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Yakult Central Institute for Microbiological Research, Yaho 1796, Kunitachi, Tokyo 186-8650, Japan
1To whom correspondence should be addressed. E-mail: mitsuyoshi-kano{at}yakult.co.jp.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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KEY WORDS: • fermented soymilk • genistein • daidzein • ethanol metabolism • rats
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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). Vegetable oils such as soybean oil and coconut oil delay the elimination rate of gastric ethanol and lessen the increase in plasma ethanol concentration (2
). Moreover, because ethanol-metabolizing enzymes such as alcohol dehydrogenase (ADH),2
acetaldehyde dehydrogenase (ALDH) and the microsomal ethanol oxidizing system (MEOS) contribute to the clearance of ethanol and toxic acetaldehyde (3
), components that stimulate these enzyme activities are expected to ameliorate alcohol toxicity. For example, sesamin and garlic stimulate ethanol metabolism, especially acetaldehyde clearance (4
,5
).
Soybeans are consumed in Japan as part of an ordinary diet. Tofu and "edamame," boiled fresh soybeans, are popular snacks to consume with alcohol, although few reports have been published about the effect of soy products on ethanol consumption. However, isoflavones prepared from the crude extract of Pueraria lobata are used as a traditional medicine for anti-inebriation and suppress alcohol intake by alcohol-preferring rats (6
,7
). The major components of the extract, daidzin and daidzein, are inhibitors in vitro of mitochondrial low Km ALDH (8
) and ADH (9
), whereas intragastric or intraperitoneal injection of daidzin to rodents does not affect these enzyme activities (10
,11
). Thus, it is unclear how isoflavones contribute to alcohol suppression.
Recently, soybean and soy protein have received much attention for their preventive effects on chronic disease (12
–14
). We investigated the physiologic functions of fermented soymilk (FSM) by a probiotic bifidobacterium (15
) (Bifidobacterium breve strain Yakult) that has been studied in clinical trials of preterm infants (16
) and patients with decompensatory cirrhosis (17
). Most of the isoflavones are deconjugated to aglycones in FSM unlike in soymilk (SM). Isoflavone aglycones can be absorbed into blood more rapidly and efficiently than the glycosides (18
,19
). This difference may be associated with the effect of FSM on lipid metabolism (20
–22
) and mammary carcinogenesis (23
). The purpose of this study was to elucidate the effect of soy products on ethanol consumption. We investigated the change in ethanol absorption and metabolism upon acute and chronic exposure to ethanol in rats using soy products with different absorbability of isoflavones, and the effect of isoflavones on ethanol metabolism in isolated rat hepatocytes.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Crude soymilk from Shikokukakouki (Tokushima, Japan) was used as the starting material for fermented soymilk. B. breve strain Yakult was obtained from the Culture Collection Research Laboratory of Yakult Central Institute for Microbiological Research (Tokyo, Japan). A seed culture prepared anaerobically in the soymilk was freshly added to the autoclaved soymilk at a 1:100 inoculation ratio and fermented statically at 37°C for 21 h. The titratable acidity, pH and viable cell count of the fermented soymilk were 0.645%, 4.8 and 1.35 x 1012 colony-forming units/L, respectively. The soymilk and fermented soymilk were used in the acute ethanol administration study. Furthermore, for use in the chronic ethanol study, the original soymilk and fermented soymilk were freeze-dried and milled until the products passed through a 0.84-mm sieve (20 mesh). The content of the crude protein, crude fat, ash and sugar in the soymilk was 4.5, 3.2, 0.7 and 2.8%, respectively. This composition was unaffected by the fermentation process as described previously (21
).
Acute ethanol administration.
Male Sprague-Dawley rats (n = 18, 10 wk old, 300–350 g; Japan S.L.C., Shizuoka, Japan) were housed individually in stainless steel wire-bottomed cages in a room with controlled lighting (lights on 0830–2030h), temperature (24 ± 2°C), and humidity (60 ± 5%). Rats were given free access to AIN-93 purified diets (24
) and distilled water. They were maintained and treated in accordance with the guidelines of the Ethical Committee for Animal Experiments of Yakult Central Institute.
