P-glycoprotein multidrug transporter in inflammatory bowel diseases: More questions than answers

Abstract

The gastrointestinal barrier is constantly exposed to numerous environmental substrates that are foreign and potentially harmful. These xenobiotics can cause shifts in the intestinal microbiota composition, affect mucosal immune responses, disturb tissue integrity and impair regeneration. The multidrug transporter ABCB1/MDR1 p-glycoprotein (p-gp) plays a key role at the front line of host defence by efficiently protecting the gastrointestinal barrier from xenobiotic accumulation. This Editorial discusses how altered expression and function of ABCB1/MDR1 p-gp may contribute to the development and persistence of chronic intestinal inflammation in inflammatory bowel diseases (IBD). Recent evidence implies multiple interactions between intestinal microbiota, innate immunity and xenobiotic metabolism via p-gp. While decreased efflux activity may promote disease susceptibility and drug toxicity, increased efflux activity may confer resistance to therapeutic drugs in IBD. Mice deficient in MDR1A develop spontaneously chronic colitis, providing a highly valuable murine IBD model for the study of intestinal epithelial barrier function, immunoregulation, infectious co-triggers and novel therapeutic approaches. Possible associations of human ABCB1 gene polymorphisms with IBD susceptibility have been evaluated, but results are inconsistent. Future studies must focus on further elucidation of the pathophysiological relevance and immunological functions of p-gp and how its ambiguous effects could be therapeutically targeted in IBD.

Getting Drugs Across Biological Barriers

“…[239] However, the commonly used inhibitors, such as verapamil, dexverapamil, dexniguldipin, and tariquidar, have not been successful in clinical trials due to severe side effects observed in cancer patients (such as acute congestive heart failure, nausea, vomiting, and depression in the case of dexverapamil, dexniguldipin, and tariquidar) and/or lack of beneficial effect (verapamil). [239, 263] …”

CYP3A5 Genotype as a Potential Pharmacodynamic Biomarker for Tacrolimus Therapy in Ulcerative Colitis in Japanese Patients

“…P-glycoprotein, a gene product of ABCB1 (or other name is MDR1) is expressed in several organs including the liver and kidney and plays a role in pumping out drugs and exogenous compounds from the cells [ 25 ]. Therefore, a decrease in Pgp is considered as to be not only responsible for altering the pharmacokinetics of tacrolimus, but is also attributed to the worsening of the disease condition of UC [ 26 , 27 ]. Based on these backgrounds, the relationship between the degree of inflammation and ABCB1 mRNA-expression level was used as a positive control for the sampling of biopsy specimens for examining the mRNA expression levels of CYP3A4 and CYP3A5 in mucosal tissues.…”

MDR1A deficiency restrains tumor growth in murine colitis-associated carcinogenesis

“…Numerous exogenous and endogenous factors may modulate ABCB1/MDR1 p-gp expression and function, including oxidative or inflammatory stress, microbial or dietary antigens, environmental or drug components as well as innate or adaptive immune responses [9]. Several lines of evidence suggest a potential role of ABCB1/MDR1 in both intestinal inflammation and tumorigenesis in the gastrointestinal tract.…”