JP2011093861A - Preventive and therapeutic agent for acute hepatic dysfunction - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide preventive and/or therapeutic compositions (medicines and/or health foods) effective for acute hepatic dysfunction (particularly, drug-induced acute hepatic dysfunction), which contain a highly safe ingredient derived from natural animals or plants as an active ingredient. <P>SOLUTION: Discharge of toxic substances in a liver which is a causal factor of acute hepatic dysfunction is promoted by the application of a composition containing, as an active ingredient, betaine(trimethylglycine) which is a highly safe amino acid derivative widely contained in animals and plants, to prevent and treat acute hepatic dysfunction. The composition is particularly effective for the prevention and treatment of drug-induced acute hepatic dysfunction. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

  The present invention relates to a preventive and / or therapeutic agent for acute liver dysfunction, comprising a highly safe natural animal or plant-derived component as an active ingredient.

  In addition to metabolism and storage of carbohydrates, proteins and lipids, production and secretion of bile, regulation of circulating blood volume, the liver is carried into the body on a daily basis through food, air, drinking water, drinking, smoking, medication, etc. It is one of the most important organs for human beings. However, liver dysfunction accounts for a high percentage of diseases found in medical docks, and it is said that 30% of Japanese adults have liver dysfunction. Liver dysfunction is roughly classified into chronic liver dysfunction (chronic hepatitis) and acute liver dysfunction (acute hepatitis) based on the causes and symptoms.

  Chronic liver dysfunction (chronic hepatitis) is a liver dysfunction in which hepatitis continues for a long time, has few initial symptoms, and the main cause is fatty liver (non-alcoholic fat due to excessive intake of high-fat diet) Hepatitis), long-term and excessive alcohol consumption (alcoholic hepatitis), and long-term viral infection (viral hepatitis). On the other hand, acute liver dysfunction (acute hepatitis) is an acute liver dysfunction that causes initial symptoms such as fever due to ingestion of pharmaceuticals (drugs), rapid alcohol consumption, viral infection, etc. is there. In particular, drug metabolism is mostly carried out in the liver, and various metabolites also appear due to drug metabolism. Therefore, the rate of liver dysfunction as a side effect of pharmaceuticals is very high.

  In general, various chemical synthetic drugs are prescribed for the prevention and treatment of these liver dysfunctions. However, as described above, there is a risk of side effects of these drugs themselves. There are many problems, such as the need for a combination of dietary therapy, because some of them are not effective enough.

  Against this background, a fatty liver ameliorating agent and an accompanying liver disorder ameliorating agent that are composed of two ingredients, betaine and raffinose, which are safe ingredients that are derived from natural products and have abundant food experience, have been provided recently. (Patent Document 1). In addition, the role of betaine in lipid metabolism including suppression of fatty liver is also described in detail (Non-patent Document 1), and it is known that betaine plays an indispensable role in phospholipid synthesis as a methyl group donor. ing. When this phospholipid synthesis is reduced, lipids cannot be sufficiently transported from the liver, which causes fatty liver and the like.

  Betaine, also known as trimethylglycine, is relatively abundant (0.07-0.30%) in beet (sugar beet), and has been isolated from beet sugar molasses for the first time in the middle of the 19th century. It is also widely found in plants and animals other than beets, and in animals it is contained in a lot of marine products such as shrimp, crab, squid, shellfish, etc., in plants it is contained in malt, mushrooms, plant leaves, bamboo shoots, seeds, Wheat bran contains about 0.35%. For this reason, our dietary experience of betaine is richer than before, and it can be said that it is a highly safe natural ingredient.

  Furthermore, betaine has been used quantitatively as a feed additive and fermentation aid for many years, and in recent years, its use in cosmetics has expanded. In Japan, betaine is recognized as a natural amino acid (seasoning), but it can be said that the taste as a seasoning is poor compared to general amino acids. However, as a food material that utilizes the physicochemical properties of betaine (taste improvement, browning prevention, moisture retention / hygroscopicity, reduced water activity, etc.), it is used mainly for processed fishery products.