After a 7-d adaptation period, rats were assigned randomly to three groups (n = 6), the control, SM and FSM groups. After being deprived of food overnight (16 h), rats were given sample beverages (10 mL/kg body) intragastrically. The control solution contained 45 g casein, 32 g corn oil and 35 g sucrose/L. To equalize energy content, protein and lipid in SM and FSM were replaced by casein and corn oil in the control solution. The carbohydrate, ash and the other components of the SM and FSM were replaced by sucrose in the control. Ethanol was added to the control solution, SM solution and FSM solution so that the final ethanol was 20%. After 0.5, 1, 2, 3, 4 or 5 h, rats were anesthetized with diethyl ether. Blood was collected from the hepatic portal vein and ventral aorta into tubes containing EDTA. Plasma was obtained by centrifugation at 2000 x g for 15 min at 4°C and stored at -70°C until analysis.
Hepatocyte culture.
Male Sprague-Dawley rats (8 wk old, 250–300 g) were housed and fed as in the acute ethanol administration study. At the end of wk 2, untreated rats were anesthetized with an intraperitoneal injection of pentobarbital sodium (Nembutal, Abbot Laboratories, Chicago, IL), 10 mg/kg body. Hepatocytes were isolated separately by in situ perfusion of the liver with collagenase (Collagenase-YAKULT S, Yakult Pharmaceutical, Tokyo, Japan) using the method of Selgen (25
). After filtration through two layers of stainless mesh (150 µm), the parenchymal cells were purified by centrifugation (3 times) at 50 x g for 1 min. The viability of isolated hepatocytes was measured immediately by the exclusion of 0.2% trypan blue after the preparation. Initial viability assessed by the trypan blue exclusion method was routinely >85%. The isolated cells were suspended at a density of 107 cells in 10 mL of Eagle’s medium essential medium containing 1 nmol/L insulin and 1 nmol/L dexamethasone on a plastic dish (90 x 20 mm; Sumitomo Bakelite, Akita, Japan) and then were cultured with 0.1–5 µmol/L genistein or daidzein (Sigma-Aldrich Japan, Tokyo, Japan) and 65 mmol/L ethanol at 37°C under 5% CO2 in a CO2-incubator (Tabai Espec, Osaka, Japan). The concentration of ethanol (65 mmol/L) in the culture medium was equal to the concentration in portal blood. After 4 h, the cultured medium was collected, and filtered through cellulose acetate (0.22 µm, Millipore, Tokyo, Japan)
Chronic ethanol exposure.
Male Sprague-Dawley rats (n = 32, 10 wk old, 300–350 g) were housed and fed as in the acute ethanol administration study. After a 7-d adaptation period, rats were assigned randomly to four groups (n = 8), and received the control diet + 5% ethanol beverage (control group), the SM diet + 5% ethanol (SM group), the FSM diet + 5% ethanol (FSM group) or the control diet + 8.9% sucrose solution (untreated group) for 24 d. The compositions of the three diets (control, SM and FSM diets) are shown in Table 1
. The ethanol and sucrose solutions were similar in energy. Body weight was recorded once each week, and food consumption (food and fluid) was recorded every 2 or 3 d. Energy intake was calculated using food and fluid compositions. After 24 d, the experimental diets were withheld for 16 h and rats were anesthetized with diethyl ether.
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The cellular fractions of the liver were prepared according to previous papers (26
–28
). Briefly, the liver was homogenized in 9 volumes of ice-cold potassium phosphate buffer (0.1 mol/L potassium phosphate containing 1 mmol/L sodium EDTA and 1 mmol/L dithiothreitol, pH 7.4). The homogenate was centrifuged at 800 x g for 10 min to remove cell debris and nuclei. The supernatant was centrifuged at 10,000 x g for 20 min. The pellet was resuspended in the same buffer, and centrifuged again at 10,000 x g for 20 min. This centrifugation was repeated twice, and the pellet obtained was resuspended in the buffer (mitochondria fraction). The above supernatant was further centrifuged at 105,000 x g for 60 min. The clear supernatant obtained was used as the cytosol fraction. The precipitate was resuspended in the buffer and centrifuged again at 105,000 x g for 60 min. The washed pellet was resuspended in the buffer (microsome fraction). Mitochondria, cytosol and microsome fractions were stored at -70°C until analysis.
Analysis.
Ethanol concentrations in the portal and aortal plasma, and cell culture medium and the ethanol concentration in the gastric contents were measured with F-kit Ethanol (Boehringer Mannheim Biochemica, Tokyo, Japan). Acetaldehyde concentrations in the aortal and the culture medium were measured with F-kit Acetaldehyde (Boehringer).
Isoflavone (genistein and daidzein) concentrations in the soymilk, fermented soymilk and the portal blood plasma were determined according to the method of Shirota-Matsumoto et al. (29
).
