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Evidence for Diminished Functional Expression of Intestinal Transporters in Caco-2 Cell Monolayers at High Passages
Abstract
Purpose To investigate the effects of passaging on the intrinsic membrane transport parameters of compounds absorbed by means of passive and carrier-mediated processes in the Caco-2 cell line.Methods Caco-2 cells at low (28-36) and high (93-108) passage numbers were used to evaluate the transport characteristics of model compounds for paracellular diffusion (mannitol), transcellular diffusion (progesterone) and carrier-mediated transport (cephalexin, cephradine, phenylalanine, proline, and taurocholic acid) using side-by-side diffusion chambers. Intrinsic intestinal transport parameters were determined by correcting the effective permeability for potential biases introduced by the microporous filter and aqueous boundary layer. Intrinsic maximal flux (Jmax), Michaelis constant (K(m)) and carrier permeability (Pc) were determined as a function of passage number.Results Compared to the low passaged cells, the high passaged Caco-2 cells were characterized by less morphological heterogeneity, higher transepithelial electrical resistance, higher transcellular diffusion, lower paracellular diffusion, lower carrier-mediated transport and lower alkaline phosphatase activity. The use of effective transport parameters overestimated the K(m) and underestimated Pc but had no effect on Jmax.Conclusions The current results provide experimental evidence that the passaging process significantly affects the biological characteristics and transport properties of Caco-2 cell monolayers. The effects are consistent with a reduction in the functional expression of a brush border enzyme and several transport proteins as passage number is increased. The underlying basis for this appears to be a selection of fast-growing subpopulations from the original heterogeneous Caco-2 cell line during passaging.
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“However, cell lines can undergo many changes as a result of short or prolonged cultivation including increased genetic and phenotypic instability, which may alter cell morphology and gene expression, chromosomal duplication and rearrangements, potential mutations in genomic and mitochondrial DNA, and epigenetic modifications. 3 , 4”
From Cell line authentication and validation is a key requirement for Journal of Cell Communication and Signaling publications (2025) · cites this paper as [3]
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“As a result, there has been a growing emphasis on validating the authenticity and integrity of both experimental and established cell lines prior to publication.”
From Cell line authentication and validation is a key requirement for Journal of Cell Communication and Signaling publications (2025) · cites this paper as [3]
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Cites
Freshney, R. I. (2005) · Wiley eBooks · doi:10.1002/9780470649367 · Cited by 3,904
Artursson, P., & Karlsson, J. E. (1991) · Biochemical and Biophysical Research Communications · doi:10.1016/0006-291x(91)91647-u · Cited by 1,928
Pinto, M. (1983) · HAL · Cited by 1,752
Garen, A., & Levinthal, C. (1960) · Biochimica et Biophysica Acta · doi:10.1016/0006-3002(60)91282-8 · Cited by 1,401
Effects of unstirred layers on membrane phenomena.
Barry, P. H., & Diamond, J. M. (1984) · Physiological Reviews · doi:10.1152/physrev.1984.64.3.763 · Cited by 471
Culture of Animal Cells. A manual for basic techniques
Stampfer, M. R., & Taylor‐Papadimitriou, J. (2000) · Cited by 328
The Use of Cultured Epithelial and Endothelial Cells for Drug Transport and Metabolism Studies
Audus, K. L., Bartel, R. L., Hidalgo, I. J., & BORCHARDT, R. T. (1990) · Pharmaceutical Research · doi:10.1023/a:1015800312910 · Cited by 267
Wilson, G., Hassan, I. F., DIX, C. J., Williamson, I., Shah, R. B., Mackay, M. W., & Artursson, P. (1990) · Journal of Controlled Release · doi:10.1016/0168-3659(90)90118-d · Cited by 242
Cell cultures as models for drug absorption across the intestinal mucosa.
Artursson, P. (1991) · PubMed · Cited by 232
Eastwood, M., Porter, R. A., Khan, U., McGrouther, G., & Brown, R. A. (1996) · Journal of Cellular Physiology · doi:10.1002/(sici)1097-4652(199601)166:1 · Cited by 194
Flagged first, then by citations
1 of the 26 references couldn’t be matched to a known paper.
