Protein Abundance of Clinically Relevant Multidrug Transporters along the Entire Length of the Human Intestine

Abstract

Intestinal transporters are crucial determinants in the oral absorption of many drugs. We therefore studied the mRNA expression (N = 33) and absolute protein content (N = 10) of clinically relevant transporters in healthy epithelium of the duodenum, the proximal and distal jejunum and ileum, and the ascending, transversal, descending, and sigmoidal colon of six organ donors (24-54 years). In the small intestine, the abundance of nearly all studied proteins ranged between 0.2 and 1.6 pmol/mg with the exception of those of OCT3 (<0.1 pmol/mg) and PEPT1 (2.6-4.9 pmol/mg) that accounted for ∼50% of all measured transporters. OATP1A2 was not detected in any intestinal segment. ABCB1, ABCG2, PEPT1, and ASBT were significantly more abundant in jejunum and ileum than in colon. In contrast to this, the level of expression of ABCC2, ABCC3, and OCT3 was found to be highest in colon. Site-dependent differences in the levels of gene and protein expression were observed for ABCB1 and ASBT. Significant correlations between mRNA and protein levels have been found for ABCG2, ASBT, OCT3, and PEPT1 in the small intestine. Our data provide further physiological pieces of the puzzle required to predict intestinal drug absorption in humans.

Mass Spectrometry-Based Targeted Proteomics as a Tool to Elucidate the Expression and Function of Intestinal Drug Transporters

“…Interestingly, in ileum the expression of ABCB1, ABCC2 and PEPT1 was considerably higher. Although these conclusions are in this case based on protein expression data from only four samples from jejunum and ileum, similar findings have been observed in our more comprehensive expression study using in each case ten samples from the entire intestinal tract from eight donors (90). A similar increase in ABCB1 protein expression from jejunum to ileum was also reported by Mouly et al (27).…”

“…This again demonstrates the limitation of mRNA expression data alone. In line with this assumption, we were only able to identify substantial correlations between mRNA and protein for ABCB1 and PEPT1 in our recent expression study (90).…”

“…We applied our recently developed and validated method to quantify the expression of clinically relevant intestinal uptake and efflux transporters (ABCB1, ABCC2, ABCC3, ABCG2, ASBT, OATP1A2, OATP2B1, OCT1, OCT3 and PEPT1) along the entire human intestine from eight body donors (90).…”

Multidrug Resistance-Associated Protein 3 Plays an Important Role in Protection against Acute Toxicity of Diclofenac

“…Glucuronide conjugates can be transported by organic anion transporting polypeptides (OATPs) of which OATP2B1 is the predominant isoform in the human intestine (Ishiguro et al, 2008;Drozdzik et al, 2014). It is likely through the mouse Oatp2b1 ortholog, which is also expressed in the intestines, that DCF-AG uptake occurs (Cheng et al, 2005).…”

Role of (Drug) Transporters in Imaging in Health and Disease

“…Besides quantification of transporters expressed in human livers, we are quantifying the expression of relevant drug transporters in human kidneys, brain, placenta, pediatric livers, and, in collaboration with Dr. Stefan Oswald and others at University of Greifswald, intestines (Drozdzik et al, 2014).…”