Cytosolic ADH activity was assayed spectrophotometrically by measuring NADH production (30
). The specific activity is expressed as µmol NADH/(min · mg protein). ALDH activities in the mitochondrial, microsomal and cytosolic fractions were assayed as total, low Km and high Km activities according to the method of Lebsack et al. (31
). The acetaldehyde concentration used as the substrate was 5 mmol/L for total ALDH and 50 µmol/L for low Km ALDH. High Km ALDH was calculated by difference. Rotenone (2 µmol/L) was added to inhibit NADH oxidase for the mitochondrial ALDH assay. Pyrazole (200 µmol/L) was added to inhibit ADH activity in the microsomal and cytosolic ALDH assays. The specific activity was expressed as nmol NADH/(min · mg protein).
MEOS activity in the microsomal fraction was assayed according to the method of Klein et al. (32
). The specific activity was expressed as nmol of acetaldehyde/(min · mg protein). Cytosolic glutathione S-transferase (GST) activity was assayed using 1-chloro-2, 4-dinitrobenzene as the substrate (33
). Thiobarbituric acid reactive substances (TBARS) in the liver were measured as a conventional index of hepatocellular damage according to the method of Ohkawa et al. (34
). The concentration of TBARS was expressed as nmol malondialdehyde/mg protein.
Glutamic oxaloacetic transaminase (GOT) and glutamic pyruvic transaminase (GPT) activities in plasma were determined using transaminase C II-test Wako (Wako Pure Chemical, Osaka, Japan). 
-Glutamyl trancepeptidase (-GTP) activity in plasma was determined using -GTP C-test Wako (Wako). Protein concentrations in liver homogenate and cell fractions were measured by the method of Lowry et al. (35
).
Statistical analysis.
The results were expressed as means and SEM. The means were compared using STATISTICA software (StatSoft, Tulsa, OK), by ANOVA and subsequent Tukey’s honestly significant difference comparisons after logarithmic transformation to stabilize the variance, if the variances differed (36
). In the case of hepatocyte culture data, experimental means were compared with the control using Dunnett’s test (37
). Differences were considered to be significant at P < 0.05.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Concentrations of the isoflavones in SM and FSM are shown in Table 2
. Isoflavones in SM almost always existed in the glycoside form, but in FSM, the aglycone ratio increased; notably, 
90% of genistein was aglycone.
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). The concentration of ethanol in the gastric contents was higher in the FSM group than the control group at 0.5 and 1 h after administration (Table 4
). Portal ethanol was lower in the FSM groups than in the control at 0.5, 1 and 3 h after administration (Table 5
), and aortal ethanol was lower in the FSM group than in the control group at 0.5–4 h after administration (Table 5)
. Aortal acetaldehyde was lower in the FSM group than the control group at 0.5–5 h after administration (Table 5)
.
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Concentrations of ethanol in the cultures containing 5.0 µmol/L genistein were lower than in the control (Table 6
). The concentration of acetaldehyde in cultures containing 2.0 and 5.0 µmol/L genistein tended to be lower than control (P = 0.08 and 0.10, respectively).
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Body and liver weights did not differ among groups (Table 7
). Fluid intakes of the FSM and untreated groups were greater than those of the control and SM groups, but there were no differences in energy intake. Total intake of ethanol was significantly greater in the FSM group than the other two ethanol-treated groups (data not shown).
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). However, the FSM group had a lower MEOS activity than the control group and was not different from the SM and untreated groups. Low Km ALDH activity in the mitochondria fraction of the control group was lower than that of the untreated group. High Km and total ALDH activities did not differ among the groups. Although ethanol alone did not affect cytosolic GST activity relative to the untreated group, the SM and FSM groups had significantly higher activity than the control group. TBARS levels in the liver homogenates and in the mitochondrial fraction of the control group were greater than those of the untreated group. TBARS in the microsomal fraction and liver enzymes, such as GOT, GPT and -GTP did not differ among groups (data not shown).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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). Xie et al. (11
) showed that daidzin in an extract of P. lobata suppresses ethanol absorption. However, our data indicate that daidzin does not affect ethanol absorption; the daidzin concentration in FSM was lower than in SM (Table 2)
and the plasma daidzein concentration did not differ between the SM and the FSM groups (Table 3)
. The portal blood passing through the gastrointestinal tract directly reflects ethanol absorption, whereas the aortal blood passing through the liver reflects hepatic ethanol metabolism in addition to absorption. After ethanol administration, aortal ethanol and acetaldehyde levels were lower in the FSM group than in the control group and the SM group generally did not differ from either group. From these results, it is unknown whether the FSM effect is dependent on lowering ethanol absorption or enhancing ethanol metabolism after acute ethanol administration.
