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Fukuoka Institute of Health and Environmental Sciences, Dazaifu City, Fukuoka 818-0135, Japan and * Research Laboratories, Chlorella Industries Company, Chikugo City, Fukuoka 833-0056, Japan
2To whom correspondence should be addressed.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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KEY WORDS: • rats • Chlorella • dioxin • polychlorinated dibenzo-p-dioxin (PCDD) • polychlorinated dibenzofuran (PCDF)
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Antilipidemic and antiatherosclerotic actions of Chlorella
have been reported (Fujiwara et al. 1990
, Sano and Tanaka 1987
). Okamoto et al. (1979)
reported
that Chlorella prevented stroke in stroke-prone
spontaneously hypertensive rats
(SHRSP);3
Chlorella alkali extracts decreased blood pressure in both
spontaneously hypertensive rats (SHR) and SHRSP (Okamoto et al. 1978
). In our previous study, a hot water extract of
Chlorella vulgaris (CVE) showed antitumor activity upon
intratumor injection into a methylcholanthrene-induced fibrosarcoma
system (Tanaka et al. 1984
). Furthermore, peritoneal
exudate cells harvested 24 h after an intraperitoneal hot water
extract of CVE injection into normal mice showed antitumor activity, as
assayed by the Winn-type in vivo neutralization test
(Konishi et al. 1985
). We recently reported that CVE
restored the capacity of murine retrovirus-induced acquired
immunodeficiency syndrome (MAIDS) mice to eliminate L.
monocytogenes in association with improvement of the deteriorated
immune response to L. monocytogenes (Hasegawa et al. 1995 and 1997
).
Dioxin is the common name for polychlorinated
dibenzo-p-dioxin (PCDD) and polychlorinated dibenzofuran
(PCDF). There are 75 PCDD congeners and 135 PCDF congeners in dioxin.
Dioxin is an industrial contaminant and ubiquitous environmental
pollutant generated by incineration of municipal waste. The main route
of human contamination by dioxin seems to be through food
(Schecter et al. 1994
, Takayama et al. 1991
). Dioxin is absorbed by the gastrointestinal system. It
has been reported that the gastrointestinal absorption ratio of
2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) dissolved in
vegetable oil was 50–90% in rats, guinea pigs and hamsters
(Nolan et al. 1979
, Olson et al. 1980
,
Piper et al. 1973
, Rose et al. 1976
,
van den Berg et al. 1994
); the absorption ratio of TCDD
in corn oil was >87% in humans (Poiger and Schlatter 1986
). The lipophilic nature of dioxin causes the congeners to
be stored in the liver, adipose tissue and breast milk. It has been
reported that dioxin is not completely eliminated from human milk and
blood, even after 2 y of nursing twins (Schecter et al. 1996
). Dioxin has been found in adipose tissues and livers of
human (Poiger and Schlatter 1986
, Ryan et al. 1985a
and
1985b
). The biological and toxicological effects of dioxin have been
studied extensively for > 20 y. TCDD has been reported to be
one of the most toxic molecules, causing acute and chronic toxicity,
including thymic involution, immunosuppression, hyperkeratosis,
hepatotoxicity and teratogenicity in animals (Landers and Bunce 1991
). Dioxin has also been found to cause tumors at several
sites in rats and mice.
To prevent toxicity in humans, it is important to inhibit the
absorption of dioxin from the gut and to excrete the dioxin stored in
the body into feces. The Yusho incident in the Fukuoka and Nagasaki
areas of Japan, which occurred in 1968, and the Yu-Cheng incident
in Taiwan in 1979 (Masuda et al.1985
) resulted from the
consumption of cooking oil contaminated with polychlorinated biphenyl
(PCB), PCDD and PCDF. The symptoms of Yusho disease include fatigue,
gastrointestinal disorder, joint pain, weight loss, anorexia,
hyperpigmentation of the nails and skin, and porphyria
(Yoshimura and Hayabuchi 1985
). We recently reported the
stimulating effect of dietary fiber on fecal excretion of PCDD and PCDF
congeners in rats administered orally the rice oil that caused Yusho
disease, and in addition, on fecal excretion of PCDD and PCDF congeners
stored in rats' bodies (Morita et al. 1993, 1995b and 1997
). In this study, which was designed to elucidate the
effect of Chlorella on fecal excretion of PCDD and PCDF
congeners, we examined the fecal excretion of PCDD and PCDF congeners
in rats administered the rice oil that caused Yusho disease, as a
substitute for purified dioxin mixtures.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Male Wistar rats were purchased from Seac Yoshitomi (Fukuoka, Japan)
and kept in the animal facility of Fukuoka Institute of Health and
Environmental Sciences. Rats were fed the semipurified basal diet shown
in Table 1
. The mineral and vitamin mixtures were obtained from Oriental Yeast
(Tokyo, Japan). Animal care and use conformed to the NIH published
guidelines.