  As described above, betaine is highly safe and has abundant dietary experience, and also has a fatty liver prevention effect (ie, a chronic non-alcoholic steatohepatitis prevention effect) by its lipid metabolism regulating action through phospholipid synthesis. Although it has been confirmed, the physiological function for other liver dysfunction is not known. Moreover, there are many liver dysfunctions that are acute and are not caused by long-term intake of a high fat diet or fatty liver (drugs, viruses, acute alcohol disorders, etc.). There has been a demand for the development of naturally-occurring and safe ingredients that exhibit effective preventive and therapeutic effects.

JP 2003-155242 A

FEEDING, Vol34, No. 6, 51-56 (1994)

  The present invention relates to a prophylactic and / or therapeutic composition (medicine and / or health food) effective for acute liver dysfunction (especially drug-induced acute liver dysfunction) comprising a highly safe natural animal or plant-derived component as an active ingredient. ).

  In order to achieve the above object, as a result of intensive studies, the present inventors orally administer a predetermined amount of a composition that is widely contained in animals and plants and contains betaine (trimethylglycine), which is a highly safe amino acid derivative, as an active ingredient. Thus, the present inventors have found that glutathione reductase activity, which is an enzyme in the liver, is enhanced, and that the amount of reduced glutathione in the liver is increased. It was found that this reduced glutathione acts as a detoxifying compound by conjugation with glutathione and is effective in the prevention and treatment of acute liver dysfunction (especially drug-induced acute liver dysfunction).

That is, the embodiment of the present invention is as follows.
(1) A preventive and / or therapeutic agent for acute liver dysfunction, comprising betaine as an active ingredient.
(2) The agent according to (1), wherein the acute liver dysfunction is a drug-induced acute liver dysfunction (for example, induced by galactosamine or a drug showing a side effect of liver dysfunction). .
(3) The agent according to (1) or (2), wherein glutathione reductase activity in the liver is enhanced.
(4) Increase glutathione reductase activity in the liver to increase the amount of reduced glutathione in the liver (and / or serum) and reduce the causative substances (drugs, metabolites, etc.) of acute liver dysfunction The agent according to any one of (1) to (3), which is discharged by a glutathione conjugate.
(5) Any one of (1) to (4), characterized by being administered by oral administration in an amount of 20 to 200 mg / kg, preferably 30 to 100 mg / kg as betaine per day The agent described in 1.
(6) Prevention of acute liver dysfunction in humans or animals other than humans, characterized by orally administering the agent according to any one of (1) to (5) to humans or animals other than humans; / Or treatment method.
(7) A pharmaceutical product containing a drug that exhibits side effects that induce liver dysfunction (particularly acute liver dysfunction) and betaine, wherein the side effect of the drug on liver dysfunction is suppressed.
(8) A pharmaceutical product for suppressing a side effect in a drug that induces liver dysfunction as a side effect, comprising betaine as an active ingredient.
(9) A food composition for medical treatment of persons with hepatic dysfunction, comprising betaine as an active ingredient.
(10) A method for producing a food composition for medical treatment of persons with hepatic dysfunction, comprising adding or mixing betaine.

  According to the present invention, administration of betaine enhances the activity of glutathione reductase (GR), which is an enzyme in the liver, and increases the amount of reduced glutathione in the liver and serum. And this reduced glutathione causes the internalization (glutathione conjugation) of electrophilic substance (harmful substance) such as carcinogenic substance rich in reactivity and glutathione by the action of glutathione-S-transferase (GST), Toxic substances are evacuated to the outside of the cell. Thereby, the causative substance (harmful substance) of acute liver dysfunction can be removed from the liver, and acute liver dysfunction can be prevented and treated. In addition, it is possible to provide pharmaceuticals and health foods that prevent the occurrence of acute liver dysfunction due to medication or the like for people whose liver function itself is lower than that of healthy individuals, even if the liver function is not impaired. Furthermore, by using a combination of a pharmaceutical ingredient that induces liver dysfunction as a side effect and betaine, it is possible to provide a pharmaceutical in which the side effect of liver dysfunction is suppressed while sufficiently obtaining a predetermined pharmacological effect. In addition, a food composition (health food, etc.) for medical treatment for persons with hepatic dysfunction can be provided.

