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U.S. Department of Agriculture, Grand Forks Human Nutrition Research Center, Grand Forks, ND 58202-9034
3To whom correspondence should be addressed. E-mail: davisci{at}mail.nih.gov. Present address: National Institutes of Health/NCI, Nutritional Sciences Research Group, Rockville, MD 20892-7328.
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ABSTRACT |
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 TOP ABSTRACT SUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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KEY WORDS: • copper • fecal water • free radical production • alkaline phosphatase activity • cytotoxicity
Colorectal cancer is a major human cancer in the United States, accounting for 130,000 new cases and >50,000 deaths each year (1
). It is estimated that 50% of the Western population can expect to develop at least one colorectal tumor by the age of 70 (2
). Diet is the single greatest contributor to human cancer, including colon cancer, and may be associated with 35–70% of the disease (3
). The stem cells of the colorectal mucosa lie near the complex, potentially mutagenic environment of the fecal stream. Therefore, an understanding of the effects of diet on the chemistry of fecal material is essential in the development of strategies to prevent colorectal cancer (4
). In recent years, there has been considerable interest in the role of the aqueous phase of human feces (fecal water) in studies examining the mechanisms underlying the dietary etiology of colon cancer (5
–12
). The hypothesis is that components of this fecal fraction are in direct contact with the colonocytes and are more likely to exert adverse effects on the cells of the colonic epithelium than components bound to food residues or bound to the bacterial mass (11
,12
).
Many different analyses have been performed on the fecal water fraction to assess cancer susceptibility. It has been demonstrated that the cytotoxicity of the fecal water to HT-29 cells is dependent on dietary factors (6
–12
). Fecal water cytotoxicity can cause epithelial cell loss in the large bowel, which leads to a compensatory crypt cell proliferation (10
). Measurement of alkaline phosphatase activity in fecal water has also been used as a marker of in vivo epithelial cell loss (7
). It has been shown that an increased cell proliferation is linked to a higher risk for the development of colonic cancer (13
,14
). Therefore, measuring the cytotoxicity and alkaline phosphatase activity of human fecal water is being used increasingly as a risk marker for this disease in dietary intervention studies (6
,9
). Furthermore, the recent findings of high genotoxic activity in human fecal water, as measured by the Comet assay (6
,9
), support the hypothesis that the biochemistry of this fecal fraction may be important in mediating the effects of dietary components on malignant transformation in the colon.
Another assay with which to assess colon cancer susceptibility is fecal free radical production. Free radical production in fecal incubates depends on the individual’s diet (4
,15
,16
). Oxygen radicals, such as superoxide and hydrogen peroxide, which are produced by aerobic metabolism, damage proteins, lipids and DNA under in vivo conditions, and this damage has been implicated in the induction of somatic mutations that may favor the development of several forms of cancer (17
).
One possible dietary factor that may increase the susceptibility to colon cancer is inadequate dietary copper. Recent studies (18
,19
) have shown that ingestion of a diet low in copper significantly increased the formation of 3,2'-dimethyl-4-aminobiphenyl- and dimethylhydrazine-induced aberrant crypt foci in rats. Aberrant crypt foci are preneoplastic lesions that have been detected in human colon resections and in experimental rats treated with chemical carcinogens (20
,21
). Three studies have shown that copper deficiency increased the incidence of chemically induced intestinal cancer in rats (22
–24
). Furthermore, a recent study showed that copper deficiency significantly increased the small intestine tumor incidence in Min mice, a genetic model for human colon cancer susceptibility (25
). Thus, low dietary copper may be a potential risk factor for colon cancer in humans. The purpose of the current study was to investigate the effects of low and adequate copper intakes on copper nutriture and putative risk factors for colon cancer susceptibility in healthy men.
