Comparative gene expression profiles of ABC transporters in brain microvessel endothelial cells and brain in five species including human.
While P-glycoprotein (PGP, ABCB1) is known to play an important role in drug exclusion at the blood brain barrier (BBB), less is known about the contribution of other members in the ATP-binding cassette (ABC) transporter family to BBB drug efflux, or whether these transporters are expressed differently in humans and in mammalian species of pharmacological interest. We used quantitative real-time PCR to determine mRNA expression levels for the majority of ABC family members in brain and in isolated brain microvessel endothelial capillary cells (BMEC) from human, rat, mouse, pig and cow. We confirmed BBB expression of several well-characterized ABC family members that are implicated in xenobiotic exclusion from the brain, including ABCB1 (PGP), ABCG2 (BCRP), ABCC1 (MRP1), ABCC4 (MRP4), and ABCC5 (MRP5). In addition, we detected high expression and enrichment in BMEC of several less well-characterized ABC transporters in one or more species, including ABCA2-4, ABCB4, ABCB6-8, ABCB10, ABCC3, ABCC6, ABCC10, and ABCE1. We also uncovered species differences in the expression of a number of transporters, including ABCG2 and ABCC4. This study identifies several additional ABC family members that may contribute to xenobiotic efflux at the human BBB, and compares the expression of a broad array of efflux transporters between human and four other species relevant to pharmacological research.
XenoPort, Inc., 3410 Central Expressway, Santa Clara, CA 95051, USA.
Mark S
MS
Warren
Noa
N
Zerangue
Katie
K
Woodford
Lori M
LM
Roberts
Emily H
EH
Tate
Bo
B
Feng
Cheryl
C
Li
Thomas J
TJ
Feuerstein
John
J
Gibbs
Bill
B
Smith
Sonia M
SM
de Morais
William J
WJ
Dower
Kerry J
KJ
Koller
D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000098:blood supply / Q000378:metabolism*; D002417:Cattle; D042783:Endothelial Cells / Q000378:metabolism*; D020869:Gene Expression Profiling; D006801:Humans; D051379:Mice; D055806:Microvessels / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013045:Species Specificity; D013552:Swine
D018528:ATP-Binding Cassette Transporters; D012333:RNA, Messenger