The human intestinal epithelial cell line Caco-2; pharmacological and pharmacokinetic applications

Meunier, Viviane; Bourrié, Martine; Berger, Yves; Fabre, Gérard

doi:10.1007/bf00756522

Cited by 356 publications

(243 citation statements)

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“…Cell Culture-As an in vitro model, we used Caco2 cells from a human colon adenocarcinoma cell line, which retain many of the characteristics of normal enterocytes (39,40). Cells were cultured in Dulbecco's modified Eagle's medium (Nissui Seiyaku, Tokyo, Japan) supplemented with 10% fetal calf serum, 0.1 mM nonessential amino acids (Invitrogen, Paisley, UK) in a humidified incubator (5% CO 2 , 37°C).…”

Section: Methodsmentioning

confidence: 99%

Enhanced Expression of the Human Multidrug Resistance Protein 3 by Bile Salt in Human Enterocytes

Inokuchi¹,

Hinoshita²,

Iwamoto³

et al. 2001

Journal of Biological Chemistry

105

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The enterohepatic circulation is essential for the maintenance of bile acids and cholesterol homeostasis. The ileal bile acid transporter on the apical membrane of enterocytes mediates the intestinal uptake of bile salts, but little is known about the bile salt secretion from the basolateral membrane of enterocytes into blood. In the basolateral membrane of enterocytes, an ATP-binding cassette transporter, multidrug resistance protein 3 (MRP3), is expressed, which has the ability to transport bile salts. We hypothesized that MRP3 might play a role in the enterohepatic circulation of bile salts by transporting them from enterocytes into circulating blood through the up-regulation of MRP3 expression, so we investigated the transcriptional control of MRP3 in response to bile salts. MRP3 mRNA levels were increased about 3-fold in human colon cells by chenodeoxycholic acid (CDCA), in a dose-and time-dependent manner. In the promoter assay, the promoter activity of MRP3 was increased about 3-fold over the basal promoter activity when treated with CDCA, and the putative bile salt-responsive elements exist in the region ؊229/؊138 including two ␣-1 fetoprotein transcription factor (FTF)-like elements. Constructs with a specific mutation in the consensus sequence of FTF elements showed no increase in basal transcriptional activity following CDCA treatment. In electrophoretic mobility shift assay with nuclear extracts, specific binding of FTF to FTF-like elements was observed when treated with CDCA. The expression of FTF mRNA levels were also markedly enhanced in response to CDCA, and overexpression of FTF specifically activated the MRP3 promoter activity about 4-fold over the basal promoter activity. FTF thus might play a key role not only in the bile salt synthetic pathway in hepatocytes but also in the bile salt excretion pathway in enterocytes through the regulation of MRP3 expression. MRP3 may contribute as a plausible bile salt-exporting transporter to the enterohepatic circulation of bile salts.

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Section: Methodsmentioning

confidence: 99%

Enhanced Expression of the Human Multidrug Resistance Protein 3 by Bile Salt in Human Enterocytes

Inokuchi¹,

Hinoshita²,

Iwamoto³

et al. 2001

Journal of Biological Chemistry

105

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“…72 Studies of epithelial cell handling of cytotoxic drugs, radiation and antimicrobial agents could offer new possibilities for documenting MBI. 73,74 …”

Section: Intestinal Permeabilitymentioning

confidence: 99%

Mucosal barrier injury: biology, pathology, clinical counterparts and consequences of intensive treatment for haematological malignancy: an overview

