JPH0733653A - Suppressor for aldehydic toxicity - Google Patents

Abstract

PURPOSE:To obtain a medicine or a functional food for preventing or improving drunken symptoms, acute intoxication and secondary effects caused by aldehydes in blood produced according to the ingestion of alcohols. CONSTITUTION:These suppressor for the aldehydic toxicity and preventing or improving agent for drunken symptoms caused by aldehydes produced in blood according to drinking contain at least one selected from the group consisting of an alpha-hydroxybutyric acid having the (R) type steric configuration, a beta-hydroxybutyric acid having the (R) type steric configuration, succinic acid and salts thereof as an active ingredient.

Description

Detailed Description of the Invention

[0001]

The present invention relates to α-hydroxybutyric acid having an (R) type configuration and β having an (R) type configuration.
-Hydroxybutyric acid, succinic acid, and an acetaldehyde toxicity inhibitor characterized by containing at least one selected from the group consisting of salts thereof as an active ingredient. The present invention relates to a drug or a functional food that protects the living body from the toxicity caused by acetaldehyde generated.

[0002]

2. Description of the Related Art Alcohols, especially ethyl alcohol, are converted into acetaldehyde mainly by oxidation in the liver by alcohol dehydrogenase. In addition, a part of it is microsomal ethanol oxidation system (microsomal ethanol oxidizi
ng system: MEOS) and catalase present in peroxisomes also oxidize to acetaldehyde (LJ Kricka and PMS Cleark, Biochemistry of a
lcohol and alcoholism, Ellis Horwood Ltd., Chichest
er, 1979). Acetaldehyde is further converted to acetic acid by aldehyde dehydrogenase. About 75% of the alcohol taken up by the liver will be released to the circulatory system as acetic acid. (Lundquist, E. et al., J. Clin. Invest.,
Vol.41, 955-961, 1962). Generally, the blood alcohol level of healthy people after drinking is 0.01-0.1% (Lundqu).
ist, E., The metabolism of alcohol, 1-52, Biologic
al basis of alcoholism, Wiley-interscience, Toront
o, 1971). On the other hand, the blood concentration of acetaldehyde is about 1/1000 that of alcohol.

Acetaldehyde is an inevitable product in terms of alcohol metabolism, and is considered to form a major cause of acute poisoning when an alcoholic beverage is excessively ingested or so-called "sickness". The following side effects of acetaldehyde are also being clarified.

(1) Inhibition of oxidative phosphorylation and suppression of coenzyme A activity in the brain and liver (Beer, CT and
Quastel, JH, Can. J. Biochem. Physiol., Vol.36,
(531-541, 1958) (2) Acceleration of catecholamine release and accompanying decrease in cardiac function (McCloy, RB et al., Cardiovasc. Re
s., Vol.8, 216, 1974).

(3) Production of tetrahydroisoquinolines. There is a theory that this substance is produced by condensation of acetaldehyde with norepinephrine or epinephrine, and forms the main cause of alcoholism (Sandler, M.
et al., Nature (London), Vol. 241, 439-443, 1973).

(4) Formation of tetrahydro-β-carbolines. This substance is formed by condensation of acetaldehyde and indoleamines and is also said to be involved in alcoholism (Rahwan, RG, Toxicol. Appl.
Pharmacol., Vol.34, 3-27,1975).

(5) Heart rate, ventilation, increase in dead space (Asmuss
en, E. et al., Acta Pharmacol. Toxicol., Vol.4, 31
1-320, 1948).

(6) Mutagenicity and chromosomal aberration induction (Obe, G. and Ristow, H., MutationRes., Vol.65, 22)
9-259, 1979).

Therefore, in order to taste alcohol in a healthy manner, it is desirable to reduce the unfavorable effects of acetaldehyde on the living body and prevent unwanted side effects.

Particularly in Japanese and other Mongoloids, about 50% of people are genetically deficient in aldehyde dehydrogenase (ALDH2). And the blood acetaldehyde concentration after alcohol intake in the enzyme deficient person is significantly higher than that in the non-deficient person (about 17
Have been pointed out (Harada, S., Lancet, 11,9)
82, 1981).