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SUBJECTS AND METHODS |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Healthy men were recruited through advertisements and were admitted to the study after they had been informed in detail, both orally and in writing, of the nature of the research and the associated risks. The eligibility requirements were age 21–55 y, nonsmoking, no apparent underlying disease, and no blood donation in the past 6 mo. Participants agreed to discontinue all nutrient supplements when their applications were submitted, generally 6–12 wk before the beginning of the study. None of the participants regularly used mineral supplements before entry into the study. None of the participants were taking any prescription medication. Protocols were approved by the Institutional Review Boards of the University of North Dakota and the USDA and followed the guidelines of the U.S. Department of Health and Human Services and the Helsinki Declaration regarding the use of human subjects.
The study participants were 17 men with the following characteristics (mean ± SEM): age, 35 ± 8 y (range: 21–52 y); admission body weight, 87 ± 14 kg (range: 58–110 kg); and body mass index (in kg/m2) 28 ± 4 (range: 17–33). All of the men were Caucasian.
The men were fed a constant weighed basal diet of conventional foods that was low in copper (0.59 mg, 0.59 ± 0.02 mg by analysis) based on an energy content of 13.65 MJ (3250 kcal) with a 3-d menu rotation (Table 1
). The diet was supplemented with 123 mg of magnesium (as magnesium chloride hexahydrate). The diet was adequate in all other known nutrients. The men participated in an equilibration period of 1 wk in which they received the basal diet supplemented with 1.0 mg copper. After the equilibration period, men were randomly assigned to receive either the basal diet or the basal diet supplemented with 2 mg copper/d for 6 wk. Afterwards, the men crossed over to the other level of copper for the last 6 wk. Copper was supplemented as cupric sulfate in beverages served at breakfast. City water, a bottled carbonated water and chewing gum were consumed as desired, after analyses indicated minimal trace element content. Limited amounts of salt and selected low energy carbonated beverages were individualized to the men’s preferences and then served consistently during both dietary periods. The low energy carbonated beverages did not contain any copper.
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Fecal analyses.
Men collected fecal material during the equilibration period and during the last 2 wk of each dietary period. Fecal water was prepared by modifying a generally accepted procedure (6
). Briefly, fecal samples were homogenized with a Masticator homogenizer (IUL Instruments, Barcelona, Spain) for 2 min and fecal water was prepared by centrifuging the sample for 2 h at 30,000 x g at 4°C. The supernatant was decanted and centrifuged again at 30,000 x g for 15 min at 4°C. The supernatant was then filtered through a 149 µm Nitex filter. Volume and pH were recorded and the samples were stored at -70°C. To decrease the day-to-day variability among samples, individual composites for each subject were made from all of the fecal water collected from each subject during each dietary period.
The HT-29 cell lysis assay, used to determine the cytotoxicity of the fecal water samples, was performed as described by Van Munster et al. (26
). A human tumor adenocarcinoma cell line (HT-29) was cultured in Dulbecco’s modified Eagle’s medium (Life Technologies, Gibco, Rockville, MD) with 10% fetal bovine serum, 2 mmol/L L-glutamine, 100,000 U/L penicillin and 100 mg/L streptomycin. The cells were trypsinized, resuspended and counted using a hematocytometer. Then 15,000 cells were placed in each well of a 96-multiwell plate. The cells were cultured for 48 h at 37°C in a humidified atmosphere of 95% air/5% CO2. The cultured cells were then incubated for 1 h with the sterile filtered (0.45-µm filter, Millipore, Bedford, MA) fecal water (100 µL). On each plate, PBS was used as a control in which no cell killing should occur and deoxycholic acid [(Sigma, St. Louis, MO) 250 and 500 µmol/L in PBS] was used as a control in which complete cell killing would occur. Every replicate was performed 8 times. After incubation, wells were washed, and the surviving cells cultured for another 48 h under the same conditions as before. Dye solution (15 µL), containing 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (Promega, Madison, WI) was placed in each well for 4 h. The plates were read at 540 nm with a Biomek 1000 Automated Laboratory Workstation (Beckman, Palo Alto, CA). The mean absorbance of each octopule was calculated, and cell survival was expressed as the percentage absorbance of the wells incubated with PBS. Fecal water samples were diluted (1:2 up to 1:100) so that the percentage survival was 
50% for the three different dietary periods. Samples from two of the men did not inhibit cell survival with either dietary treatment when incubated at a 1:2 dilution and were excluded from the analysis. Cytotoxicity was determined as (100% - % cell survival); one unit was defined as 50% cytotoxicity. Cytotoxicity/g feces was determined as cytotoxicity units/mL fecal water x mL fecal water/g feces.
