Functional Comparison of Human Colonic Carcinoma Cell Lines and Primary Small Intestinal Epithelial Cells for Investigations of Intestinal Drug Permeability and First-Pass Metabolism
Open accessAbstract
To further the development of a model for simultaneously assessing intestinal absorption and first-pass metabolism in vitro, Caco-2, LS180, T84, and fetal human small intestinal epithelial cells (fSIECs) were cultured on permeable inserts, and the integrity of cell monolayers, CYP3A4 activity, and the inducibility of enzymes and transporters involved in intestinal drug disposition were measured. Caco-2, T84, and fSIECs all formed tight junctions, as assessed by immunofluorescence microscopy for zonula occludens-1, which was well organized into circumscribing strands in T84, Caco-2, and fSIECs but was diffuse in LS180 cells. The transepithelial electrical resistance value for LS180 monolayers was lower than that for Caco-2, T84, and fSIECs. In addition, the apical-to-basolateral permeability of the paracellular marker Lucifer yellow across LS180 monolayers was greater than in fSIECs, T84, and Caco-2 monolayers. The transcellular marker propranolol exhibited similar permeability across all cells. With regard to metabolic capacity, T84 and LS180 cells showed comparable basal midazolam hydroxylation activity and was inducible by rifampin and 1α,25(OH)2D3 in LS180 cells, but only marginally so in T84 cells. The basal CYP3A4 activity of fSIECs and Caco-2 cells was much lower and not inducible. Interestingly, some of the drug transporters expressed in LS180 and Caco-2 cells were induced by either 1α,25(OH)2D3 or rifampin or both, but effects were limited in the other two cell lines. These results suggest that none of the cell lines tested fully replicated the drug disposition properties of the small intestine and that the search for an ideal screening tool must continue.
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Immortalized colon cancer cell lines have demonstrated limited clinical translatability.
“It is therefore not clear if these models accurately reflect normal expression, function, and regulation of intestinal epithelial cell transporters, but so far, immortalized colon cancer cells lines have demonstrated limited clinical translatability [41,42].”
From Regulation of Enterocyte Brush Border Membrane Primary Na-Absorptive Transporters in Human Intestinal Organoid-Derived Monolayers (2024) · cites this paper as [42]
The Discussion reports that LS180 and Caco-2 cells are poorly suited to assessing intestinal permeability and first-pass CYP3A4 metabolism simultaneously, and the Abstract says none of the tested cell lines fully replicated small-intestinal drug-disposition properties. That supports limitations of these models, but not a general finding of limited clinical translatability: the paper does not test clinical predictive performance, and its Introduction says Caco-2 permeability correlates well with drug absorption in humans. (LLM, conf=0.85)
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Haynes, J., Palaniappan, B., Crutchley, J. M., & Sundaram, U. (2024) · Cells · doi:10.3390/cells13191623 · Cited by 2 · see citing works
“It is therefore not clear if these models accurately reflect normal expression, function, and regulation of intestinal epithelial cell transporters, but so far, immortalized colon cancer cells lines have demonstrated limited clinical translatability [41,42].”
Background
- Authors
- Yamaura, Y., Chapron, B. D., Wang, Z., Himmelfarb, J., & Thummel, K. E.
- Affiliations
- University of Washington (US)
- ORCID
- Himmelfarb, Jonathan
- Venue
- Drug Metabolism and Disposition
- Publisher
- Elsevier BV
- Published
- 2016-03
- Volume
- 44
- Issue
- 3
- Pages
- 329-335
- ISSN
- 0090-9556 (ISSN-L)
- PMC
- PMC4767385
- OpenAlex
- W2271612480
- Cited by
- 55
- References
- 0
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 2 · 2023: 5 · 2022: 7 · 2021: 7 · 2020: 12 · 2019: 10 · 2018: 5 · 2017: 1 · 2016: 1
- FWCI
- 1.02
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Drug Metabolism and Disposition (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (TL1TR000422, UH2TR000504, UH3TR000504, TL1TR002318)
- National Institute of General Medical Sciences (R01GM063666)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Drug Solubulity and Delivery Systems
- Keywords
- first-pass metabolism, Caco-2 cells, LS180 cells, T84 cells, CYP3A4, tight junctions, zonula occludens-1, transepithelial electrical resistance, paracellular permeability, drug transporters, enzyme induction, 1,25-dihydroxyvitamin D3, rifampicin, midazolam hydroxylation
- MeSH terms
- Biological Transport, Calcitriol, Carcinoma, Cell Membrane Permeability, Colonic Neoplasms, Pharmaceutical Preparations, Epithelial Cells, Humans, Intestinal Absorption, Intestine, Small, Rifampin, Caco-2 Cells, Cell Line, Tumor, Cytochrome P-450 CYP3A
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