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Dried Chlorella vulgaris cells were manufactured by
Chlorella Industries (Tokyo, Japan). The dioxin used for
these experiments consisted of the rice oil that caused Yusho disease,
which was kindly supplied by Yusho patients in Japan. The rice oil was
contaminated with PCDD, PCDF and PCB. PCDD and PCDF concentrations in
the rice oil used for these experiments are shown in Table 2
. The rice oil contained 7 types of PCDD congeners and 10 types of PCDF
congeners. Hexane, acetone, chloroform, methanol, dichloromethane,
anhydrous sodium sulfate and Florisil were purchased from Wako Pure
Chemical (Osaka, Japan). These reagents were of the grade used for
residual agricultural drug measurements. All other reagents were
special grade or better. Silica gel of silver nitrate was prepared as
follows. Silver nitrate (10 g) was dissolved in 5 mL of H2O
at 70°C. Kieselgel 60 (70–230 mesh, Merck, Darmstadt, Germany) was
added to the silver nitrate solution and left overnight.
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To examine the effect of Chlorella administration on
fecal excretion of PCDD and PCDF congeners, the contaminated rice oil
was administered orally to Wistar rats in two experiments. In
Experiment 1, after a 5-d acclimation period, rats were randomly
distributed into two groups (n = 4). After
overnight food deprivation, rats (~150 g) were given 4 g of the
basal diet (Table 1)
or 4 g of the 10% Chlorella
diet once on d 1 (Table 1)
; each diet contained 0.2 mL of the rice oil
that caused Yusho disease. Rats of the two groups were given their
respective rice oil–free experimental diets for 5 d. Body weight
and food intake were measured. Fecal samples were collected from each
rat daily in Experiment 1. In Experiment 2, after overnight food
deprivation, rats (~100 g) were given 4 g of the basal diet,
containing 0.5 mL of the contaminated rice oil, once on d 1 . Rats of
the two groups were given the rice oil–free basal diet for 7 d.
They were then fed the basal diet or the 10% Chlorella
diet from d 8 to 35. Body weight, food intake and fecal weight (d 8 to
35) were measured. Rats were housed individually in metabolic cages
designed for the separate collection of feces and urine. Feces were
dried overnight at 70°C and weighed.
Analysis of dioxin.
PCDD and PCDF congeners in feces were analyzed by gas chromatography-mass spectrometry (GC-MS). Fecal samples from each rat were homogenized and extracted quantitatively with 150–300 mL of chloroform/methanol (2:1, v/v) in a cylindrical glass-fiber filter in a Soxhlet extractor. The extract from each sample was concentrated to ~5 mL by evaporation under nitrogen and then diluted with chloroform to 50 mL.
To analyze the dioxin contents in each fecal sample, 2–40 mL of the extract was put into 10- or 50-mL tubes for centrifugation, and then concentrated and dried. After the addition of 200 pg of stable isotope tracer, 13C-labeled internal standard of tetra-hepta chlorinated dibenzo-p-dioxin and dibenzofuran (Wellington Laboratories, Guelph, Canada) and/or 400 pg of 13C-labeled internal standard of octachlorinated dibenzo-p-dioxin and dibenzofuran (Wellington Laboratories), 1–10 mL of 1 mol/L NaOH in ethanol was added to each sample and then the sample was hydrolyzed overnight at room temperature. The alkali hydrolysates of each sample were shaken with 2–10 mL of hexane plus 0.5–5 mL of H2O. After removal of the aqueous layer, the hexane layer was washed with 1–5 mL of H2O, and washed 5 times with 2–10 mL of concentrated H2SO4. The hexane extract was applied to a 0.8 g silver nitrate column (7 mm diameter) and eluted from the column with 8 mL of hexane; the eluates were concentrated to 1 mL. Next, the hexane extract was applied to a 0.6 g Florisil (U.S. Silica, New York, NY) column (7 mm diameter), and dioxin was eluted with 4 mL of hexane, followed by 8 mL of dichloromethane. The eluates from the column were dried and dissolved in 15 µL of n-nonane. Levels of PCDD and PCDF congeners were measured in these samples. Dioxin analysis was performed by GC-MS (Hewlett-Packard 5890, California City, CA; Finnigan Mat-90, Bremen, Germany) using a capillary column (0.32 mm x 30 m, SP-2331, Supelco, Bellefonte, PA) with the resolution mode set at 7000 and quantified in the selected ion monitoring acquisition mode.