Total alkaline phosphatase activity was measured using a commercially available kit (Sigma Chemical, St. Louis, MO.). p-Nitrophenyl phosphate was used as the substrate, and the absorbance of the reaction product p-nitrophenol was determined spectrophotometrically at 405 nm. Intestinal alkaline phosphatase activity was inhibited using 60 mmol/L L-phenylalanine, which acts as a specific noncompetitive inhibitor of the intestinal isozyme in humans (27
). The difference in total activity (noninhibited) and the activity after inhibition with L-phenylalanine is the activity of the intestinal isoenzyme. Intestinal alkaline phosphatase activity was expressed as mmol p-nitrophenol/(min · L fecal water) (units/L) and as units/kg feces which was calculated as units/L fecal water x volume fecal water recovered/kg feces collected.
The fecal water was analyzed directly for copper, iron and zinc concentrations by flame atomic absorption spectrophotometry (Perkin-Elmer, Norwalk, CT). Commercial standards, such as National Institute of Standards liver standard reference material, were not utilized because samples were not digested before analysis. However, instrument quality control samples and a fecal pool, which was a composite of many samples, were assayed as controls to monitor any variability between runs.
The effect of dietary copper on in vitro free radical production in human feces was measured by using the method of Babbs and Gale (15
,16
) and modified by Lund et al. (4
) which is based on the following reaction: dimethyl sulfoxide + OH· 
methanesulfinic acid + CH3·. Each fecal sample (1 ± 0.05 g) was incubated for 24 h in degassed Tris-buffered saline (pH 7.6) containing 5% dimethyl sulfoxide (0.7 mol/L), glucose (1 g/L) and Na2EDTA (50 mmol/L) at 37°C. The sample was then centrifuged at 900 x g for 10 min at room temperature, the supernatant removed and the protein removed as a precipitate by lowering the pH to 1.0 for 10 min by adding 12 mol/L HCL. The pH was then returned to 7.4, the sample was centrifuged at 900 x g for 10 min at room temperature, and the supernatant was stored at -70°C before batch analysis of the methanesulfinic acid content. For each analysis, a composite was made from 5 mL of the supernatant of at least 5 fecal samples/participant collected during the different dietary periods.
Standards were prepared fresh before each assay, with 0–75 mmol methanesulfinic acid/L in the incubation medium. Both samples and standards were processed identically. A 2-mL aliquot was mixed with 0.2 mL H2SO4 (10 mol/L) and centrifuged at 500 x g for 3 min at room temperature. The supernatant was mixed with 1 mol/L sulfuric saturated 1-butanol (4 mL). The upper phase (3.5 mL) was mixed with 2 mL sodium acetate buffer (0.5 mol/L, pH 5.0) and then centrifuged at 500 x g for 3 min at room temperature before 1.8 mL of the lower aqueous phase was removed. The lower aqueous phase was then adjusted to a pH of 2.5 by adding HCl (1 mol/L) before the addition of Fast Blue BB salt (0.03 mol/L, Sigma) to form the colored product diazosulfone acid. Once the color reaction reached a plateau, after 10 min in the dark, 1.5 mL toluene:1-butanol (3:1, v/v) was added and the sample was mixed for 2 min before separation of the phases by centrifugation at 500 x g for 3 min at room temperature. The upper phase (1.0 mL) was then removed and washed with 1-butanol-saturated water (2.0 mL). The samples were centrifuged at 500 x g for 3 min at room temperature. The upper layer (1.0 mL) was removed and 100 µL pryidine:acetic acid (95:5, v/v) was added to stabilize the color. Absorbance was measured by scanning spectrophotometry at a peak absorbance between 340 and 520 nm. Peak absorbance was between 410 and 420 nm. All samples and standards were assayed in triplicate.
Hematological analyses.