We investigated whether soy components directly affect the metabolism of ethanol in the liver. Ethanol entering into the liver through the portal vein is oxidized into acetaldehyde, and then to acetate and acetyl CoA in the hepatocytes. Soy isoflavones also flow into the liver through the portal vein. We attempted to use a hepatocyte culture system to evaluate the direct effect of soy isoflavones on ethanol metabolism. The genistein, daidzein and ethanol concentrations used here were based on the concentrations in the portal blood of rats 30 min after FSM and ethanol injection. The ethanol and acetaldehyde levels were lowered at the higher concentration of genistein. The portal concentration of genistein (2 µmol/L) tended to lower ethanol and acetaldehyde (P = 0.12 and 0.08, respectively) (Table 6)
, indicating that ethanol metabolism would be enhanced by genistein at a physiologic level. In the case of 5 µmol/L genistein, the ethanol level decreased (P = 0.045) and the acetaldehyde level tended to decrease (P = 0.10). Furthermore, this result suggests that in vivo, the decrease in aortal ethanol and acetaldehyde concentration by FSM would be closely related to the direct effects of soy isoflavones on liver function. These observations are slightly different from the results of Keung and Vallee who found that daidzin and genistin in vitro inhibited human ALDH, but not the corresponding aglycones, daidzein and genistein (8
), and that in in vivo experiments using hamsters, daidzin suppressed ethanol intake without affecting acetaldehyde metabolism (10
).
Ethanol induces MEOS activity while lowering ALDH activity (31
); therefore, acetaldehyde and reactive oxygen species accumulate upon chronic or high consumption of ethanol. These toxic molecules would consequently cause cell injury through lipid peroxidation, protein inactivation and DNA damage (39
–41
). GST takes part in antioxidation through glutathione conjugation of active xenobiotic metabolites and reduction of lipid peroxides (42
). Acetaldehyde also is detoxified by conjugation (43
). We found that FSM prevented the elevation of MEOS caused by chronic ethanol exposure. Conversely, SM and FSM increased GST activity in chronically ethanol-exposed rats, and FSM tended to enhance low Km ALDH activity (P = 0.15), whereas SM did not (P = 0.31). These results suggest that the consumption of soy products would contribute to the prevention of ethanol-induced liver injury through enhancement of ethanol metabolism and the antioxidation system. In fact, chronic ethanol exposure resulted in a larger amount of TBARS in the liver, which is a putative marker of lipid peroxidation (44
), and addition of SM and FSM to diet tended to reduce the content (P = 0.18 and 0.10, respectively). SM and FSM differed somewhat in efficacy, as shown in aortal ethanol and acetaldehyde levels after oral administration and in MEOS, and GST activities. It remains to be elucidated whether the differences are associated with organic acids (acetic and lactic acids) and the probiotic bacteria accumulating during fermentation, as well as isoflavone aglycones.
Soy products alter ethanol metabolism through inhibition of cytochrome P450 (CYP)2E1 in MEOS as observed above. Chae et al. (45
) reported that genistein is a potent inhibitor of CYP1A1 and/or CYP1A2 induced by ß-naphthoflavone, and Ronis et al. (46
) recently found that soy protein increases the dexamethasone-induced mRNA expression of hepatic CYP3A2 compared with casein, suggesting a relationship between soy components and the cytochrome P450 system, although the effects of soy components on CYP2E1 are not yet known.
In summary, we showed that soy products inhibit ethanol absorption and enhance ethanol metabolism, and that isoflavones may be the active factors. Reactive agents generated during metabolism would trigger ethanol-induced cell injury, and the antioxidation system would suppress the damage. Soy isoflavones have antioxidative activity, acting to reinforce the system. Soy products also improve parameters of cell injury due to chronic ethanol exposure. These observations indicate that soymilk products contribute to the suppression of ethanol-induced cell injury. Because we are interested in the effect of soy on ethanol metabolism and cell toxicity, a more detailed study is underway in our laboratory.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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-GTP, -glutamyl transpeptidase; MEOS, microsomal ethanol oxidizing system; SM, soymilk; TBARS, thiobarbituric acid reactive substance. Manuscript received 25 May 2001. Initial review completed 11 July 2001. Revision accepted 22 October 2001.
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LITERATURE CITED |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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