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Recent Advances in Nutritional Sciences

Use of Exfoliated Cells from Target Tissues to Predict Responses to Bioactive Food Components

National Institutes of Health/NCI, Nutritional Sciences Research Group, Rockville, MD 20892-7328

²To whom correspondence should be addressed. E-mail: davisci{at}mail.nih.gov.

	ABSTRACT

TOP ABSTRACT Exfoliated Cells as Surrogates... Accumulation and Metabolism of... Effect of bioactive Food... Future Directions. LITERATURE CITED

 
A host of bioactive food components have been proposed to promote health and reduce the risk of disease states. It is clear that not all individuals respond identically to these essential and nonessential food components. Genetic polymorphisms may influence absorption, metabolism and accumulation of bioactive food components, thereby influencing their actions in target tissues. Unfortunately, serum concentrations of bioactive food components may not correlate with tissue concentrations and may therefore under- or overestimate the response in target tissues. Exfoliated cells may be useful to assess the actions of nutrients in specific tissues. Although not extensively examined, evidence already suggests the usefulness of these cells in predicting changes in gene expression, DNA methylation, DNA damage, protein expression and accumulation of dietary components. Although there are limitations on the collection of exfoliated cells, the inaccessibility of tissues they can represent raises intriguing possibilities for their ability to predict the outcome of nutritional intervention studies.

KEY WORDS: • exfoliated cells • biomarkers • cancer • colon • lung • breast

Dietary habits are fundamental to achieving a person’s genetic potential and likely to reduce the risk of a myriad of disease conditions. A large number of bioactive food components may account for these observations. Although blood and its associated cells have frequently been used to evaluate the adequacy of the diet, their evaluation may not always predict responses in target tissues. However, it is often difficult if not impossible to obtain samples of the tissue of interest noninvasively. Thus, there is a need to validate the utilization of surrogate markers that would be indicative of the accumulation and activity of bioactive food components in cells in target tissues. Exfoliated or sloughed cells may be useful.

	Exfoliated Cells as Surrogates for Cells in Target Tissues.

TOP ABSTRACT Exfoliated Cells as Surrogates... Accumulation and Metabolism of... Effect of bioactive Food... Future Directions. LITERATURE CITED

 
Exfoliated cells hold strong potential as a tool for monitoring human exposure to bioactive food components in target tissues because they can be collected easily from human samples (Table 1). Examples include colonic epithelial cells obtained from stool samples or from gastric lavage, bladder urothelial cells present in urine samples, airway epithelial cells in sputum and buccal mucosal cells obtained by rinsing the mouth. In nonlactating women, epithelial cells have been obtained by ductal lavage, from nipple aspirate fluid and from fine needle aspiration of the breast parenchyma (1–4). Furthermore, the cellular profile of breast ductal fluid obtained by nipple aspiration in healthy premenopausal women was found not to vary during the menstrual cycle, indicating that future studies utilizing these samples may be performed independent of the phase of the cycle (5). Human breast milk has also been shown to be an excellent source of luminal epithelial cells from a cohort of lactating women (6). These cells reflect what actually occurs in the breast and are the cells from which most breast cancer arises. They are also more easily accessible, readily available and noninvasively collected compared with those from surgically excised tumor tissue and reduction mammoplasty. Thus, various samples may serve as sources of representative ductal epithelial cells for studies of exposure of the mammary gland, colon, lung and bladder to bioactive food components.

DNA, RNA and protein isolated from exfoliated cells have been analyzed for various types of genetic and epigenetic changes (Table 2). For example, mammary epithelial cells present in nipple aspirate fluid have been analyzed for DNA amplification of several microsatellite regions using polymerase chain reaction and for protein expression using two-dimensional gel electrophoresis (13), thus demonstrating that exfoliated cells may be useful for genetic analysis.

	Accumulation and Metabolism of Bioactive Food Components.

