CN1278170A - Hesperidin and hesperetin as inhibitor of acyl coa-cholesterol-o-acyltransferase, inhibitor of macrophage-lipid complex accumulation on the arterial wall and preventive agent - Google Patents
Hesperidin and hesperetin as inhibitor of acyl coa-cholesterol-o-acyltransferase, inhibitor of macrophage-lipid complex accumulation on the arterial wall and preventive agent Download PDFInfo
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Abstract
本发明涉及橙皮苷和橙皮素在哺乳动物中抑制酰基CoA－胆固醇－O－酰基转移酶(ACAT)的活性、抑制巨噬细胞—脂质复合物在动脉壁上的累积、以及预防或治疗肝病的应用。
This invention relates to the use of hesperidin and hesperidin in inhibiting the activity of acyl-CoA-cholesterol-O-acyltransferase (ACAT) in mammals, inhibiting the accumulation of macrophage-lipid complexes on the arterial wall, and in the prevention or treatment of liver diseases.
Description
Invention field
The present invention relates to Hesperidin and hesperetin suppress acyl-CoA-cholesterol-O-acyltransferase (ACAT) in mammal activity, the accumulation of inhibition macrophage-lipid complex on arterial wall and the application of prevention or treatment hepatopathy.
Background of invention
In the last few years, crown cardiovascular circulation disease, for example atherosclerosis and hypercholesterolemia become the main cause of death gradually.Existing reporting, plasma cholesterol concentration are increased and are caused fat, macrophage and foam cell to be deposited on the blood vessel wall, and these depositions then cause speckle to form, and cause atherosclerosis (Ross, R., Nature, 362,801-809 (1993)) thus.One of method that reduces plasma cholesterol concentration is a diet material method, with the absorption of cholesterol reducing and lipid.Another kind method is by suppressing the absorption that wherein related enzyme suppresses cholesterol.
Acyl-CoA-cholesterol-O-acyltransferase (ACAT) promotes the esterification of cholesterol in the blood.Foam cell is to form under the effect of ACAT, and comprises a large amount of cholesteryl esters that carried by low density lipoprotein, LDL.The formation of foam cell on arterial wall increases with the activity of ACAT, so the inhibitor of ACAT also can be to prevent atherosclerotic medicament.In addition, existing people reports that the blood concentration of LDL-cholesterol can reduce (Witiak by the activity that suppresses ACAT, D.T. and D.R.Feller (eds.), Anti-Lipidemic Drugs:Medicinal, Chemical and Biochemical Aspects, Elsevier, pp 159-195 (1991)).
On the other hand, owing to excessively take in ethanol or have the food of high lipid content or infect hepatitis B or the damage of liver function might take place C virus, and might develop into hepatitis, hepatitis interstitialis chronica or hepatocarcinoma.Particularly, fatty food of excessive absorption and ethanol cause fatty liver, wherein in hepatic tissue, deposited a large amount of lipid materials, and serum GOT (glutamic-oxaloacetic transaminase), GPT (glutamic acid-acetone acid transaminase) and γ-GTP (the gamma glutamyl transpeptidase) (people such as T.Banciu that raises, Med.Interne., 20,69-71 (1982); And people such as A.Par, Acta.Med.Acad.Sci.Hung., 33,309-319 (1976)).
Having carried out many effort develops and can suppress the active medicine of ACAT; Consequently existing several from the culture of various microorganisms isolated chemical compound.The example of these chemical compounds comprises isolated pyripyropenes from the culture of Aspergillus fumigatus (people such as S.Omura, J.Antibiotics, 46,1168-1169 (1993); And from Pseudomonas sp. isolated Acaterin (people such as S.Nagamura, J.Antibiotics, 45,1216-1221 (1992)).
In addition, as the therapeutic agent of hypercholesterolemia, Merck Co., USA have developed and have sold and be called Lovastatin
The HMG-CoA reductase inhibitor.But known this medicine can bring out the side effect that creatine kinase increases in the liver.
Therefore, still be necessary to continue avirulent ACAT of development and macrophage-lipid complex cumulative inhibitor and hepatopathy prevention or therapeutic agent on the tremulous pulse epithelium.
Inventor of the present invention makes great efforts by the novel and potent ACAT inhibitor of natural materials development, macrophage-lipid complex accumulation inhibitor and remedies for liver diseases, finds that consequently Hesperidin or hesperetin have potent ACAT and suppress active, macrophage-lipid complex accumulation and suppress active and to the prevention or the therapeutic activity of hepatopathy.
