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

Abstract

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.

Persistent expression and function of P-glycoprotein on peripheral blood lymphocytes identifies corticosteroid resistance in patients with systemic lupus erythematosus

“…This clearly confirmed that P-gp expression and function were not dependent on either disease characteristics, doses of CS or use of additional immunosuppressive drugs in the present study. Similar results have also been reported [34] where the authors have shown that CYC administration was unable to influence the P-gp mRNA expression in 9 out of 10 SLE patients in vivo. However, in vitro experiment showed suppression of P-gp functional activity by CYC and emodin but not by mycophenolic acid.…”

Nature and uses of fluorescent dyes for drug transporter studies

“…suffering from autoimmune disorders [150], including systemic lupus erythematosus [151], idiopathic thrombocytopenia [152] and rheumatoid arthritis [153]. Results notably suggest a relationship between clinical sensitivity to glucocorticoid therapy and P-glycoprotein function in lymphocytes T CD4 + in systemic lupus erythematosus patients [154].…”

Differential alteration in peripheral T-regulatory and T-effector cells with change in P-glycoprotein expression in Childhood Nephrotic Syndrome: A longitudinal study

“…Funaki et al reported decrease in the MDR1 gene expression after complete remission and advocated that P-gp may play a role in the tapering of corticosteroids after remission in steroid sensitive Nephrotic Syndrome [27]. The poor treatment response due to increased P-gp expression has also been observed in other non-nephrological conditions like patients with malignancies [28], systemic lupus erythematosus [29], inflammatory bowel disease [30], rheumatoid arthritis, and other autoimmune diseases [31]. It has been demonstrated that P-gp expression and function can be suppressed by different compounds such as cyclosporine-A, and tacrolimus [32,33].…”