Blijlevens¹,

Donnelly²,

Pauw³

2000

Bone Marrow Transplant

235

153

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Summary:Mucositis is an inevitable side-effect of the conditioning regimens used for haematopoietic stem cell transplantation. The condition is better referred to as mucosal barrier injury (MBI) since it is primarily the result of toxicity and is a complex and dynamic pathobiological process manifested not only in the mouth but also throughout the entire digestive tract. A model has been proposed for oral MBI and consists of four phases, namely inflammatory, epithelial, ulcerative and healing phases. A variety of factors are involved in causing and modulating MBI including the nature of the conditioning regimen, the elaboration of pro-inflammatory and other cytokines, translocation of the resident microflora and their products, for example, endotoxins across the mucosal barrier, exposure to antimicrobial agents and whether or not the haematopoietic stem cell graft is from a donor. Neutropenic typhlitis is the most severe gastrointestinal manifestation of MBI, but it also influences the occurrence of other major transplant-related complications including acute GVHD, veno-occlusive disease and systemic infections. The pathobiology, clinical counterparts and the means of measuring MBI are discussed together with potential approaches for prevention, amelioration and, perhaps, even cure. Bone Marrow Transplantation (2000) 25, 1269-1278. Keywords: mucositis; mucosal barrier injury; diagnosis; risk factors; treatment Mucositis is an inevitable side-effect of the intensive conditioning therapy used for haematopoietic stem cell transplantation 1 and usually refers to the mucosal ulceration of mouth and throat. However, it is generally accepted that oral mucositis is in reality the most obvious manifestation of damage or injury elsewhere particularly that of the gut. Hence, mucosal barrier injury (MBI) may be a more appropriate term for this biological process. There exists no clear definition of MBI which is defined by a constellation of signs and symptoms that vary in their clinical expression. Oral MBI is reported to affect 60% to 100% of transplant recipients 2,3 and is characterised by pain, oedema, erythema, lesions, pseudomembrane formation, excessive mucous production, reduced saliva and bleeding, all of which reduce the patient's ability to eat and drink. In contrast, there are no reliable data on the incidence of gut MBI although intestinal symptoms affect almost every transplant recipient to some extent and include nausea, vomiting, abdominal cramping and watery diarrhoea occasionally accompanied by macroscopic blood loss. The exact course and severity of bowel symptoms of MBI are also difficult to ascertain because many patients are in such pain due to oral MBI that they only gain relief from narcotic analgesia which induces constipation as a result of reduced gut motility. There are also a number of scoring systems for oral MBI 4 although none is universally accepted and all lack standardisation. As yet, there is no system for registering gut MBI although there are published definitions for grading toxicity o...

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“…Caco-2 monolayers were grown using established methods to simulate tight-junctions seen in vivo, resulting in a close model for the permeation of drug. 31 The trans-monolayer studies conclude that under ideal conditions, the release of chemotherapeutics from the microdevice limits the amount of free drug available to affect surrounding tissue (Fig. 3 B).…”

Section: Resultsmentioning

confidence: 96%

Microfabrication of an asymmetric, multi-layered microdevice for controlled release of orally delivered therapeutics

2008

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SummaryThe creation of an oral drug delivery platform to administer chemotherapeutic agents effectively can not only increase patient compliance, but also potentially diminish drug toxicity. A microfabricated device offers advantages over conventional drug delivery technology. Here we describe the development of a multi-layered polymeric drug-loaded microfabricated device (microdevice) for the oral delivery of therapeutics, which offers unidirectional release of multiple therapeutics. The imaging and release of therapeutics from the multi-layered device was performed with three different fluorescently labeled albumins. The release of insulin and chemotherapeutic camptothecin was also observed to be released in a controlled manner over the course of 180 minutes in vitro. Furthermore, asymmetric delivery was shown to concrete drug at the device/cell interface, wherein 10 times more drug permeated an intestinal epithelial cell monolayer, compared to unprotected drug-loaded hydrogels. The bioactivity of the released chemotherapeutic was shown with cytostasis of colorectal adenocarcinoma cells. Cytostasis of drug loaded hydrogels was significantly higher than control empty hydrogel laden microdevices. Our results conclude that microfabrication of a hydrogel laden microdevice leads to a viable oral delivery platform for chemotherapeutics.

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The human intestinal epithelial cell line Caco-2; pharmacological and pharmacokinetic applications

Cited by 356 publications

References 50 publications

Enhanced Expression of the Human Multidrug Resistance Protein 3 by Bile Salt in Human Enterocytes

Enhanced Expression of the Human Multidrug Resistance Protein 3 by Bile Salt in Human Enterocytes

Mucosal barrier injury: biology, pathology, clinical counterparts and consequences of intensive treatment for haematological malignancy: an overview

Microfabrication of an asymmetric, multi-layered microdevice for controlled release of orally delivered therapeutics

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