From this point of view, many studies have been conducted on substances that lower the blood concentration of acetaldehyde, and to date, L-cysteine, L-2-methylthiazoline-4-carboxylic acid, thiamine hydrochloric acid ( Sprinc
e, H. et al., Agents and Actions, Vol.4 / 2, 125-13
0, 1974), sodium bisulfite, D-penicillamine (N
agasawa, HT, et al., Life Sci., Vol.20, 1187-11
94, 1977), Nicotinamide (Eriksson, CJP, FE
BS Lett., Vol.40, 317, 1974) has been reported.

However, regarding the effectiveness of compounds having an SH group such as L-cysteine, thiamine hydrochloride, and D-penicillamine, there is no effect on the blood concentration of acetaldehyde in the administration area where D-penicillamine is clinically acceptable. There is also a negative opinion because it does not reach (Inoue, K. et al., Jpn. J. Alcohol and Drug Depen.
dence, Vol. 19 (1), 74-82, 1984). Further, L-cysteine is relatively toxic, and other thiol compounds also have a pharmacological action different from the purpose of the present invention, and thus it cannot be said to be an ideal acetaldehyde toxicity reducing agent.

Recently, it has been reported that one of the amino acids, L-α-alanine, effectively suppresses the acute toxicity of acetaldehyde (Fujiwara, N. et al., Jpn. J. A.
lcohol and Dependence, Vol.23 (1), 58-69, 1988).

Α- and β-hydroxybutyric acid is a kind of ketone body. These substances were initially thought to be useless metabolites found in the body under pathological conditions because they are found in urine during diabetes and starvation. However, in recent years, it has been reported that the (R) form of β-hydroxybutyric acid has a protective action on myocardial metabolism (JP-A-58-20).
1746). In addition, β- hydroxybutyric acid, in vitro
Have been reported to be used in tissues in preference to long-chain fatty acids and glucose (Forsey, RGPet a
L., Physiol. Pharmacol. Vol. 65, 401-406, 1987; Rob
inson AM and Willamson DH, Physiol. Rev. Vo
l.60. 143-147, 1980). From this point of view, β-hydroxybutyric acid is considered to be an excellent energy substrate, and by utilizing this characteristic, it has recently been applied to an infusion solution when glucose supplementation is interrupted in vivo due to severe injury or burn injury. (JP-A-2-191212).

On the other hand, succinic acid is present in a large amount in plants, but is also present in cells of animals and microorganisms, and is one of the fermentation products of yeast and bacteria. Hydrogenation of fumaric acid and maleic acid. It is obtained by reducing malic acid with hydrogen iodide, fermenting ammonium tartrate or potassium malate, and the sodium salt is a savory component of shellfish, and is used as a seasoning for fish sausages, kamaboko and the like. It is also known that it is an intermediate in the citric acid cycle and is produced by decomposition of succinyl CoA produced by dehydrogenation of 2-oxoglutarate, and is dehydrogenated to fumaric acid by succinate dehydrogenase.

However, it has not been known so far that α or β-hydroxybutyric acid having a (R) type configuration and succinic acid have an action of suppressing the toxicity of acetaldehyde in the living body.

[0017]

The object of the present invention is to provide a highly safe inhibitor against the toxicity of blood acetaldehyde produced by the intake of alcohol, more specifically, the sickness symptoms and acute poisoning caused by acetaldehyde,
It is intended to provide a drug or a functional food for preventing or improving a side effect.

[0018]

Means for Solving the Problems As a result of intensive studies to solve the above problems, the present inventors have found that α-hydroxybutyric acid having an (R) -type configuration and an (R) -type configuration are obtained. The inventors have found that β-hydroxybutyric acid, succinic acid, and salts thereof possess extremely effectively protect the living body from the toxicity of blood acetaldehyde, and have completed the present invention.

That is, according to the present invention, α-hydroxybutyric acid having an (R) type configuration and β having an (R) type configuration
The present invention provides an inhibitor of acetaldehyde toxicity, which comprises at least one selected from the group consisting of hydroxybutyric acid, succinic acid, and salts thereof as an active ingredient.

Hydroxybutyric acid used in the present invention is α
It may be either -hydroxybutyric acid (2-hydroxybutyric acid) or β-hydroxybutyric acid (3-hydroxybutyric acid), and the hydroxybutyric acid has an (R) -type configuration for the asymmetric carbon at the 2-position or 3-position. What is possessed is an active ingredient for suppressing the toxicity of acetaldehyde. Therefore, in actual use, not only (R) type but also (RS) type hydroxybutyric acid can be used. The hydroxybutyric acid may also be in the form of a pharmaceutically acceptable salt, for example,
In addition to inorganic salts such as sodium salt, potassium salt and ammonium salt, salts of basic amino acids such as L-lysine salt, L-histidine salt and L-arginine salt can be mentioned.

