High-speed screening of human ATP-binding cassette transporter function and genetic polymorphisms: new strategies in pharmacogenomics.
Drug transporters represent an important mechanism in cellular uptake and efflux of drugs and their metabolites. Hitherto a variety of drug transporter genes have been cloned and classified into either solute carriers or ATP-binding cassette (ABC) transporters. Such drug transporters are expressed in various tissues such as the intestine, brain, liver, kidney, and, importantly, cancer cells, where they play critical roles in the absorption, distribution, and excretion of drugs. We developed high-speed functional screening and quantitative structure-activity relationship analysis methods to study the substrate specificity of ABC transporters and to evaluate the effect of genetic polymorphisms on their function. These methods would provide powerful and practical tools for screening synthetic and natural compounds, and the deduced data can be applied to the molecular design of new drugs. Furthermore, we demonstrate a new "SNP array" method to detect genetic polymorphisms of ABC transporters in human samples.
Ishikawa
Toshihisa
T
Department of Biomolecular Engineering, Tokyo Institute of Technology, Graduate School of Bioscience and Biotechnology, Midoriku, Yokohama, Japan.
Sakurai
Aki
A
Kanamori
Yoichi
Y
Nagakura
Makoto
M
Hirano
Hiroyuki
H
Takarada
Yutaka
Y
Yamada
Kazunari
K
Fukushima
Kazuhisa
K
Kitajima
Masato
M
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D002623:Chemistry Techniques, Analytical / Q000379:methods*; D022162:Cytoplasmic Vesicles / Q000737:chemistry; D015195:Drug Design; D005822:Genetic Vectors; D006801:Humans; D008958:Models, Molecular; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D010597:Pharmacogenetics / Q000379:methods*; D011110:Polymorphism, Genetic; D021281:Quantitative Structure-Activity Relationship; D013379:Substrate Specificity; D014162:Transfection
C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D009363:Neoplasm Proteins