Comparison of body weight, food intake, liver weight, and total liver lipid amount in a betaine administration test to rats was shown (P> 0.05 between the different signs of a and b). A comparison of serum AST, ALT, and LDH activities in a betaine administration test to rats was shown (P> 0.05 between the different signs of a and b). A comparison of liver GST, GPx, and catalase activities in a betaine administration test to rats was shown. Comparison of TBARS value, liver GR activity, and GSH amount in the betaine administration test to rats was shown (significantly different at P> 0.05 between different symbols of a, b, and c). A comparison of body weight, food intake, and liver weight in a betaine administration test to rats with galactosamine-induced liver dysfunction was shown (significantly different at P> 0.05 between different symbols). A comparison of atherosclerosis index and serum cholesterol level in the betaine administration test to rats with galactosamine-induced hepatic dysfunction was shown (significant difference between different symbols with P> 0.05). Comparison of serum GOT and GPT activities, serum ALP activity, and serum LDH activity in betaine administration test to rats with galactosamine-induced liver dysfunction was significant (P> 0.05 between a, b, and c different signs) There is a difference). A comparison of serum and liver GSH levels in a betaine administration test to rats with galactosamine-induced liver dysfunction was shown (significantly different between P and 0.05 between different signs of a and b). A comparison of liver GST, GPx, and GR activities in a betaine administration test to galactosamine-induced hepatic dysfunction rats was shown (significant difference between different symbols with P> 0.05).

  In the present invention, betaine is used as an active ingredient. Betaine can be extracted from many plants and animals, or naturally derived from biosynthetic products. In particular, it is preferable to use a beet (sugar beet) extracted and purified by a conventional method, but is not limited to beet-derived betaine. Any form such as liquid, powder, granule, paste, etc. can be used, and the form is not particularly limited.

  The composition according to the present invention enhances glutathione reductase activity in the liver of humans or animals other than humans, increases the amount of reduced glutathione in the liver, and is used for the prevention and treatment of acute liver dysfunction. is there. In particular, the composition according to the present invention is very effective for acute liver dysfunction induced by drug intake or rapid alcohol intake. It is also very effective in that the liver works effectively even when it is not in an oxidative stress state (even when the liver is in a normal state). Therefore, liver function caused by excessive intake of a high fat diet, fatty liver, etc. It is characterized by having a preventive and therapeutic effect sufficiently for liver dysfunction that is not a disorder (for example, liver dysfunction due to drug side effects).

  Furthermore, by including both betaine and drugs with side effects that induce liver dysfunction (especially acute liver dysfunction) (pharmaceutical ingredients) in the drug, the side effects of liver dysfunction are suppressed while maintaining the prescribed pharmacological effect. Can also be provided. Alternatively, the side effect can be suppressed by using a drug containing betaine as an active ingredient in combination with a drug that induces liver dysfunction as a side effect. There are hepatic disorder type, cholestasis type, mixed type of these, etc. as side effects of hepatic dysfunction of pharmaceutical ingredients, such as antipyretic anti-inflammatory analgesics, anticancer drugs, antifungal drugs and the like. In addition, even if it does not cause liver dysfunction alone, liver dysfunction may occur when multiple drugs are taken together.