The succinic acid used in the present invention may also be in the form of a pharmaceutically acceptable salt, and examples thereof include inorganic salts such as sodium salt, potassium salt and calcium salt.

The hydroxybutyric acid and succinic acid used in the present invention can be used alone or in combination.

The acetaldehyde toxicity inhibitor of the present invention is
It protects the body from the toxicity of acetaldehyde produced in the blood with the intake of alcoholic beverages,
It can be used not only as a medicine but also as a food or drink. Examples of the toxicity caused by acetaldehyde include sickness symptoms caused by overdose and acute alcohol poisoning, and secondary effects described in the prior art of the present specification. Also, as symptoms of sickness, for example, skin flushing,
Feeling hot, palpitation, tachycardia, headache, head weight, nausea, nausea, bad breath,
Examples include urine odor.

When the active ingredient of the present invention is used as a medicine,
The dosage form may be any dosage form as long as oral or parenteral administration is conveniently carried out, for example, injection solutions, infusion solutions, powders, granules, tablets, capsules, enteric agents. , Ointments, inhalants, troches and the like, and these may be used alone or in combination depending on the symptoms. Further, it may be a readily soluble preparation that is added to alcoholic beverages and mineral water.

These various preparations are known auxiliary agents which can be usually used in the technical field of pharmaceutical preparation such as an excipient, a binder, a disintegrating agent, a lubricant, a corrigent, etc. as a main ingredient according to the purpose according to a conventional method. Can be used for formulation.

When the active ingredient of the present invention is used in foods and drinks, it may be in the form of the above-mentioned formulation, but it can be processed and produced by a general production method by adding the active ingredient of the present invention to a food material. The type and form of the food are not particularly limited, and for example, solid or liquid food or a favorite food, such as bread, noodles, rice, confectionery (biscuits, cakes, candy, chocolate, Japanese sweets, gummy gum, chewing gum), tofu and the like. Agricultural foods such as processed products, sake, fermented foods such as medicinal liquor, mirin, vinegar, soy sauce, miso, dressing, yogurt, ham, bacon, sausage,
It may be in the form of livestock products such as mayonnaise, seafood such as kamaboko, fried tempura and rice, beverages such as fruit juices, soft drinks, sports drinks, alcoholic drinks, coffee drinks and tea drinks.

Ingestion as a health food or a functional food is used for preventive improvement and maintenance of health for symptoms caused by acetaldehyde in blood with drinking, and auxiliary ingredients commonly used in the fields of medicine and food, such as lactose and sucrose. Sugar, liquid sugar,
Honey, magnesium stearate, oxypropyl cellulose, various vitamins, citric acid, malic acid, fragrance,
With inorganic salts and the like, it can be in the form of capsules, tablets, drinks and the like. In the case of a drink, it is also possible to add a desired beverage-like character by mixing with other physiologically active ingredients, minerals, vitamins, hormones, nutritional ingredients, flavoring agents, etc., if necessary.

In the acute toxicity test using mice, the active ingredient of the present invention showed no deaths after intraperitoneal administration of 11 mmol / kg, and no abnormalities in general symptoms and body weight were observed.
Confirmed to be a very attenuated or harmless substance. In an experiment using mice described later, the active ingredient of the present invention was 5.5 mmo to suppress the toxicity of acetaldehyde (lethal dose of acetaldehyde: 11 mmol / kg).
1 / kg was required. However, in the case of humans, the blood acetaldehyde concentration at the time of drinking is never as high as the lethal dose in mice, and it is known that most people have unpleasant sickness symptoms when the concentration is about 20 μmol / l or more. Therefore, assuming that the active ingredient of the present invention antagonizes the action of acetaldehyde at the same ratio as the result of the lethal experiment in mice, the active ingredient of the present invention is effective in suppressing the sickness symptom at 0.06 mg / kg. Presumed to be. Therefore, the dose of the active ingredient of the present invention is,
Although it varies depending on the body weight and the like, it is usually 2.5 mg-1 g, preferably 5 mg-1 g per dose for oral administration to adults, and 0.25-100 for parenteral administration.
mg, preferably 0.5-100 mg. When ingested as food or drink, 2.5mg-1g per dose,
Preferably 5 mg-1 g is desirable.