After an overnight fast, blood samples were drawn from the participants during the equilibration period and at 3-wk intervals during each dietary period. Analyses of plasma zinc and copper were made by flame atomic absorption spectrophotometry (Perkin-Elmer, Norwalk, CT) after dilution with deionized water. Ceruloplasmin was determined by colorimetrically measuring p-phenylenediamine oxidase activity (28
). Ceruloplasmin was also measured immunochemically by using the Behring Nephelometer 100 analyzer (Behring Diagnostics, Westwood, MA). Superoxide dismutase activity in erythrocytes was measured by inhibition of pyrogallol autooxidation (29
). Platelet cytochrome c oxidase was determined using previously described methods (30
,31
).
A Coulter S + IV hematology analyzer (Coulter Electronics, Hialeah, FL) was used to determine hematologic indices. Serum cholesterol, HDL cholesterol and LDL cholesterol concentrations were determined using a Cobas Fara II Centrifugal analyzer (Roche Diagnostics Systems, Montclair, NJ). Glutathione (32
) and glutathione peroxidase activity (33
) were determined by previously described methods.
Statistical analyses.
To test for diet and feeding sequence effects, the data were analyzed by repeated-measures ANOVA with the SAS mixed-effect model program (SAS Version 8.02, SAS Institute, Cary, NC). Individuals served as their own controls. Because the fecal constituent data did not follow a normal distribution, data were transformed by using the natural log before statistical analysis. These data are expressed as geometric means ± 1 SEM. Pearson’s correlation coefficients were used to assess relations between variables within a dietary treatment. Multiple regression analyses were used to determine the partial R2 for cytotoxicity vs. alkaline phosphatase activity after adjusting for multiple observations for each subject. Values are reported as means ± SEM Statistical significance was set at P 
0.05.
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RESULTS |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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]. Dietary treatment did not affect the percentage of fecal water extracted/g feces or the percentage wet weight of the feces as determined by freeze drying samples of all of the feces collected (data not shown). There were also no differences in fecal water pH, iron or zinc concentrations when men consumed the different diets (Table 2
).
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]. Free radical-generating capacity was correlated with fecal water iron concentrations (P < 0.04, R2 = 0.32, n = 17) only when men consumed the moderate copper diet.
|
). Although dietary copper did not significantly affect fecal water cytotoxicity to HT-29 cells [51.94 (26.31–102.510 vs. 42.30 (24.97–89.57) U/mg feces] when they consumed low rather than adequate dietary copper, fecal water intestinal alkaline phosphatase activity and cytotoxicity were correlated (P < 0.003, R2 = 0.28, n = 45) when multiple regression analysis was utilized to adjust for the multiple observations for each subject (Fig. 4
), suggesting that similar results were obtained from both in vivo (alkaline phosphatase activity) and in vitro measures of fecal water cytotoxicity.
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). Dietary copper also did not affect hematocrit, hemoglobin, plasma iron, total iron binding capacity, glutathione, glutathione peroxidase activity, VLDL cholesterol or triglycerides (data not shown).
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DISCUSSION |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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–25
). Generation of reactive oxygen species at the mucosal surface where the fecal water comes into contact with oxygen may cause damage to the protective mucus, leading to cellular damage. This is supported by the observation of Lund et al. (34
) that increased free radical production in the luminal contents of the colon was associated with increased lipid peroxidation in the mucosa of the rat cecum and large intestine. Furthermore, the correlation between fecal free radical-generating capacity and fecal water iron concentrations when men consumed the adequate copper diet is similar to observations by Erhardt et al. (35
) and supports the hypothesis by Babbs (15
) that bacteria release superoxides, which are converted to the highly reactive hydroxyl radical through the catalytic activity of iron.