Research works printed but not linked: 7
- P. Artursson. Critical Rev. Ther. Drug Carrier Sys. 8:305–330 (1991).
- A. Zweibaum, M. Laburthe, E. Grasset, and D. Louvard. In M. Field and R. A. Frizzell (eds.), Intestinal Absorption and Secretion, Handbook of Physiology, Vol. IV, Sect. 6, Am. Physiol. Soc., Bethesda, 1991, pp. 223–255.
- M. Pinto, S. Robine-Leon, M.-D. Appay, M. Kedinger, N. Triadou, E. Dussaulx, B. Lacroix, P. Simon-assmann, K. Haffen, J. Fogh, and A. Zweibaum. Biol. Cell 47:323–330 (1983).
- C. E. Chandler, L. M. Zaccaro, and J. B. Moberly. Am. J. Physiol. 264:G1118–1125 (1993).
- A. B. R. Thompson and J. M. Dietschy. In T. Z. Csáky (ed.), Pharmacology of Intestinal Permeation II. Handbook of Experimental Pharmacology, Springer-Verlag, Berlin Heidelberg, 1984, Vol. 70/II, pp. 165–269.
- A. Zweibaum. In F. Alvarado and C. H. Van Os (eds.), Ion Gradient-Coupled Transport. Elsevier Sci. Publishers, Amsterdam, 1986, pp. 345–353.
- L. Mahraoui, M. Rousset, E. Dussaulx, D. Darmoul, A. Zweibaum, and E. Brot-Laroche. Am. J. Physiol. 263:G312–318 (1992).
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“High-passage (n 5 108) human epithelial colorectal adenocarcinoma (Caco 2) cells have reduced differentiation compared with the low-passage (n 5 28–36) cells reflected as uniform cell morphology and function (Yu et al. 1997).”
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“46 Using capillary electrophoresis, the quality of RNA samples was verified through the RNA integrity number (RIN) and the 18S/28S rRNA ratio.”
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Pang, S., Ahsan, E. S., & Foy, C. A. (2010) · Journal of Immunological Methods · doi:10.1016/j.jim.2010.07.010 · Cited by 1
“Variability is also introduced due to cell passage (Yu et al., 1997) and scale-up (Hu and Aunins, 1997).”
BackgroundRole of SNARE Proteins in the Insertion of KCa3.1 in the Plasma Membrane of a Polarized Epithelium
Farquhar, R., Cheung, T. T., Logue, M. J. E., McDonald, F. J., Devor, D. C., & Hamilton, K. L. (2022) · Frontiers in Physiology · doi:10.3389/fphys.2022.905834 · Cited by 1
Harwood, M. D. (2015) · Research Explorer (The University of Manchester) · Cited by 1
Carl, S. M., Herrera‐Ruiz, D., Bhardwaj, R. K., Gudmundsson, O. S., & Knipp, G. T. (2014) · doi:10.1002/9781118705308.ch5 · Cited by 1
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Dzeyk, J. (2012) · Otago University Research Archive (University of Otago)
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Synergistic interactions of targeted therapy within signal transduction pathways
Glaysher, S. L. (2012) · UPT. Syiah Kuala University Library (Syiah Kuala University)
Pastor, D. M., Poritz, L. S., Olson, T. L., Kline, C. L. B., Harris, L., Chinchilli, V. M., & Irby, R. (2010)
Richards, S. L., Anderson, S. L., & Yost, S. A. (2010)
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Thairu, N. (2013) · doi:10.25560/14361
Sanjuan, V. M. (2014) · Repository of Digital Objects for Teaching Research and Culture (University of Valencia)
Thani, A., & Thani, N. A. A. (2016) · Middlesex University Research Repository (Middlesex University Of London)
Li, Q., Yoshimura, H., & Ozawa, T. (2021) · Methods in molecular biology · doi:10.1007/978-1-0716-1258-3_8
Peregrin, K. (2011) · UPT. Syiah Kuala University Library (Syiah Kuala University)
MAMMALIAN OLIGOPEPTIDE TRANSPORTERS
