Regional Distribution of Solute Carrier mRNA Expression Along the Human Intestinal Tract

Abstract

ABSTRACT:Intestinal absorption of drugs, nutrients, and other compounds is mediated by uptake transporters expressed at the apical enterocyte membrane. These compounds are returned to the intestinal lumen or released into portal circulation by intestinal efflux transporters expressed at apical or basolateral membranes, respectively. One important transporter superfamily, multiple members of which are intestinally expressed, are the solute carriers (SLCs). SLC expression levels may determine the pharmacokinetics of drugs that are substrates of these transporters. In this study we characterize the distribution of 15 human SLC transporter mRNAs in histologically normal biopsies from five regions of the intestine of 10 patients. The mRNA expression levels of CNT1, CNT2, apical sodium-dependent bile acid transporter (ABST), serotonin transporter (SERT), PEPT1, and OCTN2 exhibit marked differences between different regions of the intestine: the first five are predominantly expressed in the small intestine, whereas OCTN2 exhibits strongest expression in the colon. Two transporter mRNAs studied (OCTN1, OATP2B1) are expressed at similar levels in all gut sections. In addition, ENT2 mRNA is present at low levels across the colon, but not in the small intestine. The other six SLC mRNAs studied are not expressed in the intestine. Quantitative knowledge of transporter expression levels in different regions of the human gastrointestinal tract could be useful for designing intestinal delivery strategies for orally administered drugs. Furthermore, changes in transporter expression that occur in pathological states, such as inflammatory bowel disease, can now be defined more precisely by comparison with the expression levels measured in healthy individuals.

Intestinal transporters for endogenic and pharmaceutical organic anions: the challenges of deriving in-vitro kinetic parameters for the prediction of clinically relevant drug–drug interactions

“…[19] However, several other reports indicate that OATP1A2 is not expressed at mRNA levels in the intestine. [12,14,35] Instead the interaction with grapefruit juice for fexofenadine could have been due to an interaction with OATP2B1. Failure of initially identifying fexofenadine (and possibly other substances) as a substrate for OATP2B1 may be explained by the pH-dependence of this transporter.…”

“…The intestinal expression of the absorptive transporter OATP1A2 is less evident. Two scientific papers have suggested that OATP1A2 is expressed at mRNA levels in the small intestine, and this transporter has also been [12,13] Jejunum > colon [14] Ileum [15] Ileum > duodenum [13] BCRP ABCG2 Ex Ileum > duodenum, colon [16] Duodenum > ileum > colon [17] Jejunum > colon [14,18] Duodenum [19] Jejunum [20] Small intestine [21] Duodenum = ileum = colon [22] Small intestine and colon [23] MCT1 SLC16A1 Ab Colon > duodenum > ileum [16] Colon > duodenum [24] Colon > jejunum [18] Colon > ileum [25] Jejunum = colon [15] Small intestine [21,26] Colon > ileum > jejunum [24] Colon [25] MCT3 SLC16A8 N.R. N.R.…”

“…However, it is generally accepted that the absorptive transporters ASBT, MRP3, MCT1, OATP2B1 and OSTa/b have moderate to high intestinal expression levels. [12,[14][15][16]18,20,21,29,32,33,36,39,40] The three known intestinal exsorptive transporters for organic anions (BCRP, MRP2 and OSTa/b) all have relatively high expression levels -especially BCRP has a high intestinal expression compared with other tissues. [14,16,18,20,21,23,39] A high transporter expression level is likely indicative of an important role in the absorption or elimination of endogenous and exogenous substances.…”

“…Jejunum, ileum > duodenum [28] Jejunum [20] Small intestine [21,34] Colon [34] Small intestine and colon [34] OATP1A2 (OATP-A) SLCO1A2 Ab Duodenum [19] Small intestine [21] NOT in duodenum, ileum or colon [12] NOT in jejunum or colon [14] NOT in small intestine [35] Duodenum [19] OATP2B1 (OATP-B) SLCO2B1 Ab Duodenum = ileum = colon [12,16] Jejunum = colon [14] Jejunum > colon [18] Duodenum [19] Jejunum [36] Small intestine [21,35] Small intestine [37] OATP3A1_v1 (OATP-D) SLCO3A1 N.R. Jejunum [14] Small intestine and colon [35,36] NOT in colon [14] N.R.…”

Functional expression of carnitine/organic cation transporter OCTN1 in mouse brain neurons: Possible involvement in neuronal differentiation

“…Carnitine/organic cation transporter OCTN1/SLC22A4, classified as a xenobiotic transporter, is ubiquitously expressed in the body, and transports various therapeutic agents including organic cations and zwitterions (Tamai et al, 1997;Meier et al, 2007;Taubert et al, 2009). However, OCTN1 has mainly been characterized in vitro, and little is known about its function in vivo.…”