  Pharmaceutical ingredients that induce liver dysfunction include acetaminophen, diclofenate sodium, loxoprofen sodium, acetylsalicylic acid, mefenamic acid, ibuprofen, indomethacin, pranoprofen (antipyretic anti-inflammatory analgesic ingredient), halothane (anesthetic ingredient), Troglitazone, acarbose, voglibose, glibenclamide, epalrestat (metabolic disease component), benzbromarone (gout component), cyclophosphamide, 6-mercaptopurine (anticancer component), rifampicin, isoniazid, salazosulf Fapyridine, ofloxacin, levofloxacin, norfloxacin, ciprofloxacin hydrochloride, sulfamethoxazole / trimethoprim, griseofulvin (chemotherapeutic component), phenytoin, carbamazepine Sodium valproate, chlorpromazine hydrochloride, haloperidol (psychological / neurological component), apridin, hydrochloride, trapidil, nifedipine, nicardipine hydrochloride, methyldopa (circulatory component), thiopronin, famotidine, lansoprazole, cimetidine, sulpiride, omeprazole, hydrochloric acid Ranitidine (digestive component), piperacillin sodium, cefotiam, cefaclor, minocycline hydrochloride, cefazolin sodium, ampicillin, cefmetazole sodium, fosfomycin, clarithromycin, amoxicillin, cefteram pivoxil, cefpodoxime proxetil, flomoxef Examples include sodium (antibacterial component).

  The composition according to the present invention is orally administered to humans or animals other than humans. For example, in humans, it is effective to administer 20 to 200 mg / kg (body weight), preferably 30 to 100 mg / kg (body weight) of betaine per day. In animals other than humans, the dose may be set by performing a predetermined conversion from the dose to humans.

Thus, administration of a composition comprising the betaine of the present invention as an active ingredient, or combined administration of betaine and a drug having a side effect of inducing liver dysfunction enhances glutathione reductase activity in the liver, Increase the amount of reduced glutathione. This reduced glutathione causes glutathione conjugation between the harmful substance and glutathione by the action of glutathione-S-transferase (GST), and rapidly discharges the harmful substance together with the conjugate outside the cell, thereby preventing acute liver dysfunction. Can be treated.
Therefore, as a composition containing betaine as an active ingredient, a preventive and therapeutic drug for acute liver dysfunction, a food composition for medical treatment of a person with hepatic dysfunction (such as a health food), and the like can be provided.

In the case of a medicine, examples of the form include tablets, capsules, granules, powders, syrups and the like. These various preparations are usually used in the pharmaceutical formulation technical field such as excipients, binders, disintegrants, lubricants, flavoring agents, solubilizing agents, suspension agents, coating agents and the like according to conventional methods. It can be formulated with known adjuvants that can be used.
There is no limitation on the form as a food composition for medical treatment, and it is solid (powder, granule, etc.), gel, paste, liquid or suspension, etc. Can be selected as appropriate, for example, by adding to a normal food.

  Examples of the present invention will be described below, but the present invention is not limited to these examples.

  A test was conducted to confirm the effect of betaine administration on the liver in the normal state. As experimental animals, 15 8-week-old male F344 rats were purchased from Charles River Japan Co., Ltd. The breeding conditions were a room temperature of 23 ± 1 ° C., a humidity of 60 ± 5%, and a light / dark cycle of 12 hours (light 7:00, dark 19:00).

  AIN93G standard diet administration group (C), betaine 1% additive diet administration group (B1), and betaine 2% additive diet administration group (B2) are provided, and each group is administered orally for 4 weeks. Compared. The composition of each feed is shown in Table 1.

  Serum was collected every week and liver, cecum and feces were collected on the last day of administration. As indices, serum AST (aspartate aminotransferase), ALT (alanine aminotransferase), LDH (lactate dehydrogenase) activity, catalase in the liver, glutathione-S-transferase (GST), glutathione reductase (GR) ), Glutathione peroxidase (GPx) activity and reduced glutathione (GSH) level, serum and liver thiobarbituric acid reactive substance (TBARS) values.

Serum AST, ALT, and LDH activities were measured by the JSCC standardization method, and liver catalase activity was measured by a conventional method using hydrogen peroxide as a substrate.
The GSH amount was measured by the method of Chon and Lye (Anal. Biochem., 14: 434-440 (1966)), and the GR activity was measured by the method of Worthington and Rosemeyer (Eur J Biochem. 67 (1), 231-238). (1976)), GPx activity was measured by the method of Lawrence and Burk (J Clin Invest 65 (5): 1024-1031 (1980)).

