Dietary prevention of azoxymethane-induced colon carcinogenesis with rice-germ in F344 rats
Kunihiro Kawabata,
Takuji Tanaka1,
Taro Murakami2,
Tadashi Okada2,
Hiromichi Murai2,
Tomohiro Yamamoto3,
Akira Hara3,
Masahito Shimizu,
Yasuhiro Yamada,
Kengo Matsunaga,
Toshiya Kuno,
Naoki Yoshimi,
Shigeyuki Sugie and
Hideki Mori4
First Department of Pathology, Gifu University School of Medicine, 40 Tsukasa-machi, Gifu 500-8705,
1 First Department of Pathology, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Ishikawa 920-0293,
2 Oryza Oil and Fat Chemical Co. Ltd, Ichinomiya 493-8001 and
3 Department of Biochemistry, Gifu Pharmaceutical University, 5-6-1 Mitahorahigashi, Gifu 502-0003, Japan
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Abstract
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The modifying effect of dietary administration of defatted rice-germ and
-aminobutyric acid (GABA)-enriched defatted rice-germ on azoxymethane (AOM)-induced colon carcinogenesis was investigated in two experiments with male F344 rats. In the first experiment (the pilot study), the effects of the defatted rice-germ, the GABA-enriched defatted rice-germ and rice-germ on AOM-induced (15 mg/kg body wt once a week for 3 weeks) formation of aberrant crypt foci (ACF) were examined. The latter two preparations (2.5% in the diet) significantly inhibited ACF formation (P < 0.005). In the second experiment, a long-term study of the effects of rice-germ was done. One group was treated with AOM alone, four groups received the carcinogen and were fed the diets containing 2.5% rice-germ or 2.5% GABA-enriched defatted rice-germ for 5 (initiation phase) or 30 weeks (post-initiation phase), two groups were treated with rice-germ or GABA-enriched defatted rice-germ alone and one group was kept on the basal diet. At the termination of the study, dietary exposure to rice-germ during the initiation phase significantly reduced the incidence of colonic adenocarcinoma (71 versus 29%, P < 0.01). GABA-enriched defatted rice-germ or rice-germ during the post-initiation phase also decreased the frequency of colonic adenocarcinoma (71 versus 20%, GABA-enriched defatted rice-germ feeding, P < 0.01; 27%, rice-germ feeding, P < 0.01). These data suggest that constituents of rice-germ are possible dietary preventatives for human colon cancers.
Abbreviations: ACF, aberrant crypt foci; AOM, azoxymethane; GABA,
-aminobutyric acid; PCNA, proliferating cell nuclear antigen.
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Introduction
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Dietary factors play an important role in prevention of human diseases, including cancers (1,2). Experimental and epidemiological evidence suggests that increased dietary fiber is associated with a decreased risk of colon cancer, which is the third most malignant neoplasm in the world (3) and the second leading cause of cancer deaths in the USA. In Japan, the progressive introduction of Western dietary habits, especially an increasing fat intake and decreasing carbohydrate and dietary fiber intake, has increased colon cancer incidence (4).
Rice is the main cereal food as well as the staple food for the populations of Asian countries. It has been reported that rice components have several roles in prevention of disesase. Rice seeds are known to contain antioxidative components, such as ferulic acid, phytic acid, tocopherols and oryzanols. Rice bran and rice-germ are major constituents of rice seeds (5,6). In spite of the assumption of a disease preventive potential of rice seeds, there has been no clear evidence for a cancer preventive potential of rice seed itself or the rice-germ. Saikura et al. (7) determined the distribution of free amino acids within the rice kernel and examined the effects of soaking in water on their contents for the purposes of better understanding the chemical nature of the rice kernel. They found that the
-aminobutyric acid (GABA) content of rice-germ increases remarkably with soaking under slightly acidic conditions. GABA has been localized to endocrine-like cells of the rat antrum, small intestine and colon (8,9). However, the role of GABA in mucosal physiology is unclear. GABA exerts an inhibitory neural action in the gut via interaction with baclofen-sensitive GABAB sites. It has been reported that baclofen, a GABAB receptor agonist, inhibits the growth of colon tumors induced by azoxymethane (AOM) in rats (10).
