Genuine Functions of P-Glycoprotein (ABCB1)

Abstract

P-glycoprotein (P-gp, ABCB1, MDR1) was recognized as a drug-exporting protein from cancer cells three decade ago. Apart from the multidrug transporter side effects of P-gp, normal physiological functions of P-gp have been reported. P-gp could be responsible for translocating platelet-activating factor (PAF) across the plasma membrane and PAF inhibited drug transport mediated by P-gp in cancer cells. P-gp regulated the translocation of sphingomyelin (SM) and GlcCer, and short chain C(6)-NBD-GlcCer was found in the apical medium of P-gp cells exclusively and not in the basolateral membrane. SM plays an important role in the esterification of cholesterol. High expression of P-gp prevents stem-cell differentiation, leading to the proliferation and amplification of this cell repertoire, and functional P-gp plays a fundamental role in regulating programmed cell death, apoptosis. The transporter function of P-gp is therefore necessary to protect cells from death. P-gp can translocate both C(6)-NBD-PC and C(6)-NBD-PE across the apical membrane. This PC translocation was also confirmed with [(3)H]choline radioactivity. Progesterone is not transported by P-gp, but blocks P-gp-mediated efflux of other drugs and P-gp can mediate the transport of a variety of steroids. Cells transfected with human P-gp esterified more cholesterol. P-gp might also be involved in the transport of cytokines, particularly IL-1beta, IL-2, IL-4 and IFNgamma, out of activated normal lymphocytes into the surrounding medium. P-gp expression is also associated with a volume-activated chloride channel, thus P-gp is bifunctional with both transport and channel regulators. We also present information about P-gp polymorphism and new structural concepts, "gate" and "twist", of the P-gp structure.

MDR1-P-glycoprotein behaves as an oncofetal protein that promotes cell survival in gastric cancer cells

“…After 48 h, the cell were collected and divided in two aliquots: the first was lysed and total extracts blotted with anti-P-gp antibodies (a). Another aliquot was exposed to 3% H 2 increased level of nitric oxide synthase that exposes the cells to a significant oxidative stress. 31 The cells with high levels of P-gp and Bcl-x L could escape stress-imposed death and accumulate DNA damage ultimately leading to cell transformation and cancer development.…”

Different Modalities of Intercellular Membrane Exchanges Mediate Cell-to-cell P-glycoprotein Transfers in MCF-7 Breast Cancer Cells

“…First, the substrate binding pocket of P-gp fits to a variety of chemically unrelated molecules, giving the protein the ability to transport a broad spectrum of substances encompassing lipids, peptides, and xenobiotics (4 -6). Second, native expression of the MDR1/ABCB1 gene is essentially restricted to tissue-blood epithelia in the brain, placenta, liver, testis, colon, and kidney in addition to isolated hematopoietic stem and immune cells (7)(8)(9). As a consequence, P-gp drains a variety of compounds across physiologic permeation barriers and lowers their concentrations in cell compartment.…”

The complexity of roles of P-glycoprotein in refractory epilepsy: Pharmacoresistance, epileptogenesis, SUDEP and relapsing marker after surgical treatment

“…In addition to the much known drug pump model, some studies indicate that P-gp may mediate drug resistance through channels function regulation [53]. Supporting this idea, it has been described that MDR1 protein behaves as some type of Cl -transporter, stimulates Cl -channel activity and may alter cell volume in several cell types [54].…”