Regional Expression Levels of Drug Transporters and Metabolizing Enzymes along the Pig and Human Intestinal Tract and Comparison with Caco-2 Cells.
Intestinal transporter proteins and metabolizing enzymes play a crucial role in the oral absorption of a wide variety of drugs. The aim of the current study was to characterize better available intestinal in vitro models by comparing expression levels of these proteins and enzymes between porcine intestine, human intestine, and Caco-2 cells. We therefore determined the absolute protein expression of 19 drug transporters and the mRNA expression of 12 metabolic enzymes along the pig intestinal tract (duodenum, jejunum, ileum;N= 4), in human intestine (jejunum;N= 9), and Caco-2 cells. Expression of the included transporters and enzymes was in general well comparable between porcine and human intestinal tissue, although breast cancer resistance protein, monocarboxylate transporter 5, multidrug resistance protein (MRP) 1, MRP1, MRP3 (∼2-fold), and organic anion-transporting polypeptide (OATP) 4A1 (∼6-fold) was higher expressed in pig compared with human jejunum. Alternatively, expression level of relevant transporter proteins (glucose transporter 1, OATP4A1, MRP2, MRP1, and OATP2B1) was significantly higher (3- to 130-fold) in Caco-2 cells compared with human jejunum. Moreover, all examined CYPs showed at least a fivefold lower gene expression in Caco-2 cells compared with human jejunum, with the smallest differences for CYP1A1 and CYP3A5 and the largest difference for CYP3A4 (871-fold higher expression in human jejunum compared with Caco-2 cells). In conclusion, a comprehensive overview is provided of the expression levels of clinically relevant transporter proteins and metabolic enzymes in porcine and human intestinal tissue and Caco-2 cells, which may assist in deciding upon the most suitable model to further improve our understanding of processes that determine intestinal absorption of compounds.
TNO, Zeist, The Netherlands (M.M.H.L, C.A.M.K, H.M.W, E.S); Institute for Risk Assessment Sciences, Utrecht, The Netherlands (R.H.H.P, J.A.S,); Research Centre Technology & Innovation; and Innovative Testing in Life sciences and Chemistry, University of Applied Sciences, Utrecht, The Netherlands (S.F.C.V, R.H.H.P, C.A.M.K).
Stefan F C
SF
Vaessen
TNO, Zeist, The Netherlands (M.M.H.L, C.A.M.K, H.M.W, E.S); Institute for Risk Assessment Sciences, Utrecht, The Netherlands (R.H.H.P, J.A.S,); Research Centre Technology & Innovation; and Innovative Testing in Life sciences and Chemistry, University of Applied Sciences, Utrecht, The Netherlands (S.F.C.V, R.H.H.P, C.A.M.K).
Marola M H
MM
van Lipzig
TNO, Zeist, The Netherlands (M.M.H.L, C.A.M.K, H.M.W, E.S); Institute for Risk Assessment Sciences, Utrecht, The Netherlands (R.H.H.P, J.A.S,); Research Centre Technology & Innovation; and Innovative Testing in Life sciences and Chemistry, University of Applied Sciences, Utrecht, The Netherlands (S.F.C.V, R.H.H.P, C.A.M.K).
Raymond H H
RH
Pieters
TNO, Zeist, The Netherlands (M.M.H.L, C.A.M.K, H.M.W, E.S); Institute for Risk Assessment Sciences, Utrecht, The Netherlands (R.H.H.P, J.A.S,); Research Centre Technology & Innovation; and Innovative Testing in Life sciences and Chemistry, University of Applied Sciences, Utrecht, The Netherlands (S.F.C.V, R.H.H.P, C.A.M.K).
Cyrille A M
CA
Krul
TNO, Zeist, The Netherlands (M.M.H.L, C.A.M.K, H.M.W, E.S); Institute for Risk Assessment Sciences, Utrecht, The Netherlands (R.H.H.P, J.A.S,); Research Centre Technology & Innovation; and Innovative Testing in Life sciences and Chemistry, University of Applied Sciences, Utrecht, The Netherlands (S.F.C.V, R.H.H.P, C.A.M.K).
Heleen M
HM
Wortelboer
TNO, Zeist, The Netherlands (M.M.H.L, C.A.M.K, H.M.W, E.S); Institute for Risk Assessment Sciences, Utrecht, The Netherlands (R.H.H.P, J.A.S,); Research Centre Technology & Innovation; and Innovative Testing in Life sciences and Chemistry, University of Applied Sciences, Utrecht, The Netherlands (S.F.C.V, R.H.H.P, C.A.M.K) evita.vandesteeg@tno.nl.
Evita
E
van de Steeg
D000818:Animals; D018938:Caco-2 Cells; D002462:Cell Membrane / Q000378:metabolism; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism*; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D005260:Female; D014453:Glucuronosyltransferase / Q000378:metabolism; D006801:Humans; D007408:Intestinal Absorption / Q000502:physiology*; D007413:Intestinal Mucosa / Q000378:metabolism*; D008297:Male; D026901:Membrane Transport Proteins / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D034421:Sus scrofa / Q000378:metabolism; D013552:Swine
D026901:Membrane Transport Proteins; D012333:RNA, Messenger; D019363:Cytochrome P-450 CYP1A1; D051544:Cytochrome P-450 CYP3A; D014453:Glucuronosyltransferase