RT Journal Article
SR Electronic
T1 Correlation of Gene Expression of Ten Drug Efflux Proteins of the ATP-Binding Cassette Transporter Family in Normal Human Jejunum and in Human Intestinal Epithelial Caco-2 Cell Monolayers
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 164
OP 170
VO 299
IS 1
A1 Jan Taipalensuu
A1 Hans Törnblom
A1 Greger Lindberg
A1 Curt Einarsson
A1 Folke Sjöqvist
A1 Håkan Melhus
A1 Per Garberg
A1 Brita Sjöström
A1 Bo Lundgren
A1 Per Artursson
YR 2001
UL http://jpet.aspetjournals.org/content/299/1/164.abstract
AB This investigation describes the expression and interindividual variability in transcript levels of multiple drug efflux systems in the human jejunum and compares the expression profiles in these cells with that of the commonly used Caco-2 cell drug absorption model. Transcript levels of ten-drug efflux proteins of the ATP-binding cassette (ABC) transporter family [MDR1, MDR3, ABCB5, MRP1–6, and breast cancer resistance protein (BCRP)], lung resistance-related protein (LRP), and CYP3A4 were determined using quantitative polymerase chain reaction in jejunal biopsies from 13 healthy human subjects and in Caco-2 cells. All genes except ABCB5 were expressed, and transcript levels varied between individuals only by a factor of 2 to 3. Surprisingly, BCRP and MRP2transcripts were more abundant in jejunum than MDR1transcripts. Jejunal transcript levels of the different ABC transporters spanned a range of three log units with the rank order: BCRP ≈ MRP2 > MDR1 ≈ MRP3 ≈ MRP6 ≈ MRP5 ≈ MRP1 > MRP4 > MDR3. Furthermore, transcript levels of 9 of 10 ABC transporters correlated well between jejunum and Caco-2 cells (r2 = 0.90). However,BCRP exhibited a 100-fold lower transcript level in Caco-2 cells compared with jejunum. Thus, the expression of a number of efflux protein transcripts in jejunum are equal to, or even higher than, that of MDR1, suggesting that the roles of these proteins (in particular BCRP and MRP2) in intestinal drug efflux have been underestimated. Also, we tentatively conclude that the Caco-2 cell line is a useful model of jejunal drug efflux, if the low expression of BCRP is taken into account. The American Society for Pharmacology and Experimental Therapeutics