The increase in the amounts of PCDD and PCDF congeners excreted in feces due to the Chlorella diet was calculated using the following equation: acceleration index of fecal excretion of PCDD and PCDF congeners due to Chlorella diet = [(% fecal excretion in the Chlorella group)/(% fecal excretion in the control group) - 1]. The percentage of gastrointestinal absorption in rats administered the rice oil was calculated using the following equation: % gastrointestinal absorption = (100 - % fecal excretion of administered PCDD and PCDF congeners). The inhibition of gastrointestinal absorption in the Chlorella group compared with the control group was calculated using the following equation: % inhibition of gastrointestinal absorption due to Chlorella diet = [(% gastrointestinal absorption in the control group) - (% gastrointestinal absorption in the Chlorella group)]/[(% gastrointestinal absorption in the control group) x 100].
Statistics.
Differences between the two groups were tested by Student's t test. Excretions of different congeners were compared by the Mann-Whitney U test. Stat works version 1.2 for the Macintosh (Cricket Software, Philadelphia, PA) was used. A P-value < 0.05 was considered significant.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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There was no significant difference in body weight gain between the
control group and the Chlorella group (Table 3
, Experiment 1). Food intake and total fecal weight were significantly
greater in the rats fed the Chlorella diet compared with
those fed the basal diet. In Experiment 2, there was no significant
difference in body weight gain or food intake between the control group
and the Chlorella group (Table 3)
. The total fecal weight
during the 28-d period from d 8 to 35 was significantly greater in the
rats fed the Chlorella diet compared with the control rats.
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The percentages of fecal excretion of PCDD and PCDF congeners from d 1
to 5 after administration of the rice oil are shown in Table 4
(Experiment 1). In the control group, the percentages of fecal
excretion of PCDD congeners were 1.6–68.5%; those of PCDF congeners
were 0.15–63.7%. The fecal excretions of highly chlorinated PCDD and
PCDF congeners were greater in the control rats administered the rice
oil. On the other hand, in the Chlorella group, the
percentages of fecal excretions of PCDD congeners were 19.7–3.3%, and
those of PCDF congeners were 1.81–83.0%. The percentages of fecal
excretions of PCDD and PCDF congeners were significantly greater in
rats fed the Chlorella diet than in the control rats. The
percentages of inhibition of gastrointestinal absorption due to the
Chlorella diet were 18.4–47.0% for PCDD congeners and
1.6–53.2% for PCDF congeners (Table 4)
. Thus, gastrointestinal
absorption of the congeners was significantly inhibited in rats fed
Chlorella. The amounts of PCDD congeners excreted in feces
of rats fed Chlorella were 0.2- to 11.3-fold greater
(P < 0.05) than those of control rats (Fig. 1
). Rats fed the 10% Chlorella diet had 0.3- to 12.8-fold
greater (P < 0.05) excretions of PCDF congeners
compared with controls. In the rats fed Chlorella, excretion
of 2,3,7,8-T4CDD was significantly greater than
that of highly chlorinated PCDD congeners, and excretions of for
2,3,7,8-T4CDF,
1,2,3,7,8-P6CDF, and
2,3,4,7,8-P5CDF were significantly greater than
those of highly chlorinated PCDF congeners (Fig. 1)
. Tetra-penta
chlorinated dioxins are the most toxic, whereas hepta-octa
chlorinated dioxins have comparatively lower toxicity (Safe 1990
). The 2,3,7,8-T4CDD and
T4CDF congeners are retained almost exclusively
in tissues, epecially liver and fat (van den Berg 1984
).
In this study, highly toxic PCDD and PCDF congeners, i.e., less
chlorinated compounds, were more easily excreted into the feces than
weakly toxic highly chlorinated PCDD and PCDF congeners due to
Chorella administration (Fig. 1)
.
