Advances in Studies of P-Glycoprotein and Its Expression Regulators

• Published in: Biological & pharmaceutical bulletin 2018/01/01, Vol.41(1), pp.11-19
• Main Authors: Yano, Kentaro, Tomono, Takumi, Ogihara, Takuo
• Format: Article
• Language: English
• Subjects: Animals; ATP-Binding Cassette, Sub-Family B, Member 1 - genetics; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism; bimodal change; Blood-Brain Barrier - metabolism; Brain; brain distribution; Cell Membrane - metabolism; Cilnidipine; Drug-Related Side Effects and Adverse Reactions - metabolism; Epithelial-Mesenchymal Transition - genetics; Epithelial-Mesenchymal Transition - physiology; epithelial-to-mesenchymal transition; Ezrin; ezrin, radixin and moesin (ERM) protein; Gene expression; Gene Expression Regulation; Glycoproteins; Humans; Intestine, Small - metabolism; Ischemia; Localization; membrane localization; Mesenchyme; Moesin; mRNA; Neuroprotection; Oral administration; Oseltamivir; P-Glycoprotein; Pharmaceutical Preparations - blood; Post-translation; Protein Processing, Post-Translational - genetics; Protein Processing, Post-Translational - physiology; Proteins; Radixin; Side effects; Small intestine; Substrate Specificity; Tissues
• ISSN: 0918-6158; 1347-5215
• DOI: 10.1248/bpb.b17-00725

This review deals with recent advances in studies on P-glycoprotein (P-gp) and its expression regulators, focusing especially on our own research. Firstly, we describe findings demonstrating that the distribution of P-gp along the small intestine is heterogeneous, which explains why orally administered P-gp substrate drugs often show bimodal changes of plasma concentration. Secondly, we discuss the post-translational regulation of P-gp localization and function by the scaffold proteins ezrin, radixin and moesin (ERM proteins), together with recent reports indicating that tissue-specific differences in regulation by ERM proteins in normal tissues might be retained in corresponding cancerous tissues. Thirdly, we review evidence that P-gp activity is enhanced in the process of epithelial-to-mesenchymal transition (EMT), which is associated with cancer progression, without any increase in expression of P-gp mRNA. Finally, we describe two examples in which P-gp critically influences the brain distribution of drugs, i.e., oseltamivir, where low levels of P-gp associated with early development allow oseltamivir to enter the brain, potentially resulting in neuropsychiatric side effects in children, and cilnidipine, where impairment of P-gp function in ischemia allows cilnidipine to enter the ischemic brain, where it exerts a neuroprotective action.