We have previously reported several chemopreventive agents against colon carcinogenesis from edible plants (11). Aberrant crypt foci (ACF) in the colon of rodents exposed to carcinogen and of humans are regarded as possible precursor lesions for colon cancers (12,13) and as useful biomarkers for detecting modulatory effects of xenobiotics on colon carcinogenesis (14). Although the modes of action of most chemopreventive agents are still unknown, many of them are antioxidants which scavenge free radicals, which damage lipids, proteins, cell membranes and DNA. Rice-germ contains fiber and antioxidative agents, including ferulic acid, phytic acid, oryzanols and other phenolic compounds. Among them, fiber, ferulic acid and phytic acid have been reported to inhibit chemical carcinogenesis (1518). The potential effects of grains and plant foods on colon carcinogenesis are exceedingly complex, with the involvement of bile acids, pH changes and the bacterial profile. However, an important mode of chemoprevention by grains and plant foods might be due to fermentation of their resistant starches or fiber in the colon (1921).
In the present study, two experiments were conducted to investigate the modifying effects of rice-germ and GABA-enriched defatted rice-germ on colon tumorigenesis. Though biological activity of oil components in the rice-germ may be important, our attention has focused more on the defatted components in this study. As a pilot study (Figure 1a
), rice-germ and GABA-enriched defatted rice-germ were given to rats in order to determine whether these rice-germs could modulate the occurrence of ACF. A long-term bioassay (Figure 1b
) was then performed to confirm and evaluate the preventive effects of dietary rice-germ and GABA-enriched defatted rice-germ on AOM-induced large bowel carcinogenesis. Furthermore, the effects of rice-germ and GABA-enriched defatted rice-germ on the cell proliferation activity of colonic mucosal epithelium were estimated by measuring the proliferating cell nuclear antigen (PCNA)-positive index.


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Fig. 1. Experimental protocol. (a) Experiment 1 (pilot study). , azoxymethane (15 mg/kg body wt, s.c. injection); animals, 5-week-old male F344 rats; rice-germ preparations, 2.5% defatted rice-germ, 2.5% GABA-enriched defatted rice-germ and 2.5% rice-germ; group 1, AOM alone; group 2, AOM + 2.5% defatted rice-germ; group 3, AOM + 2.5% GABA-enriched defatted rice-germ; group 4, AOM + 2.5% rice-germ; group 5, 2.5% defatted rice-germ; group 6, 2.5% GABA-enriched defatted rice-germ; group 7, 2.5% rice-germ; group 8, no treatment. (b) Experiment 2 (long-term study). , azoxymethane (15 mg/kg body wt, s.c. injection); animals, 5-week-old male F344 rats; rice-germ preparations, 2.5% GABA-enriched defatted rice-germ and 2.5% rice-germ; group 1, AOM alone; group 2, AOM + 2.5% GABA-enriched defatted rice-germ; group 3, AOM + 2.5% rice-germ; group 4, AOM + 2.5% GABA-enriched defatted rice-germ; group 5, AOM + 2.5% rice-germ; group 6, 2.5% GABA-enriched defatted rice-germ; group 7, 2.5% rice-germ; group 8, no treatment.
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Materials and methods
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Animals and diet
Male F344 rats (Shizuoka Laboratory Animal Center, Shizuoka, Japan), 4 weeks old, were used. All animals were housed in wire cages (3 or 4 rats/cage) with free access to drinking water and CE-2 basal diet (CLEA Japan Inc., Tokyo, Japan) under controlled conditions of humidity (50 ± 10%), lighting (12 h light/dark cycle) and temperature (23 ± 2°C). They were quarantined for 2 weeks and randomized into experimental and control groups for the pilot study and the long-term bioassay. Powdered CE-2 diet (345.2 cal) was used as the basal diet throughout the study.
Chemicals
AOM was obtained from Sigma Chemical Co. (St. Louis, MO). Defatted rice-germ, rice-germ and GABA-enriched defatted rice-germ were supplied by Oryza Oil and Fat Chemical Co. (Ichinomiya, Japan). Samples of 100 g of the rice-germ, defatted rice-germ and GABA-enriched defatted rice-germ contained ~14, 32 and 335 mg GABA, respectively. AOM (15 mg/kg body wt) was given by s.c. injection between 10:00 and 11:00 a.m. The defatted rice-germ, rice-germ and GABA-enriched defatted rice-germ were mixed in the powdered basal diet (CE-2) at a concentration of 2.5%. These experimental diets were prepared weekly and stored in a cold room (<4°C) until use.