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The percentages of fecal excretion of PCDD and PCDF congeners from d 8
to 35 after administration of the contaminated rice oil are shown in
Table 5
(Experiment 2). In the control group, the percentages of fecal
excretion of PCDD congeners were 1.06–5.79%, and those of PCDF
congeners were 0.006–3.66%. On the other hand, in the
Chlorella-treated group, the percentages of fecal excretion
of PCDD congeners were 2.60–7.49%; those of PCDF congeners were
0.012–6.68%. The percentages of fecal excretion of most PCDD and PCDF
congeners in rats fed the 10% Chlorella diet were
significantly greater than those of control rats. The fecal excretions
of highly chlorinated PCDD,
1,2,3,4,6,7,8,9-O8CDD, and highly chlorinated
PCDF, 1,2,3,4,6,7,8,9-O8CDF, were greater than
those of less chlorinated PCDD, tetra-hepta chlorinated PCDD, and
less chlorinated PCDF, tetra-hepta chlorinated PCDF, in both groups
administered the rice oil. The amounts of PCDD congeners excreted in
feces of rats fed Chlorella were 0.3- to 3.4-fold higher
(most P < 0.05) than those of control rats (Fig. 2
). Rats fed the 10% Chlorella diet had 0.5- to 2.5-fold
greater (most P < 0.05) excretions of PCDF congeners
than those of controls. In Experiments 1 and 2, the more chlorinated
congeners were excreted the most overall in the two groups. However,
the highly toxic and less chlorinated congeners were excreted the most
in Experiments 1 and 2 due to Chlorella administration.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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collected feces from 5-mo-old breast-fed infants and
measured excreted dioxin (nonabsorbed amount); they found excretion
percentages of ~6% (excreted amount/intake) for
2,3,7,8-T4CDD, 6% for
1,2,3,7,8-P5CDD, 12% for
1,2,3,4,7,8-H6CDD, 9% for
1,2,3,6,7,8-H6CDD, 20% for
1,2,3,7,8,9-H6CDD, 38% for
1,2,3,4,6,7,8-H7CDD, 4% for
2,3,7,8-T4CDF, 3% for
1,2,3,7,8-P5CDF, 5% for
2,3,4,7,8-P5CDF, 10% for
1,2,3,4,7,8-H6CDF, 11% for
1,2,3,6,7,8-H6CDF, 9% for
2,3,4,6,7,8-H6CDF and 49% for
1,2,3,4,6,7,8-H7CDF. When Abraham's data are
compared with the rat data obtained in this study (Table 4)
, the dioxin
excretion in the rat control group was similar to that in infants,
suggesting that there are no marked differences in dioxin absorption
between humans and rats, and that there is very high gastrointestinal
absorption in both species. We previously reported the effects of
dietary fibers such as rice bran on dioxin excretion into feces in rats
(Morita et al. 1995b and 1997
). Morita et al. (1997)
reported that the rice bran fibers significantly
increased dioxin excretion compared with burdock, soybeans, and
cabbage. The excretion ratios for PCDD and PCDF congeners were
significantly greater in the rice bran–fed rats than in controls,
ranging from 0.6 to 2.3 times for PCDD congeners and from 0.5 to 10.4
times for PCDF congeners. In this study, the excretion ratios for PCDD
and PCDF congeners were significantly greater in the
Chlorella-fed rats than in controls, ranging from 0.8 to 5.6
times for PCDD congeners and from 0.9 to 11.1 times for PCDF congeners.
These results suggest that Chlorella promotes dioxin
excretion more markedly than rice bran fiber. The biological
half-life of 2,3,7,8-T4CDD in a 42-y-old man
was calculated to be 5.8 y. Moreover, with regard to the
metabolism and excretion of dioxin, the metabolic turnover and
excretion rates of 2,3,7,8-T4CDD were slow
(Poiger and Schlatter 1986
). On the other hand, the
metabolic turnover and excretion rates of hepta-octa chlorinated
dioxins are relatively high, and there is almost no storage of
hepta-octa chlorinated dioxins in the body. Chlorella
administration stimulated the fecal excretion of
2,3,7,8-T4CDD, which is toxic and hard to
metabolize, more than that of penta-octa chlorinated PCDD
congeners, which are less toxic and more easily metabolized
(Safe 1990
, Tables 4
and 5
in this paper). The
biological half-life of 2,3,7,8-T4CDD in
humans was calculated to be 5.8 y, and 0.03% of the amount
accumulated in the body is excreted every day.