TOP ABSTRACT Exfoliated Cells as Surrogates... Accumulation and Metabolism of... Effect of bioactive Food... Future Directions. LITERATURE CITED

Although blood and blood constituents have frequently been used to evaluate the response to bioactive food components, the concentration of these agents in the blood and in the target tissue of interest may not be related. For example, tea contains a number of polyphenols (catechins) including (-)-epigallocatechin-3-gallate (EGCG), (-)-epigallocatechin (EGC), (-)-epicatechin gallate (ECG), (-)-epicatechin (EC) and (+) gallocatechin. When the bioavailability, tissue distribution and biological activities of tea catechins were measured in rats, the levels of catechins in different tissues differed from those in plasma (38). For example, the large intestine and bladder had twice the concentrations and the liver had one eighth the concentration of tea catechins as plasma. When individual catechins were examined, the highest concentration of EGC was detected in bladder and kidney, whereas the highest EGCG level was found in the large intestine (38), demonstrating that there is selective uptake of tea catechins in different tissues. Results from animal studies also indicate that tissues differ in their extent of accumulation, rate of accumulation, time to saturation and turnover time of ß-carotene (39). These studies also suggest that although blood ß-carotene levels may yield information on recent intake, absorption and transport of ß-carotene, they do not indicate actual tissue levels (40). Plasma and adipose carotenoids represent different markers for nutritional status and cannot be used interchangeably (40). Similarly, Nair and co-workers (41) investigated the relationship between serum and mucosal tissue antioxidant levels. In control subjects, serum antioxidant levels were predictive of colon antioxidant levels for ß-cryptoxantin, -carotene and ß-carotene but not for -tocopherol, -tocopherol, lutein + zeaxanthin or lycopene. In contrast, none of the antioxidant levels in serum were predictive of colonic tissue levels in patients with adenomatous polyps (41), thus also indicating that genetic differences between normal and cancerous tissues will affect the accumulation of bioactive food components. Therefore, cells exfoliated from the tissue of interest may be better samples than blood for the accumulation of essential and nonessential dietary constituents.

In contrast to tea polyphenols and ß-carotene, colonic mucosal concentrations of folate are accurately predicted by blood measurements of folate status (42). Folate concentrations in human colonic mucosa obtained by endoscopic biopsy were directly correlated with serum folate and with erythrocyte folate concentrations and inversely associated with serum homocysteine concentrations (42). This demonstrates that for some bioactive food components, the concentration in serum is a good indicator of status of certain target organs but for other bioactive food components, it is not.

The metabolism of dietary compounds may affect their behavior and action in cells in target tissues. For example, although >600 carotenoids exist in plants and 50 of them might be consumed in the human diet, only five to seven are found in serum in high concentrations (43). Carotenoids undergo isomerization or metabolism and the resulting compounds, which are often not identified by the usual analytical techniques, may differ in their biological effects (43). The absorption and subsequent distribution of these isomers in tissues vary. After ingestion of a mixture of ß-carotene isomers, only the all-trans form is found in blood, whereas 13-cis or 9-cis isomers may represent up to 20% in some tissues (43). Because these isomers have different biological activities, measurement of blood ß-carotene does not indicate what is happening in the cells of the target tissues. Soy isoflavonoids, such as genistein, have been shown to undergo metabolism in target tissues (44). Furthermore, this metabolism has been shown to increase the biological activity of the parent compound (44), thus emphasizing the point that despite similar intake of bioactive food components, the absolute response of an individual or a specific tissue may reflect complex interactions occurring among nutrients, and amelioration of environmental and/or genetic factors.

	Effect of bioactive Food Components on Molecular Analysis in Exfoliated Cells.

TOP ABSTRACT Exfoliated Cells as Surrogates... Accumulation and Metabolism of... Effect of bioactive Food... Future Directions. LITERATURE CITED

 
Diet has been shown to modify molecular markers such as DNA damage and gene expression in exfoliated cells. For example, utilizing the COMET assay, the amount of single-strand breaks in exfoliated colorectal mucosal cells was significantly lower when healthy individuals consumed a vegetarian diet compared with a high meat diet (17). Similarly, supplementation with a carotenoid-rich vegetable juice decreased cell DNA damage by 20% as measured by the COMET assay in lung epithelial cells obtained by bronchoalveolar lavage (18). In contrast, no changes were observed in DNA damage in leukocytes (18). Bioactive food components have also been shown to modulate gene expression in exfoliated cells. For example, Chapkin et al. (45) observed that dietary fiber differentially alters cellular fatty acid-binding protein expression in exfoliated colonocytes during tumor development.