The acetaldehyde toxicity suppressor of the present invention may contain a known sickness ameliorating component which has been conventionally used, as long as the effect of the present invention is not impaired. Examples of these components include persimmon juice, amino acids such as alanine, glutamine and ornithine, and alcohol absorption inhibitors such as tannin. The acetaldehyde toxicity suppressor of the present invention can be effective even if it is taken at any time before, after or during drinking, but it is particularly preferable to take before or during drinking.

The present invention will be described below with reference to examples.
These do not limit the invention.

[0031]

【Example】

Example 1 The following experiment confirmed a significant life-saving effect of α and β-hydroxybutyric acid on acute lethality of acetaldehyde.

Test Method (i) Experimental Animal: CDF ₁ male mice (Charles River Japan) were purchased at 7 weeks of age and used for experiments after 1 week of preliminary breeding. The weight of the mouse used is about 24.5-29 g.
Met.

(Ii) Rearing condition: The room temperature of the mouse is 23 ± 1-
In a breeding room set to 2 ° C, humidity 55 ± 5%, ventilation rate 12-15 times / hour (all fresh air method), lighting time (12 hours / day) (lights at 7:00 am, lights off at 7:00 pm) Six animals were raised in a polyisopentene cage (manufactured by Charles River Japan, 235 × 325 × 170 Hmm). Fixed feed CE-2 (CLEA Japan, Inc.) and drinking water were freely available.

(Iii) Preparation of reagent: Acetaldehyde was diluted with distilled water so that the dose was 11 mmol / kg. Moreover, the dose of (R) -α-hydroxybutyric acid (hereinafter referred to as “α-HBA”) or (R) -β-hydroxybutyric acid (hereinafter referred to as “β-HBA”) is 1
It was dissolved in physiological saline so as to be 1 mmol / kg and used for the test. All injection volumes were 10 ml / kg.

(Iv) Acetaldehyde acute lethality inhibition test: α-HBA or β-HBA was intraperitoneally administered, and 30 minutes later, acetaldehyde was intraperitoneally administered, and the survival rate was observed 2 hours and 24 hours after the administration of acetaldehyde. did.

(V) Statistical processing: χ ² as an effect judgment standard
An assay was used.

As shown in Table 1 and FIG. 1, in the control group administered with physiological saline, the survival rate after intraperitoneal administration of 11 mmol / kg of acetaldehyde was 25% after 2 hours and 24 hours. It was On the other hand, 11 mm
When ol / kg of α-HBA or β-HBA was intraperitoneally administered 30 minutes before the administration of acetaldehyde, the survival rate increased to 83%.

[0038]

[Table 1] Table 1 Reduction of acute toxicity of acetaldehyde by α-HBA or β-HBA 2 hours after administration Number of surviving animals / number of animals used (%) Saline 3/12 (25.0) α-HBA 11 mmol / kg 10/12 (83.3) * β-HBA 11 mmol / kg 10/12 ( 83.3) * 24 hours after administration Number of surviving animals / number of animals used (%) Saline 3/12 (25.0) α-HBA 11 mmol / kg 10/12 (83.3) * β-HBA 11 mmol / kg 10/12 (83.3) * *: Significantly different from the control group administered with physiological saline (p <0.05).

As described above, α-HBA and β-HBA
It showed a significant life-saving effect on the acute lethality of acetaldehyde, suggesting that it is a desirable inhibitor of acetaldehyde toxicity. It is not yet clear how α-HBA and β-HBA suppress the toxicity of acetaldehyde, but acetaldehyde stimulates the adrenal cortex and sympathetic nerves, promotes the release of catecholamines, and induces β-receptors in the heart. Increase your heart rate through. It is believed that large doses of acetaldehyde in animals intensify this effect, causing arrhythmias and death. Therefore, as a mechanism for suppressing the acetaldehyde toxicity of α-HBA and β-HBA, it is possible to antagonize the action of catecholamine whose release is promoted by acetaldehyde.

Example 2 The acetaldehyde of Example 1 (dose 11 mmol / k
The same test as in Example 1 was carried out except that g) was replaced with epinephrine (dose 55 μmol / kg). The results are shown in Table 2 and FIG.

