Lack of involvement of P-glycoprotein (P-gp) in pemphigus patients with poor response to steroid therapy

Fuente, Hortensia de la; Baranda, Lourdes; Hernandez, Martha; Torres-Álvarez, Bertha; Llórente, Luis; Layseca, Esther; González‐Amaro, Roberto

doi:10.1016/s0923-1811(01)00169-4

Cited by 3 publications

(2 citation statements)

References 27 publications

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“…P-gp expression levels in lymphocytes were analyzed using standard flow cytometry procedures as described previously (12). Lymphocytes (1×10 6 ) were incubated with 5 μl PE-conjugated anti-P-gp (CD243) monoclonal antibody (eBioscience, Inc., San Diego, CA, USA) or 5 μl PE-conjugated matched-isotype control antibody (IgG2a, eBioscience) for 30 min at 4°C, washed twice in PBS and subsequently analyzed on a FACScan (Becton-Dickinson, Mountain View, CA, USA).…”

Section: Methodsmentioning

confidence: 99%

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Detection of active P-glycoprotein in systemic lupus erythematosus patients with poor disease control

Zhang

Shi

Lei

2012

Experimental and Therapeutic Medicine

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Active P-glycoprotein (P-gp) molecules have been shown to transport steroids out of peripheral lymphocytes, resulting in poor responses to systemic steroid therapy in patients with systemic lupus erythematosus (SLE). This study was carried out to investigate the correlation between the expression or activity of P-gp in peripheral lymphocytes and disease control in SLE patients with a long history of systemic steroid treatment. A total of 60 SLE patients who had received systemic steroid treatment for longer than 6 months and 30 healthy subjects were monitored. SLE patients were subclassified into those with active and severely active forms of the disease according to their disease activity (estimated by SLEDAI-2000). The expression levels and activity of P-gp in peripheral blood lymphocytes were determined. Lymphocytes, obtained from three patients with severely active SLE, with high levels of P-gp expression were treated with cyclophosphamide, mycophenolic acid or emodin in vitro and Rh123-efflux activity was measured. P-gp expression in the peripheral lymphocytes of the SLE patients was significantly higher compared with that of the healthy controls, and a positive correlation between disease activity and P-gp expression levels was observed in these 60 patients. A significant increase in P-gp expression was observed in the severely active compared with the active SLE group. Treatment of lymphocytes with 100 μM cyclophosphamide or 100 μM emodin in vitro induced up to a 2-fold increase in the mean fluorescence intensity, as detected by the Rh123-efflux assay. In conclusion, the high expression levels of P-gp in the peripheral lymphocytes of SLE patients leads to poor disease control by systemic steroids. Emodin, an active ingredient derived from Chinese herbs, possesses a promising effect for overcoming P-gp-mediated steroid resistance by inhibiting the P-gp efflux function.

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Section: Methodsmentioning

confidence: 99%

“…P-gp activity was measured using the Rh123 efflux assay as described previously (12). The fluorescent dye Rh123 (Sigma-Aldrich, St. Louis, MO, USA) was added to 2 ml lymphocytes (1x10 6 /ml) at a final concentration of 10 μg/ml and cells were incubated at 37°C for 30 min.…”

Section: Methodsmentioning

confidence: 99%

Detection of active P-glycoprotein in systemic lupus erythematosus patients with poor disease control

Zhang

Shi

Lei

2012

Experimental and Therapeutic Medicine

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A3669G Polymorphism of Glucocorticoid Receptor Is More Present in Patients With Pemphigus Vulgaris Than in Healthy Controls and Contributes to Steroid‐Resistance

Lepekhova,

Olisova,

Shimanovsky

et al. 2024

Dermatologic Therapy

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There are two main isoforms of glucocorticoid receptor (GR) α‐ and β‐isoforms. GRβ isoform is the dominant inhibitor of the GRα receptor and plays a significant role in a poor response to systemic glucocorticoids (GCs) under numerous conditions. The A3669G (rs6198) polymorphism (SNP) in the untranslated region of human GR stabilizes the mRNA of the dominant‐negative GRβ isoform. However, the mechanisms which generate mRNA encoding the GRβ isoform have been poorly defined, especially in pemphigus patients who do not respond to GCs. The main aim was to study gene SNP of GR in patients with pemphigus vulgaris (PV) and healthy controls. We investigated whether the A3669G SNP of the human GRβ gene is a susceptibility allele for PV and contributes to GC resistance development. The presence of the A3669G SNP was determined by high‐resolution melting analysis and then confirmed by direct sequencing. GR A3669G SNP (AG genotype) occurred more frequently in PV patients (n = 72; 25%) compared with healthy controls (n = 92; 3.2%; p < 0.001). Allele G was significantly more presented in PV patients (p < 0.001). Out of 48 patients with AA genotype of A3669G SNP, only 6 had GC resistance, whereas 11 out of 18 with AG genotype developed GC resistance (p < 0.0001). The frequency of a poor response to GC in the group of patients with AG genotype was 4.89 times higher compared to AG negative one (p < 0.0001).Our study showed that the A3669G SNP was more present in PV patients. Moreover, GC resistance appeared more frequently in patients with the AG genotype (p < 0.0001). Since those patients predominantly with severe pemphigus had GC resistance (p = 0.001), we feel that A3669G SNP (AG genotype) contributes to its development. However, more studies are needed to determine whether A3669G SNP of the human GR gene associated with the disease severity and poor response to GCs in these patients.

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Assessment of genomic and non-genomic molecular indicators for the development of steroid resistance in dermatoses of various etiologies

Lepekhova,

Olisova,

Teplyuk

et al. 2024

Russian Journal of Skin and Venereal Diseases

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Resistance to systemic glucocorticosteroids (CSs) in various dermatological conditions represents a serious clinical problem, often leading to treatment failure and exacerbation of the disease. The purpose of the review is to determine the relationships between genomic and non-genomic molecular factors based on the development of steroid resistance (SR) in dermatoses of various etiologies. Genomic factors, including glucocorticoid receptor (GR) polymorphisms and changes in steroid metabolizing enzymes, may alter patient sensitivity to CSs. We selected 8 studies describing various genomic and non-genomic mechanisms in patients with pemphigus, bullous pemphigoid, atopic dermatitis, nummular eczema, limited neurodermatitis, pityriasis rubra, and cutaneous systemic lupus erythematosus. Investigating of these specific mechanisms of SR might improve and optimize therapeutic approaches for these diseases in the future.

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Lack of involvement of P-glycoprotein (P-gp) in pemphigus patients with poor response to steroid therapy

Cited by 3 publications

References 27 publications

Detection of active P-glycoprotein in systemic lupus erythematosus patients with poor disease control

Detection of active P-glycoprotein in systemic lupus erythematosus patients with poor disease control

A3669G Polymorphism of Glucocorticoid Receptor Is More Present in Patients With Pemphigus Vulgaris Than in Healthy Controls and Contributes to Steroid‐Resistance

Assessment of genomic and non-genomic molecular indicators for the development of steroid resistance in dermatoses of various etiologies

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