Formation of micronuclei in exfoliated cells from different organs, such as oral and nasal cavity, bladder, cervix and esophagus has been used as an end point to detect exposure to genotoxins and bioactive food components (22). Micronuclei in exfoliated cells emerge during mitosis of the basal layers of the epithelium as extrachromosomal DNA particles when chromosome fragments or whole chromosomes lag behind and fail to be included in the main nuclei of the daughter cells (23). Although the spontaneous frequencies of micronuclei are similar in all types of exfoliated cells, absolute quantities may be useful in estimating specific exposures (23). Dietary folate restriction increased cytogenetic damage in both the lymphocytes and buccal cells of postmenopausal women (25). Other dietary components such as ß-carotene, vitamin A and their combination decreased the formation of micronuclei in exfoliated cells of betel chewers (26). Other chemoprotective agents that have led to a decrease in micronuclei frequencies in oral mucosal cells of healthy individuals and/or patients with oral lesions include -tocopherol, iotretionin, and turmeric and related substances (22,27,28). Intervention studies with combined treatment of 15 mg retinol, 200 mg riboflavin and 50 mg zinc in Chinese subjects living in an area with a high incidence of esophageal cancer led to a reduction in the micronuclei frequency in esophageal cells (0.19% in the supplemented group vs. 0.31% in the placebo group) but not in oral cells (29). Green tea was protective against micronuclei formation in exfoliated oral cells of individuals with oral leukoplakia; this decrease was paralleled by a decrease in the frequency of both micronuclei and chromosomal aberrations in peripheral blood lymphocytes (30). After 6 mo of a mixed tea intervention, the micronuclei formation in exfoliated oral cells was reduced from 10.5 to 5.4/1000 cells, and the micronucleated cells and chromosome aberration rate in the peripheral blood lymphocytes were reduced from 3.9 to 2.6/1000 cells and from 2.5 to 1.7/100 cells, respectively (30). In contrast, these values increased in placebo-treated controls. These results show that tea has a significant chemopreventive effect against DNA damage in exfoliated cells. Thus, the assay of micronucleated exfoliated cells has been utilized to study the protective effect of bioactive food components in a biological response with relevance to cancer, i.e., chromosomal breakage in target epithelial cells.

	Future Directions.

TOP ABSTRACT Exfoliated Cells as Surrogates... Accumulation and Metabolism of... Effect of bioactive Food... Future Directions. LITERATURE CITED

 
Future studies must evaluate the potential usefulness of more "state of the art" analyses in exfoliated cells in nutritional studies. Examples include microarray analysis for changes in gene expression and surface enhanced laser desorption ionization (SELDI) MS for protein expression. The National Cancer Institute is currently conducting two studies utilizing nipple aspirations. First, they are comparing protein expression via two-dimensional gels and SELDI MS from the breasts of women with different risks for breast cancer with the expression patterns in serum. It may be possible to define patterns of protein expression (fingerprints) that correlate with the risk of breast cancer. They are also collecting nipple aspirate fluid from high risk women who are being treated with the chemoprevention drug, difluoromethylornithine, both before and after drug administration to look for modulation of potential surrogate end points. Similar studies should be conducted looking at the effect of bioactive food components on many different types of exfoliated cells. Future studies are also required to determine whether dietary-induced changes in biomarkers that are measured in exfoliated cells are indicative of changes in target tissues or whether they are representative of global changes within the body.

In summary, exfoliated cells hold potential as a tool for monitoring human exposure and response to bioactive food components. Many sources of exfoliated epithelial cells can be obtained for lung, colon, mammary, bladder and buccal cells. Although bioactive food components have been shown to inhibit carcinogen-DNA adduct formation, DNA damage by the Comet assay and micronuclei formation in exfoliated cells, very few studies have utilized exfoliated cells to analyze exposure to bioactive food components. Future studies are warranted to determine the quality and quantity of exfoliated cells that can be obtained as well as the potential usefulness of exfoliated cells as surrogate markers of exposure for cells in target tissues in nutritional intervention studies.

	FOOTNOTES

 
¹ Manuscript received 28 January 2003.

	LITERATURE CITED

TOP ABSTRACT Exfoliated Cells as Surrogates... Accumulation and Metabolism of... Effect of bioactive Food... Future Directions. LITERATURE CITED

 

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This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Davis, C. D. Search for Related Content PubMed PubMed Citation Articles by Davis, C. D.