Experimental procedure
In the first experiment (the pilot study), 69 rats were divided into eight groups as shown in Figure 1a
. Groups 14 received three weekly s.c. injections of AOM at a dose of 15 mg/kg body wt. Rats in group 1 were fed the basal diet alone and those in groups 24 were given the diets containing 2.5% defatted rice-germ, 2.5% GABA-enriched defatted rice-germ and 2.5% rice-germ, respectively, for 5 weeks, starting 1 week before the first dosing with AOM. Groups 57 were given the experimental diets alone. Group 8 was an untreated control. At week 5, all animals were killed and the colons were fixed in 10% buffered formalin and stained with a 0.2% methylene blue solution for analysis of ACF.
For the second experiment (the long-term study), a total of 102 rats were randomly divided into eight groups. Groups 15 received three weekly s.c. injections of AOM (15 mg/kg body wt). Rats in groups 2 and 3 were fed the diets containing 2.5% GABA-enriched defatted rice-germ and 2.5% rice-germ, respectively, starting at 5 weeks of age and continued until 2 weeks after the last injection of AOM. Groups 4 and 5 were fed the basal diet mixed with 2.5% GABA-enriched defatted rice-germ and 2.5% rice-germ, respectively, for 30 weeks during the post-initiation phase, starting 2 weeks after the last injection of AOM. Groups 6 and 7 did not receive AOM and were fed diets mixed with the rice-germ preparations during the study (35 weeks). Group 8 served as an untreated control. The experimental diets were stored in a dark cold room (<4°C) until used and provided in food pots. All rats were carefully observed daily and weighed weekly until they reached 14 weeks of age and then every 4 weeks. Consumption of the experimental diets was also recorded to estimate intake of test compounds. The experiment was terminated at 35 weeks after the start and all animals were killed by an ether overdose to assess the incidences of preneoplastic and neoplastic lesions in all organs, including large bowel.
At autopsy, the intestine was excised, opened longitudinally, flushed clean with saline and examined for the presence of tumors. Abnormal lesions of other organs were also examined histologically. Colons, after fixation in 10% buffered formalin, were processed for histopathological examination by conventional methods. Intestinal neoplasms were diagnosed according to the criteria described by Ward (22).
Determination of ACF
The colons of all rats in the pilot study were used to score ACF. At autopsy, the colons were flushed with saline, excised, cut open longitudinally along the main axis and then washed with saline. The colons were cut into three sections (~4 cm each) starting from the anus, placed between filter papers to reduce mucosal folding and fixed in 10% buffered formalin for at least 24 h. Fixed colon sections were dipped in a 0.2% solution of methylene blue in distilled water for 30 s, then briefly washed with distilled water. Using a light microscope at a magnification of x40, ACF were distinguished by their increased size, their more prominent epithelial cells and their increased pericryptal space compared with surrounding normal crypts. The number of ACF observed per colon, the number of aberrant crypts observed in each focus and the location of each focus were recorded. After scoring, colons were processed for measurement of the PCNA-positive cell index and for histological examination.
PCNA immunohistochemistry
Anti-PCNA antibody (Dako Co., Kyoto, Japan) was used with the avidinbiotin complex method. Immunohistochemical staining was performed according to the method in a previous paper (23). Tissue sections were deparaffinized with xylene, hydrated through a graded ethanol series and incubated with 0.3% hydrogen peroxide for 30 min to block endogenous peroxidase activity. They were then incubated with 10% normal horse serum at room temperature for 30 min to block background staining and then stained with anti-PCNA antibody. To determine the PCNA-positive index, 15 full-length crypts were examined. The numbers and positions of PCNA positively stained nuclei in each crypt column were recorded. The cell position was determined by dividing the crypt into left and right segments. The first basal cells in each segment was considered `position l'. Numbers of positively stained nuclei were counted and divided by the total number of nuclei to give the PCNA-positive index (%). The scorer was unaware of the group to which the specimens belonged.
Polyamine levels
In the pilot study, polyamine levels in the colonic mucosa were assayed by the method of Koide et al. (24). At autopsy, the colons for measurement of polyamine level were immediately removed, slit open longitudinally and freed of all contents. The colonic mucosa was scraped with a bladed knife and stored at 70°C.
