P-Glycoprotein and Drug Resistance in Systemic Autoimmune Diseases

Abstract

Autoimmune diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and psoriatic arthritis (PsA) are chronic inflammatory disorders of unknown etiology characterized by a wide range of abnormalities of the immune system that may compromise the function of several organs, such as kidney, heart, joints, brain and skin. Corticosteroids (CCS), synthetic and biologic immunosuppressive agents have demonstrated the capacity to improve the course of autoimmune diseases. However, a significant number of patients do not respond or develop resistance to these therapies over time. P-glycoprotein (P-gp) is a transmembrane protein that pumps several drugs out of the cell, including CCS and immunosuppressants; thus, its over-expression or hyper-function has been proposed as a possible mechanism of drug resistance in patients with autoimmune disorders. Recently, different authors have demonstrated that P-gp inhibitors, such as cyclosporine A (CsA) and its analogue Tacrolimus, are able to reduce P-gp expression and or function in SLE, RA and PsA patients. These observations suggest that P-gp antagonists could be adopted to revert drug resistance and improve disease outcome. The complex inter-relationship among drug resistance, P-gp expression and autoimmunity still remains elusive.

P-glycoprotein in autoimmune rheumatic diseases

“…Recent studies have determined that Pgp levels are elevated in patients with active SLE when compared with patients SLE patients in clinical remission [1]. Henmi et al, found that Pgp is overexpressed in T CD4 cells of 12 patients with SLE that had a poor response to treatment with corticosteroids [41].…”

“…Drugs that have been shown to modulate the activity of Pgp are gefitinib, verapamil, nifedipine, chloropromazine, progesterone, tamoxifen, amiodarone, hidroxychloroquine, ketoconazole, antibiotics (cefoperazone, ceftriaxone) ciclosporine and tacrolimus [1,7,10,17,25,26,30,31]. The first generation of modulators (verapamil, quinidine), were poor inhibitors of Pgp that required high plasma levels, which made them inappropriate for clinical use because of the toxicity and side effects related with these doses.…”

“…MDR-1 gene polymorphisms cause changes in the function of Pgp and patients with these variants are at an increased risk of developing a variety of conditions such as inflammatory bowel disease (IBD) [1], steroid induced osteonecrosis of the femoral head [2,3] and lung cancer [4]; however, its role in the development of autoimmune diseases remains unclear [5]. More than 50 single nucleotide polymorphisms (SNP) of the MDR1 gene have been described [6].…”

“…Pgp has an important role in the response and excretion of drugs [1]. The transcription of MDR-1 and the expression of Pgp are mediated through the human Y-box binding protein (YB-1) [16].…”

“…The permeability glycoprotein (P-glycoprotein, Pgp) is a transmembrane protein of 170 kD encoded by the multidrug resistance gene 1 (MDR-1); also known as the adenosine triphosphate binding cassette B1 gene (ABCB1) [1]. This protein is responsible for the resistance to drugs used in chemotherapy, human immunodeficiency virus (HIV) therapy, epilepsy and inflammatory bowel disease (IBD).…”