Membrane transporters mediate the influx and efflux of various drugs,and play essential roles in drug absorption,distribution,metabolism and excretion（ADME）.The unique characteristics of membranes transporters poten...Membrane transporters mediate the influx and efflux of various drugs,and play essential roles in drug absorption,distribution,metabolism and excretion（ADME）.The unique characteristics of membranes transporters potentiate them as targets for developing drugs with ideal pharmacokinetics profiles,including targeted distribution,improved clinical efficacy and low adverse reaction.In this review,we summarize the tissue-specific expression,transport functions and substrates profiles of the major influx and efflux transporters,including solute carrier（SLC） superfamily and adenosine triphosphate（ATP）-binding cassette（ABC） superfamily.Moreover,we describe examples of successful drug or prodrug design based on the function of transporters that yielded drugs with excellent ADME properties.Lastly,we discuss the in vitro and in vivo methods that are broadly applied in the drug designing process to study the interactions between the drugs and the transporters.展开更多
In the present study, total membrane proteins from tumor cell lines including HepG2, Hep3 B2,H226, Ovcar3 and N87 were extracted and digested with γLys C and trypsin. The resulting peptide lysate were pre-fractionate...In the present study, total membrane proteins from tumor cell lines including HepG2, Hep3 B2,H226, Ovcar3 and N87 were extracted and digested with γLys C and trypsin. The resulting peptide lysate were pre-fractionated and subjected to untargeted quantitative proteomics analysis using a high resolution mass spectrometer. The mass spectra were processed by the Max Quant and the protein abundances were estimated using total peak area(TPA) method. A total of 6037 proteins were identified, and the analysis resulted in the identification of 2647 membrane proteins. Of those, tumor antigens and absorption,metabolism, disposition and elimination(ADME) proteins including UDP-glucuronosyltransferase,cytochrome P450, solute carriers and ATP-binding cassette transporters were detected and disclosed significant variations among the cell lines. The principal component analysis was performed for the cluster of cell lines. The results demonstrated that H226 is closely related with N87, while Hep3 B2 aligned with HepG2. The protein cluster of Ovcar3 was apart from that of other cell lines investigated. By providing for the first time quantitative untargeted proteomics analysis, the results delineated the expression profiles of membrane proteins. These findings provided a useful resource for selecting targets of choice for anticancer therapy through advancing data obtained from preclinical tumor cell line models to clinical outcomes.展开更多
基金National Science and Technology Major Project(Grant No. 2012ZX09506001-004)
文摘Membrane transporters mediate the influx and efflux of various drugs,and play essential roles in drug absorption,distribution,metabolism and excretion（ADME）.The unique characteristics of membranes transporters potentiate them as targets for developing drugs with ideal pharmacokinetics profiles,including targeted distribution,improved clinical efficacy and low adverse reaction.In this review,we summarize the tissue-specific expression,transport functions and substrates profiles of the major influx and efflux transporters,including solute carrier（SLC） superfamily and adenosine triphosphate（ATP）-binding cassette（ABC） superfamily.Moreover,we describe examples of successful drug or prodrug design based on the function of transporters that yielded drugs with excellent ADME properties.Lastly,we discuss the in vitro and in vivo methods that are broadly applied in the drug designing process to study the interactions between the drugs and the transporters.
文摘In the present study, total membrane proteins from tumor cell lines including HepG2, Hep3 B2,H226, Ovcar3 and N87 were extracted and digested with γLys C and trypsin. The resulting peptide lysate were pre-fractionated and subjected to untargeted quantitative proteomics analysis using a high resolution mass spectrometer. The mass spectra were processed by the Max Quant and the protein abundances were estimated using total peak area(TPA) method. A total of 6037 proteins were identified, and the analysis resulted in the identification of 2647 membrane proteins. Of those, tumor antigens and absorption,metabolism, disposition and elimination(ADME) proteins including UDP-glucuronosyltransferase,cytochrome P450, solute carriers and ATP-binding cassette transporters were detected and disclosed significant variations among the cell lines. The principal component analysis was performed for the cluster of cell lines. The results demonstrated that H226 is closely related with N87, while Hep3 B2 aligned with HepG2. The protein cluster of Ovcar3 was apart from that of other cell lines investigated. By providing for the first time quantitative untargeted proteomics analysis, the results delineated the expression profiles of membrane proteins. These findings provided a useful resource for selecting targets of choice for anticancer therapy through advancing data obtained from preclinical tumor cell line models to clinical outcomes.