The effect of dietary copper on free radical production is paradoxical. As the free ion, there is no doubt that copper can promote damage to cellular molecules and structures through free radical formation (36
). In theory and in the test tube, copper ions can induce formation of reactive oxygen species that can damage biomolecules, including unsaturated lipids and DNA, probably via Fenton-like chemistry (37
). However, the chemical form of dietary copper present in the colon is unknown and probably reflects complexes rather than the free ion. Furthermore, although excess copper can induce oxidative stress that causes cell and organ damage, copper is really more notable for its role in preventing oxidative damage (36
). As a cofactor of the antioxidant enzymes copper-zinc superoxide dismutase and ceruloplasmin, copper plays a crucial role in antioxidant defense. Indeed, the chemistry of copper makes it an ideal participant in redox reactions because it cycles easily between the cuprous and cupric state (36
). It has been hypothesized that the various anticancer effects and apoptotic DNA fragmentation activities of several plant-derived polyphenols may be explained by their ability to mobilize intracellular or extracellular copper in cancer cells (38
).
The effect of dietary copper on the free radical-generating capacity of the feces did not appear to be mediated through systemic changes in copper status that altered copper antioxidant enzymes in the colonic mucosal cells because none of the hematological indicators of copper or antioxidant status differed with the dietary treatments. Although it is possible that the colonic mucosal enzymes are more susceptible to dietary copper deficiency and may in fact show alterations sooner that the systemic indices, two previous studies in rats have shown that colonic copper concentrations respond less to changes in dietary copper than plasma copper concentrations (18
,19
). Other possible explanations for the higher free radical-generating capacity of the feces when men consumed the low copper diet is that dietary copper is changing either the amount of bacteria that produce free radicals, the amount of free radicals produced by the bacteria or the types of bacteria present. For example, Enterococcus faecalis is a microorganism of the human intestinal tract that produces substantial extracellular superoxide, and derivative reactive oxygen species such as hydrogen peroxide and hydroxyl radical, through autoxidation of membrane-associated demethylmenaquinone (39
). Huycke et al. (39
) observed that in a rat model of intestinal colonization, E. faecalis resulted in significantly higher stool concentrations of hydrogen peroxide and 5,5-dimethyl-1-pyrroline N-oxide adducts of hydroxyl and thiyl radicals, as identified by electron spin resonance-spin trapping compared with rats colonized with different bacteria. The importance of intestinal bacteria in the pathophysiology of the colon is further emphasized by the fact that 45–60% of fecal solids are bacteria (40
). Babbs (15
) attributed the generation of reaction oxygen species by fecal samples to the bacteria present because, in his studies with autoclaved feces, free radicals could not be detected. In contrast, Owen et al. (41
) believe that reactive oxygen species are produced by a soluble factor within the fecal stream rather than by indigenous bacteria. Furthermore, the effect of dietary copper on different bacterial cell populations is unknown. Future research is required to determine what is causing the free radical production in the fecal matrix and how it is modified by dietary copper.
In the current study, low dietary copper caused higher cytotoxicity of the fecal water to HT-29 cells, which are a human colon carcinoma cell line, and induced more lysis of the men’s colonocytes in vivo as measured by intestinal alkaline phosphatase activity compared with the adequate copper diet. Similar to previous studies, cytotoxicity and alkaline phosphatase activity in the fecal water were positively correlated (7
,10
,42
). Both of these measures are indicative of increased exposure of the colonic mucosa to luminal irritants. Kinzler and Vogelstein (43
) argued that dietary factors that lead to colon cancer are probably not mutagens, but rather luminal irritants that damage epithelial cells. This leads to a compensatory epithelial regeneration, which increases the risk of endogenous mutations in cell turnover genes (44
). Indeed, diet-induced changes in cytolytic activity of fecal water have been shown to be highly correlated with in vivo colonic epithelial cell proliferation in rats (7
,10
,43
,45
).
In summary, the current study demonstrates that low dietary copper adversely affects the fecal environment such that men had higher fecal free radical production, fecal water cytotoxicity and alkaline phosphatase activity when consuming low dietary copper compared with adequate dietary copper. These are putative risk factors for colon cancer, and changes in the composition of the feces may explain the higher colon cancer susceptibility in copper-deficient compared with copper-adequate animals.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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2 The U.S. Department of Agriculture, Agriculture Research Service, Northern Plains Area, is an equal opportunity/affirmative action employer and all agency services are available without discrimination.
Manuscript received 20 September 2002. Initial review completed 21 October 2002. Revision accepted 26 October 2002.
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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