Statistical methods
Fisher's exact probability test, Student's unpaired t-test or Welch's t-test was used for statistical analyses. A value of P < 0.05 was considered significant.
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Results
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The pilot study
In the pilot study there were no significant differences in body weight gains in all groups. The mean liver weights did not significantly differ among the groups. The daily intakes of diets with or without rice-germ preparations were between 15.1 and 15.4 g/rat. During the study (5 weeks) no clinical signs of toxicity were observed in any group. Histologically, there were no toxic changes in liver, kidney, lung and heart of the rats in all groups. As shown in Table I
, colonic ACF were recognized only in rats treated with AOM (groups 14). The total number of ACF/colon, number of ACF/cm2 colon and total number of aberrant crypts (ACs)/colon of groups 3 or 4 were significantly smaller than of group 1. The number of AC/focus of group 4 was also significantly smaller than of group 1 (P < 0.005 and P < 0.001, respectively). In this experiment, polyamine levels of colonic tissues in groups 3 and 4 tended to be lower than of group 1, although the difference (Figure 2
) was not significant.
General observations in the long-term study
Food intake of groups 27 did not differ from that of groups 1 and 8, which were fed the basal diet without the rice-germ preparations (data not shown). In this study, dietary administration of two rice-germ preparations caused no clinical signs of toxicity, low survival, poor condition or histological changes suggesting toxicity in the liver, kidney and lung. The body weight gains of rats treated with AOM and fed the rice-germ preparations (groups 2 and 3) were comparable throughout the experimental period (Figure 3
). The body weight gains of rats fed the experimental diets after AOM treatment (groups 4 and 5) were slightly lower than those fed basal diet.
Incidences, multiplicity and distribution of intestinal neoplasms
Macroscopically, most tumors developed in the large intestine (mainly in the middle and distal colon) although some did form in the small intestine of rats in groups 15. They were sessile or pedunculated tumors and histologically tubular adenomas, adenocarcinomas or signet ring cell carcinomas, with a higher incidence of adenocarcinoma. A few rats had renal mesenchymal tumors and/or altered hepatocellular foci in groups 15, but these lesions were not found in other groups. Animals in groups 68 did not have any neoplasms in the organs examined, including the intestine. The incidences and multiplicities of intestinal neoplasms are shown in Tables II and III
. In general, the values of groups 25 were small compared with those of group 1. Statistically, the incidences of tumors in the entire intestine of groups 3 and 4 were significantly lower than of group 1 (P < 0.05 and P < 0.02, respectively). Furthermore, the incidences of large intestinal tumors in groups 35 were lower than in group 1 (P < 0.01 and P < 0.05, respectively).
As to the multiplicity of colonic carcinomas (number of carcinomas/rat), a significant reduction was found in rats fed the rice-germ preparations (groups 4 and 5) when compared with group 1 (P < 0.010.05). The values for the large intestines of groups 25 were smaller than of group 1.
PCNA-positive index
The results on PCNA-positive index in the colonic mucosal epithelium are shown in Figure 4
. PCNA-positive indices with the rice-germ preparations (groups 3 and 4) during or after AOM injection were significantly smaller than that of rats exposed to AOM alone (P < 0.05). Supplementation with the rice-germ preparations produced a downward shift in the proliferative region of the crypt compared with crypts exposed to AOM alone (P < 0.02).
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Discussion
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Feeding of rice-germ and GABA-enriched defatted rice-germ significantly decreased the development of ACF (number of ACF/colon), as revealed by quantification of ACF in the pilot study. These results suggest that rice-germ and GABA-enriched defatted rice-germ could inhibit the growth of colonic ACF and suppress progression of preneoplasia to malignant neoplasms but that defatted rice-germ had no inhibitory effects. These observations suggest that rice-germ and GABA-enriched defatted rice-germ may be an important class of dietary cancer preventives and that further investigations of effects of dietary rice-germ on carcinogenesis would be worthwhile. Our data suggest that rice-germ and GABA-enriched defatted rice-germ are new dietary preventive agents against colon cancer development.