  In the measurement of GST activity, liver cytoplasm was diluted 5-fold with 200 mM phosphate buffer (pH 6.5), 200 mM phosphate buffer (pH 6.5) was 500 μl per sample, 10 mM GSH was 100 μl, and ultrapure water was added. A method of adjusting a reaction solution so that 200 μl, 10 mM 1-chloro-2,4-dinitrobenzene (CDNB) is 100 μl, mixing this reaction solution with 100 μl of a sample, and immediately measuring an absorbance time change at 340 nm I went there.

  As a result, although there was no change in body weight and food intake during the administration period in each group, the betaine administration group significantly increased the liver weight (FIG. 1). In addition, serum AST, ALT, and LDH activities, which are indicators of liver damage, were significantly reduced in the betaine administration group (FIG. 2). Furthermore, although there was no difference in the TBARS value, liver GST and GPx activity, the activity of GR, an enzyme having an auxiliary effect on the elimination of active oxygen, increased, and the amount of GSH also increased significantly (FIG. 3). , FIG. 4).

Glutathione is one of the antioxidant components in the cell, and also plays a role as a transporter that protects cells from changes in internal and external environments by discharging toxins and the like outside the cell. Therefore, it is known that when the amount of glutathione in the cell is greatly reduced, the cell is damaged. In addition, glutathione has a reduced form and an oxidized form, but it has been found that the action of reduced glutathione is important for improving oxidative stress and discharging toxic substances.
The above results show that betaine intake increases the amount of reduced glutathione even in normal liver under conditions without oxidative stress, suggesting that it has a preventive effect on acute liver dysfunction caused by drugs, etc. .

  A study was conducted to further confirm the effects of betaine administration on acute liver dysfunction. As experimental animals, 20 8-week-old male F344 rats were purchased from Charles River Japan Co., Ltd. The breeding conditions were a room temperature of 23 ± 1 ° C., a humidity of 60 ± 5%, and a light / dark cycle of 12 hours (light 7:00, dark 19:00).

  There are four groups: AIN93G standard diet administration group (C), AIN93G standard diet + galactosamine administration group (CG), betaine 1% supplement diet + galactosamine administration group (B1G), betaine 2% supplement diet + galactosamine administration group (B2G) Each group was fed orally for 5 weeks to compare the effects. In addition, as for the details of sample administration of each group, C group administers the standard diet (C) of Table 1 of Example 1, and CG group, B1G group, and B2G group each of C, B1, and B2 of Table 1 After the sample was orally administered for 2 weeks, galactosamine was dissolved in 1 ml of physiological saline at a ratio of 400 mg / kg body weight to each group and administered intraperitoneally. In group C, a standard diet was administered for 2 weeks, and then 1 ml of physiological saline was intraperitoneally administered.

  Galactosamine is a kind of amino acid that exists as N-acetylgalactosamine in vivo. It is a drug having liver toxicity, and it is known that acute liver dysfunction is induced by administration to rats and the like. Liver dysfunction due to galactosamine is caused by excessive consumption of uridine in the liver. The detailed mechanism is that galactosamine is converted to UDP-glucosamine from UDP-galactosamine in its metabolic pathway, thereby capturing UTP, and thus reducing UTP, UDP, UMP or UDP-glucose, UDP-glucuronic acid in hepatocytes. However, the ability to metabolize nucleic acids, proteins and lipids is said to be inhibited.

  Serum from each group was collected weekly, and liver, cecum and feces were collected on the last day of administration. As indices, serum cholesterol levels (T-Chol, HDL-Chol, VLDL + IDL + LDL-Chol), atherosclerosis index (A index), serum GOT (glutamate oxaloacetate transaminase) and GPT (glutamate pyruvate transaminase) activity, serum ALP (Alkaline phosphatase) activity, serum LDH activity and serum GSH amount, GSH amount in liver, GST activity, GR activity and GPx activity were measured.