[0041]

[Table 2] Table 2 Reduction of acute toxicity of epinephrine by α-HBA or β-HBA 2 hours after administration: Number of surviving animals / Number of animals used (%) Epinephrine 55 μmol / kg 5/13 (38.4) α-HBA 11 mmol / kg 13/13 (100) * β-HBA 11 mmol / kg 12/12 (100 ) * 24 hours after administration / Number of surviving animals / Number of used animals (%) Epinephrine 55 μmol / kg 1/13 (7.6) α-HBA 11 mmol / kg 6/13 (46.1) * β-HBA 11 mmol / kg 6 / 12 (50) ** : Significantly different from the control group administered with physiological saline (p <0.05).

Α-HBA and β-HBA suppressed the acute lethality of epinephrine. From these results, it is considered that the inhibitory effect of these ketone bodies on the acute lethality of acetaldehyde is manifested by antagonizing the physiological action of catecholamine released in excess.

Example 3 α-HBA and β-HBA of Example 1 (dose 11 mm
ol / kg), β-HBA (dose 5.5 mmol /
kg) or succinic acid (dosage 5.5 mmol / kg,
The same test as in Example 1 was performed except that the amount was changed to 2.75 mmol / kg). As a result, as shown in Table 3 and FIG. 3, the succinic acid dose of 5.5 mmol / kg was β-
The acute toxicity of acetaldehyde was suppressed to the same level as HBA (dose 5.5 mmol / kg).

[0044]

[Table 3] Table 3 Reduction of acute toxicity of acetaldehyde by β-HBA or succinic acid 2 hours after administration Number of surviving animals / number of used animals (%) Saline 2/13 (15.3) β-HBA 5.5 mmol / kg 7/12 (58.3) * succinic acid 2.75 mmol / kg 3/13 (23.0) Succinic acid 5.5 mmol / kg 7/12 (58.3) * Number of surviving animals / number of animals used 24 hours after administration (%) Saline 2/13 (15.3) β-HBA 5.5 mmol / kg 7/12 (58.3) * succinic acid 2.75 mmol / kg 3/13 (23.0) succinic acid 5.5 mmol / kg 7/12 (58.3) * *: as a control group by administration of physiological saline There is a significant difference (p <0.05).

Formulation example Using the above as one dose unit, β-hydroxybutyric acid and lactose are mixed, compressed into tablets, and then crushed, and magnesium stearate is mixed. Each mixture was filled into No. 2 capsules.

[0046] The above was used as one dose unit, and after mixing these, a small amount of water was added, and the mixture was kneaded by a kneading machine, sized, dried, sized again, filtered, and packaged in units described above.

Formulation Example 3 (drink) (R) -β-hydroxybutyric acid 200 g DL-sodium tartrate 1 g succinic acid 0.09 g liquid sugar 8 kg citric acid 120 g vitamin C 100 g fragrance 150 ml potassium chloride 10 g magnesium sulfate 5 g Blended and added water to make 100 l.

[Brief description of drawings]

FIG. 1 is a graph showing the effect of reducing acute toxicity of acetaldehyde by α-HBA or β-HBA, showing the survival rate 24 hours after administration of acetaldehyde.

FIG. 2 is a graph showing the effect of α-HBA or β-HBA on reducing acute toxicity of epinephrine, showing survival rates 2 hours and 24 hours after administration of epinephrine.

FIG. 3 is a graph showing the effect of reducing the acute toxicity of acetaldehyde by β-HBA or succinic acid, showing the survival rate 24 hours after the administration of acetaldehyde.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Hiroshi Wada 1-1-1 Wakayamadai, Shimamoto-cho, Mishima-gun, Osaka Suntory Ltd. Research Laboratories

Claims (2)

[Claims] 1. An α-hydroxybutyric acid having an (R) -type configuration, a β-hydroxybutyric acid having an (R) -type configuration,
An inhibitor of acetaldehyde toxicity, comprising at least one selected from the group consisting of succinic acid and salts thereof as an active ingredient. 2. An α-hydroxybutyric acid having an (R) type configuration, a β-hydroxybutyric acid having an (R) type configuration,
A preventive or ameliorating agent for a sickness symptom caused by acetaldehyde generated in the blood during drinking, which comprises at least one selected from the group consisting of succinic acid and salts thereof as an active ingredient.