The effects of dietary rice-germ and GABA-enriched defatted rice-germ on AOM-induced colonic ACF indicate that this short-term marker of colon carcinogenesis may be useful in screening chemopreventive agents (25) of colon tumorigenesis. This lesion has been suggested to be the premalignant lesion of chemically induced colon cancer. However, it would probably be prudent to use tumor incidence as the end-point for definitive investigations because there are many sites at which chemopreventive compounds may affect tumorigenesis (14). Though rice-germ and GABA-enriched defatted rice-germ had an inhibitory effect on AOM-induced ACF, rice-germ may have blocking and suppressing effects on AOM-induced colon carcinogenesis when fed in the diet during the initiation and post-initiation phases. GABA-enriched defatted rice-germ may have solely suppressing effects on AOM-induced colon carcinogenesis compared with rice-germ.
Several dietary factors are known to modulate carcinogenesis in humans (26) and rodents (27). The results in the present study confirmed the epidemiological data suggesting that the consumption of dietary fiber and, particularly, mixtures of soluble and insoluble fibers are inversely related to cancer risk, including colon cancer (28,29). In this experiment it may be that water-soluble fibers were important as the active principle from the two types of rice-germ agents. It has been established that short chain fatty acids can stimulate growth in the alimentary canal (18). Phytic acid (inositol hexaphosphate) is an abundant plant constituent, constituting 15% by weight of edible legumes, cereals, oil seeds and nuts. The modifying effects of phytic acid on carcinogenesis have been investigated in several experiments (15,30,31). Although most of them targeted the phytic acids in wheat bran, we used rice-germ. A diet high in wheat bran, which inhibits colorectal carcinogenesis (32), is known to increase loss of short chain fatty acids in the feces (33). It might be possible that soluble fiber in rice-germ is balanced against the generation of potentially promoting short chain fatty acids.
One possible mechanism for the decrease in colonic tumors might be through their inhibition of cell proliferation in colonic mucosa. In this experiment we assayed the PCNA-positive cell index and polyamine levels in colonic mucosa. Increases in these parameters correlate with a greater risk of developing colon cancer (3436). Our results evaluating the effects of rice-germ preparations on proliferation of colonic epithelium showed that rice-germ and GABA-enriched defatted rice-germ lowered the increased proliferation of crypt cells caused by AOM treatment. Similar results have been reported for other possible dietary cancer preventive agents and other natural substances (37). Increased cell proliferation is suggested to play an important role in multistage carcinogenesis (38), including colon tumorigenesis (36). Zheng et al. (39) have also reported a better correlation of ACF with ability to reduce PCNA labeling index in ACF than with reduction in the size of the proliferative component in ACF in rats. As for the effects of rice-germ preparations, several other mechanisms may also operate. The type of fiber may influence the profile, the shift from propionate to butyrate observed in animals fed on hydrolyzed guar being suggested to be of importance to carcinogenesis. (40). These rice-germ preparations may have produced a decrease in pH in both the cecum and colon, as increased acidity may be a cause of proliferation (41) and effects on pH have been demonstrated with both soluble and non-soluble types of fiber, correlated with fermentability but only loosely linked to proliferation (42).
Thus, in the present study inhibitory effects of rice-germ and GABA-enriched defatted rice-germ on AOM-induced colon tumorigenesis paralleled suppression of cell proliferation in colonic crypts. Therefore, it is possible that a significant anticancer property of these rice-germ preparations may be partly due to their antiproliferative effects on carcinogen-exposed crypts. Although the exact mechanism(s) of the chemopreventive effects and constituents of rice-germ need to be determined, the evidence described here warrants further research on the modifying effects of the constituents of rice-germ on colon cancer. The modifying action of ferulic acid in a long-term bioassay is now on-going in our laboratory.
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Acknowledgments
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We would like to thank Kyoko Takahashi, Yuki Ozawa and Chikako Usui for technical assistance, Kimiko Nakamura for secretarial assistance and Kazumasa Satoh for animal care. This work was supported in part by Grants-in-Aid (nos 10671782 and 11138255) from the Ministry of Education, Science, Sports and Culture, Japan, and a grant (HS-52260) from the Japan Health Sciences Foundation and the Program for Promotion of Fundamental Studies in Health Science from the Organization for Pharmaceutical Safety and Research (OPSR), Japan.
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Notes
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4 To whom correspondence should be addressed. Email: hidmori{at}cc.gifu-u.ac.jp 
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Received April 26, 1999;
revised July 12, 1999;
accepted July 30, 1999.