Genome-wide assessment of the carriers involved in the cellular uptake of drugs: a model system in yeast.
BACKGROUND
The uptake of drugs into cells has traditionally been considered to be predominantly via passive diffusion through the bilayer portion of the cell membrane. The recent recognition that drug uptake is mostly carrier-mediated raises the question of which drugs use which carriers.


RESULTS
To answer this, we have constructed a chemical genomics platform built upon the yeast gene deletion collection, using competition experiments in batch fermenters and robotic automation of cytotoxicity screens, including protection by 'natural' substrates. Using these, we tested 26 different drugs and identified the carriers required for 18 of the drugs to gain entry into yeast cells.


CONCLUSIONS
As well as providing a useful platform technology, these results further substantiate the notion that the cellular uptake of pharmaceutical drugs normally occurs via carrier-mediated transport and indicates that establishing the identity and tissue distribution of such carriers should be a major consideration in the design of safe and effective drugs.
School of Chemistry, University of Manchester, Manchester, UK.
Karin
K
Lanthaler
Elizabeth
E
Bilsland
Paul D
PD
Dobson
Harry J
HJ
Moss
Pınar
P
Pir
Douglas B
DB
Kell
Stephen G
SG
Oliver
D001692:Biological Transport; D002172:Canavanine / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism*; D002463:Cell Membrane Permeability; D004353:Drug Evaluation, Preclinical; D017353:Gene Deletion; D055106:Genome-Wide Association Study; D023281:Genomics / Q000379:methods*; D006801:Humans; D026901:Membrane Transport Proteins / Q000378:metabolism; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D012441:Saccharomyces cerevisiae / Q000235:genetics* / Q000378:metabolism*
D026901:Membrane Transport Proteins; D004364:Pharmaceutical Preparations; D002172:Canavanine