Ubiquitin-Mediated Proteasomal Degradation of ABC Transporters: a New Aspect of Genetic Polymorphisms and Clinical Impacts

• Published in: Journal of pharmaceutical sciences 2011-09, Vol.100 (9), p.3602-3619
• Main Authors: Nakagawa, Hiroshi, Toyoda, Y.u., Wakabayashi-Nakao, Kanako, Tamaki, Hideaki, Osumi, Masako, Ishikawa, Toshihisa
• Format: Article
• Language: English
• Subjects: ABC tramsporters; ABC transporter; Animals; ATP-Binding Cassette Transporters - genetics; ATP-Binding Cassette Transporters - metabolism; Biological and medical sciences; Conductance; Cystic fibrosis; Disposition; Disulfide bonds; Drug metabolism; Drugs; Endoplasmic reticulum; Endoplasmic Reticulum - metabolism; Enzymes; Gene polymorphism; General pharmacology; genetic polymorphism; Glycosylation; Heredity; Hydrolysis; Medical sciences; multidrug resistance-associated proteins; multidrug sesistance transporters; Pharmaceutical technology. Pharmaceutical industry; pharmacogenomics; Pharmacology. Drug treatments; Polymorphism, Genetic; Proteasome Endopeptidase Complex - metabolism; proteasomes; protein folding/refolding; Protein transport; Quality control; Reviews; single nucleotide polymophism (SNP); Single-nucleotide polymorphism; Thiopurine S-methyltransferase; Ubiquitin - physiology
• ISSN: 0022-3549; 1520-6017; 1520-6017
• DOI: 10.1002/jps.22615

The interindividual variation in the rate of drug metabolism and disposition has been known for many years. Pharmacogenomics dealing with heredity and response to drugs is a part of science that attempts to explain variability of drug responses and to search for the genetic basis of such variations or differences. Genetic polymorphisms of drug metabolizing enzymes and drug transporters have been found to play a significant role in the patients' responses to medication. Accumulating evidence demonstrates that certain nonsynonymous polymorphisms have great impacts on the protein stability and degradation, as well as the function of drug metabolizing enzymes and transporters. The aim of this review article is to address a new aspect of protein quality control in the endoplasmic reticulum and to present examples regarding the impact of nonsynonymous single-nucleotide polymorphisms on the protein stability of thiopurine S-methyltransferase as well as ATP-binding cassette (ABC) transporters including ABCC4, cystic fibrosis transmembrane conductance regulator (CFTR, ABCC7), ABCC11, and ABCG2. Furthermore, we will discuss the molecular mechanisms underlying posttranslational modifications (intramolecular and intermolecular disulfide bond formation and N-linked glycosylation) and ubiquitin-mediated proteasomal degradation of ABCG2, one of the major drug transporter proteins in humans. © 2011 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 100:3602–3619, 2011