CAT, SOD activities, and TAS were significantly lower in CSU patients compared to healthy controls [P < 0.05, [Table 2]].
After treatment, GST, GPx, CAT, SOD activities, and TAS were significantly increased in patients compared to those before treatment (P < 0.001).
GSTM1 and GSTT1 polymorphism analysis
GSTs are known to be polymorphic enzymes in humans. We investigated the association between the GSTM1 and GSTT1 gene polymorphisms and CSU. [Figure 1] reveals the presence or absence of GSTM1 and GSTT1 genes by gel electrophoresis. The results of the genotype distribution are resumed in [Table 3]. Our study demonstrated that GSTM1 null genotype was more frequent in the CSU patients (91%) than in controls (18%). Moreover, we observed a significant association in GSTM1 null (GSTM1-) genotype (P = 0.002) whereas, no significant association in GSTT1 was observed with CSU. Our results demonstrated that subjects with the GSTM1- genotype were at an increased risk of developing CSU [OR = 0.1; 95% CI = 0.027-0.372].
|Figure 1: Analysis of polymorphisms of glutathione S-transferase GSTM1 and GSTT1 by gel electrophoresis. M: 100 bp DNA marker. T_: Negative control. Lane 1: Control GSTM1 active/GSTT1 null genotypes. Lane 2: control GSTM1 active (215 bp)/GSTT1 active (480 bp) genotypes. Lane 3: Patient GSTM1 null/GSTT1 null genotypes. Lanes 4, 5: Patients GSTM1 null/GSTT1 active genotypes|
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|Table 3: Antioxidant enzyme activities and total antioxidant status in CSU patients before and after Desloratadine intake compared to controls|
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Desloratadine efficacy on Antioxidant status in patients with GSTM1+ or GSTM1- genotype or GSTT1+ or GSTT1-
[Table 4] summarizes antioxidant status before and after treatment in patients assorted by GSTM1 polymorphism. Before treatment, GST activity was significantly lower in patients having GSTM1+ genotype than those having GSTM1- genotype (P = 0.001). TAS and antioxidant enzymes GPx, SOD, and CAT did not differ in patients having GSTM1+ genotype and those having GSTM1- genotype. After treatment, TAS and antioxidant enzymes GST, GPx, SOD, and CAT were significantly elevated in patients having GSTM1- genotype than those having GSTM1+ genotype (P < 0.05).
|Table 4: Genotype distribution of GSTM1 and GSTT1 in CSU patients and controls|
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| Discussion|| |
The role of oxidative stress in the pathogenesis of CSU has been studied previously. These studies have evaluated oxidative stress in plasma, lesional skin, and in erythrocytes. We have previously found the involvement of oxidative stress in CSU pathogenesis. One of the most important aspects of the current study is the improvement of patients' antioxidant status after taking desloratadine 5 mg daily revealed by antioxidant enzyme activities and TAS. Desloratadine was shown to exert a protective effect against oxidative stress in human erythrocytes. In fact, several antihistamines were reported to inhibit free radical reactions. Precisely, histamine H1-antagonist as dithiaden, inhibits generation of reactive oxygen species by phagocytes. Besides, there exists other aromatic secondary amines, such as phenylenediamines and diarylamines, were widely used as pharmacological antioxidants due to their electrophilic compounds neutralizing effects. Cassano et al. showed that treatment with desloratadine caused a relevant reduction of radical oxygen species generation and superoxide dismutase activity. It might be hypothesized that the early CSU onset may have a stronger genetic component in its pathology. Polymorphic analysis reported a significant association of GSTM1- genotype in patients with CSU. In addition, Chi-square test showed that GSTM1 null may be considered as a risk factor. This may reflect that the absence of GSTM1 activity could be a contributing factor for CSU onset. Subsequent to the absence of GSTM1 activity, antioxidant defense capacities may exhibit diminished ability to handle with oxidative stress leading to an early pathogenesis. Hence, GSTM1 absence may enhance susceptibility to CSU due to reduced efficiency of oxidative stress products detoxification. However, GSTT1 polymorphic genes showed no association with CSU [Table 5].
|Table 5: Antioxidant status in patients assorted by GSTM1 polymorphism before and after desloratadine intake|
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There exist few studies on the association of GST polymorphisms with dermatological disorders. Previous investigations showed a significant association between the GSTT1 and/or GSTM1 null genotypes and rosacea occurrence and vitiligo onset. Whereas a Korean study showed that GSTM1 null and GSTM1/GSTT1 null/present polymorphisms was associated with increased vitiligo risk. Besides, the same study stated that GSTT1 null polymorphism may increase vitiligo risk in Mediterranean countries. Cho et al. showed that GSTM1 null genotype was found to be associated with childhood onset of atopic dermatitis in Korean subjects.
When antioxidant capacities were assorted according to GSTM1 and GSTT1 polymorphisms, GST activity was revealed to be higher in GSTM1- genotype than GSTM1+genotype. These genotyping findings revealed that the absence of GSTM1 activity could be a contributing factor for CSU development. Moreover, in patients with GSTM1- genotype, the absence of GSTM1 expression may not be sufficient to alter the overall enzymatic activity (17.24 ± 6.12 U/ml) since the GST system is a multigene family. In contrast, several epidemiological studies showed that GSTM1 and GSTT1 null allele variants resulted in the absence of GST enzyme activity.
A finding worth noting is that Desloratadine effect depends on GST polymorphism. After treatment, antioxidant status in patients having GSTM1- genotype were more improved than those having GSTM1+ genotype. This revealed that patients with GSTM1- exhibited a better response to desloratadine. It seems that the absence of GSTM1 accentuated desloratadine antioxidant effect. To our knowledge, this is the first study that investigated desloratadine effect in relation to GST polymorphism whereas anticancer treatment and GST polymorphism were widely investigated. Recently, it was found that GSTM1- was found to be correlated with better treatment response to chemotherapy and a lower risk of death in advanced non-small cell lung cancer patients.
| Conclusion|| |
We investigated that in one hand the absence of GSTM1 gene expression was associated with CSU susceptibility. In the other hand, we reported that the absence of GSTM1 isoenzyme activity did not alter the overall GST activity. GSTM1 absence may boost CSU pathogenesis since antioxidant capacities would be diminished or unable to detoxify oxidant stress products.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
- Study of the efficacy of Desloratadine 5 mg/day on antioxidant Status and clinical assessment in Tunisian patients with CSU
- Identification of possible associations between GSTT1 and GSTM1 genotypes and susceptibility to CSU in Tunisian patients.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]
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