Carl, S. M., Herrera‐Ruiz, D., Bhardwaj, R., Gudmundsson, O. S., Mowery, S. A., & Knipp, G. T. (2022) · doi:10.1002/9781119739883.ch6
Davis, J. M. (2021) · Royal Society of Chemistry eBooks · doi:10.1039/9781788017862-00258
In situ quantification of ribosome number by electron tomographyPreprint
Hankouri, M. E., Nousch, M., Müller‐Reichert, T., & Fabig, G. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.09.27.614074
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Barros, G. M. D. O., Bagri, K. M., Mermelstein, C., & Quintas, L. E. M. (2025) · Cell Biology International · doi:10.1002/cbin.70091
Galkin, A. (2008) · Työväentutkimus Vuosikirja
Dibao-Dina, A. (2015) · doi:10.70675/4a440a09z402az42b0za4afzd686d3aadbf2
“Caco-2 Cellules issues d’un adénocarcinome colorectal humain CE / WE Contre-électrode ("Counter Electrode") / Electrode de travail ("Working Electrode") CO2 dioxyde de carbone CPE Elément à Phase Constante ("Constant Phase Element") DAPI 4’,6’-diamidino-2-phenylindole DEP Diélectrophorèse ("Dielectrophoresis") DIC (mi…”
BackgroundInfluentialIn vitro alternatives to animal models for the assessment of nanoparticle respiratory toxicity
McAllister, K., Brooks, S., Clift, M. J. D., & Murphy, F. (2026) · Nanomedicine · doi:10.1080/17435889.2026.2698783
Cady, N. M., Meyer, S. R., Kim, K., Lo, B. C., So, N., Chen, G., Rosshart, S. P., Shah, Y. M., Núñez, G., Sexton, J. Z., et al. (2026) · mSphere · doi:10.1128/msphere.00926-25
“To avoid inconsistencies between experiments due to cell senescence (25, 37, 38), we used a primary human organoid-derived cell line that was passaged in a narrow, predefined range (16–20 total passages).”
Janiga-MacNelly, A., & Lavado, R. (2026) · BioMed Research International · doi:10.1155/bmri/4933959
Arora, D. (2008) · VCU Scholars Compass (Virginia Commonwealth University) · doi:10.25772/aj4e-9507
“Such passage effects have also been reported for the human intestinal Caco-2 cell line [Yu et al, 1997].”
Enteroendocrine peptides in intestinal inflammation
Moran, G. W. (2011) · OpenGrey (Institut de l'Information Scientifique et Technique)
Metadata
- Authors
- Yu, H., Cook, T. J., & Sinko, P. J.
- Affiliations
- Rutgers, The State University of New Jersey (US)
- Corresponding author
- Sinko, Patrick J.
- ORCID
- Sinko, Patrick J.
- Venue
- Pharmaceutical Research
- Published
- 1997-06
- Volume
- 14
- Issue
- 6
- Pages
- 757-762
- ISSN
- 0724-8741 (ISSN-L)
- 1573-904X
- OpenAlex
- W294850324
- Cited by
- 133
- References
- 26
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 5 · 2023: 3 · 2022: 9 · 2021: 8 · 2020: 2 · 2019: 3 · 2018: 4 · 2017: 2 · 2016: 3 · 2015: 5 · 2014: 7 · 2013: 6 · 2012: 6
- FWCI
- 1.21
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Pharmaceutical Research (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Drug Solubulity and Delivery Systems
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Keywords
- Caco-2 cells, cell passage number, intestinal transporters, paracellular diffusion, carrier-mediated transport, effective permeability, Michaelis constant, alkaline phosphatase, brush border enzymes, transepithelial electrical resistance, mannitol, progesterone, cephradine, taurocholate
- MeSH terms
- Alkaline Phosphatase, Biological Transport, Carrier Proteins, Cell Count, Cell Membrane Permeability, Diffusion, Epithelium, Humans, Electric Impedance, Caco-2 Cells
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