  Serum GOT and GPT activity, serum LDH activity and serum GSH amount, GSH amount in liver, GST activity, GR activity and GPx activity were measured by the same method as in Example 1. Serum ALP activity was measured by the P-nitrophenyl phosphate method, which is a method corresponding to JSCC standardization. The cholesterol level was measured by a direct test method, and the atherosclerosis index was determined by calculation from the total cholesterol level and the HDL cholesterol level.

As a result, there was no change in the feeding efficiency (weight gain / feeding amount) during the administration period in each group, but the liver weight showed a tendency to decrease (FIG. 5). As for serum components, betaine administration suppressed the decrease of HDL cholesterol (HDL-Chol), which is good cholesterol, and also suppressed the increase of the atherosclerosis index (FIG. 6). In addition, the total cholesterol (T-Chol) and bad cholesterol (VLDL + IDL + LDL-Chol) amount also showed a slightly increasing tendency (FIG. 6). Furthermore, in the betaine 1% administration group, the increase in serum ALP activity and serum LDH activity, which is said to be an index of serum GOT, GPT activity, and drug-induced liver injury, was significantly suppressed (FIG. 7). Significantly increased the amount of GSH (FIG. 8).
The activities of glutathione reductase (GR), glutathione peroxidase (GPx), and glutathione-S-transferase (GST) all decreased in the galactosamine administration group, but the activity of the betaine administration group recovered its activity ( Activity decreasing suppression tendency) was observed (FIG. 9).

  From this result, in acute liver dysfunction induced by galactosamine, it was shown that intake of betaine increases the amount of reduced glutathione in the serum and liver, and has a preventive and therapeutic effect on drug-induced acute liver dysfunction . In particular, in the rat test, the betaine 1% feed administration group was effective, and it was shown that the prevention and treatment effect of acute liver dysfunction is enhanced by setting the betaine dose as an active ingredient within a specific range.

  The present invention is summarized as follows.

  The present invention relates to a prophylactic and / or therapeutic composition (medicine and / or health food) effective for acute liver dysfunction (especially drug-induced acute liver dysfunction) comprising a highly safe natural animal or plant-derived component as an active ingredient. ).

  By administering a composition containing betaine (trimethylglycine), an amino acid derivative that is widely contained in animals and plants, and having high safety as an active ingredient, harmful substances in the liver that cause acute liver dysfunction are discharged. To prevent and treat acute liver dysfunction. This composition is particularly effective for the prevention and treatment of drug-induced acute liver dysfunction.

Claims (10)

  A preventive and / or therapeutic agent for acute liver dysfunction, comprising betaine as an active ingredient.   The agent according to claim 1, wherein the acute liver dysfunction is drug-induced acute liver dysfunction.   The agent according to claim 1 or 2, which enhances glutathione reductase activity in the liver.   The glutathione reductase activity in the liver is enhanced to increase the amount of reduced glutathione in the liver, and the causative agent of acute liver dysfunction is excreted by the reduced glutathione conjugate. 4. The agent according to any one of 3.   The agent according to any one of claims 1 to 4, wherein the agent is administered in an amount of 20 to 200 mg / kg as betaine per day by oral administration.   A method for preventing and / or treating acute liver dysfunction in animals other than humans, characterized by orally administering the agent according to any one of claims 1 to 5 to animals other than humans.   A drug having suppressed side effects of a drug, comprising a drug having a side effect of inducing liver dysfunction and betaine.   A pharmaceutical product for suppressing a side effect in a drug that induces liver dysfunction as a side effect, comprising betaine as an active ingredient.   A food composition for medical treatment of persons with impaired liver function, comprising betaine as an active ingredient.   A method for producing a food composition for medical treatment of persons with hepatic dysfunction, comprising adding or mixing betaine.

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