The dioxin is absorbed from mucosal cells lining the gastrointestinal
tract; we speculate that absorbed dioxins were transferred into the
intestinal lumen and reabsorbed from mucosal cells, perhaps via bile
from liver. Some dioxin that accumulates in the body is secreted with
bile into the intestine (McKinley et al. 1993
).
Inhibition of dioxin reabsorption increases its excretion into feces,
resulting in a decrease in its accumulation in the body. The
Chlorella group had 3.4- and 2.5-fold greater excretions of
the highly toxic 2,3,7,8-T4CDD and
2,3,4,7,8-P5CDF, respectively, absorbed into the
body compared with the control group. These results suggest that
Chlorella inhibited dioxin reabsorption, thereby promoting
the excretion amounts of dioxin from the body into feces.
Chlorella contains components with various physiologic
functions, such as vitamin C, vitamin E, ß-carotene, dietary fibers,
chlorophyll and glycoproteins.
The mechanism by which Chlorella stimulates dioxin excretion
from the body is still unclear. However, three factors appear to be
associated with inhibition of absorption and reabsorption in the
intestine. The first factor is dietary fiber in Chlorella
cells. We reported previously that several types of dietary fiber bind
dioxin (Morita et al. 1995a
) and stimulate the excretion
of PCDD and PCDF congeners (Morita et al. 1995b and 1997
). After ingestion of Chlorella, dietary fibers
contained in Chlorella cells may inhibit dioxin absorption
from the digestive tract, promoting its excretion into feces. The
second factor that may be involved in the inhibition of absorption and
reabsorption of dioxin is the chlorophyll in Chlorella
cells. It has been reported that chlorophyllin, a chlorophyll
derivative, forms a complex with heterocyclic amines (Dashwood
et al. 1992
, Negishi et al. 1989
). The
chlorophyll contained in Chlorella cells may form a complex
with dioxin congeners with a planar structure, thereby inhibiting
absorption in the digestive tract. The percentage of chlorophyll in
Chlorella cells used in this experiment was 2%. However,
the effectiveness of chlorophyll in Chlorella cells on
dioxin excretion has not been undetermined. In future studies using
chlorophyll derived from Chlorella or other sources, we will
study its effects on dioxin excretion. The third component that may be
involved in the reabsorption of dioxin is the lipid in
Chlorella cells. We tested rice bran fibers in combination
with cholestyramine, an anticholesterol drug, in patients with Yusho
disease and obtained high excretions of PCDF, especially
2,3,4,7,8-P5CDF (Iida et al. 1995
). It has been reported that Chlorella has
cholesterol-lowering effects similar to that of cholestyramine
(Sano 1982
). These authors studied the effect of
Chlorella lipids composed of glycolipid and phospholipid
in rats fed a high cholesterol diet and found that
Chlorella prevented the absorption of endogenous and
exogenous cholesterol in bile and increased the excretion of
cholesterol from the body. Therefore, fiber, chlorophyll, and lipids
contained in Chlorella cells may be involved in the
inhibition of absorption of dioxin in the digestive tract and
reabsorption of dioxins in bile. To prevent damage by dioxin in humans,
dioxin ingested via food should be captured in the digestive tract and
absorption should be decreased by ingestion of foods such as
Chlorella, which contains abundant dietary fiber and
chlorophyll. In addition, excretion of dioxin already accumulated in
the body should be promoted by increasing catabolism and inhibiting
reabsorption of bile and dioxin secreted into the digestive tract. In
conclusion, Chlorella may be useful for promoting dioxin
excretion from the body.
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FOOTNOTES |
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3 Abbreviations used: CVE, hot water extract of
Chlorella vulgaris; GC-MS, gas
chromatography-mass spectrometry; MAIDS, murine
retrovirus-induced acquired immunodeficiency syndrome; PCB,
polychlorinated biphenyl; PCDD, polychlorinated
dibenzo-p-dioxin; PCDF, polychlorinated dibenzofuran;
SHR, spontaneously hypertensive rats; SHRSP, stroke-prone
spontaneously hypertensive rats; TCDD,
tetrachlorodibenzo-p-dioxin.
Manuscript received January 13, 1999. Initial review completed February 24, 1999. Revision accepted June 1, 1999.
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