Hesperidin (C
28H
34O
15, M.W:610.55) and aglucon---the hesperetin (C of Hesperidin
16H
14O
6, M.W:302.27) be the bioflavonoids (Horowitz, Gentili, Tetrahedron, 19,773 (1963)) that is present in Fructus Citri Limoniae, grapefruit, mandarin orange, citron and the orange (Citrus sinensis).
Existing reporting, Hesperidin or hesperetin have and strengthen capillary tube, reduce permeability, antiplatelet aggregation, antiinflammatory, antiviral and bring high blood pressure down and activity (Meyer, O.C., Angiology, 45, the 579-584 (1994) of cholesterol; Stmckmann, people such as J.R., Angiol., 45,419-428 (1994); Matsubara, people such as Y., Japan Organic Synthesis Chem.AssociationJournal, 52,318-327 (1994, Mar.); Galati, people such as E.M., Famaco., 51 (3), 219-221 (1996, Mar.); Monforte, people such as M.T., Farmaco., 50 (9), 595-599 (1995, Sep.); JP 95-86929; JP 95-86930; Chung, people such as M.I., Chin.Pharm.J. (Taipei)., 46, and 429-437 (1994, Nov.); Galati, people such as E.M., Famaco., 40 (11), 709-712 (1994, Nov.); And Emim, people such as J.A., J.Pharm.Pharmacol., 46 (2), 118-122 (1994)).
In addition, Hesperidin has been used to prevention and treatment cerebral anemia, retinal hemorrhage and pelioma.
But at present still the ACAT of nobody's report Hesperidin or hesperetin suppresses active, macrophage-lipid complex accumulation and suppresses active and to the prevention or the therapeutic activity of hepatopathy.
The invention summary
Therefore, the purpose of this invention is to provide Hesperidin or hesperetin and suppress the active new purposes of ACAT in the mammal.
Another object of the present invention provides Hesperidin or hesperetin suppresses macrophage-lipid complex cumulative new purposes on the arterial endothelium wall in the mammal.
A further object of the present invention provides the new purposes of hepatopathy in Hesperidin or hesperetin prevention or the treatment mammal.
The accompanying drawing summary
Reach description with reference to the following drawings, above-mentioned and other purposes of the present invention and advantage will be more apparent, in the accompanying drawings:
Figure 1A, 1B and 1C have shown that 1% cholesterol of administration respectively, 1% cholesterol add 1mg/kgLovastatin
, and 1% cholesterol add the rabbit arterial of 0.1% Hesperidin; And
On behalf of 1% cholesterol of administration respectively, 1% cholesterol, Fig. 2 A, 2B and 2C add 1mg/kgLovastatin
, and 1% cholesterol add the microscopic features of the rabbit liver of 0.1% Hesperidin.
Detailed Description Of The Invention
According to an aspect of the present invention, it provides aurantiamarin or hesperetin to suppress the active new purposes of acyl-CoA-cholesterol in the mammal-O-acyltransferase (ACAT).
According to another aspect of the present invention, it provides aurantiamarin or hesperetin to suppress the new purposes that macrophage-lipid complex is accumulated at the arterial endothelium wall in the mammal.
According to a further aspect of the invention, it provides the new purposes of hepatopathy in aurantiamarin or hesperetin prevention or the treatment mammal.
Hesperidin and hesperetin can extract from the skin of Fructus Citri tangerinae platymiscium, perhaps according to Zemplen, and Bognar (Ber., 75,1043 (1943)) and Seka, the method that Prosche (Monatsh., 69,284 (1936)) describes is synthesized.In addition, hesperetin can make by the hydrolysis Hesperidin.
Hesperidin or hesperetin are active and the accumulation of macrophage-lipid complex on the arterial endothelium wall is inhibited to ACAT when 0.1mg/kg/ days or higher dosage, and to hepatopathy have the prevention and therapeutical effect, described inhibitory action increases with dosage.
And although strong effectiveness is arranged, Hesperidin or hesperetin almost do not show toxicity or mitogenesis in the Mus experiment.More specifically, when giving the Mus oral administration with the dosage of 100mg/kg, Hesperidin or hesperetin do not have toxigenicity, and for the heavy people of 50kg, above-mentioned dosage is equivalent to oral administration 3-10g Hesperidin or hesperetin/kg body weight.In addition, Hesperidin and hesperetin are free from side effects to liver function.
The present invention also is provided for suppressing the pharmaceutical composition that ACAT is active and macrophage-lipid complex is accumulated and prevented or treat hepatopathy on the arterial endothelium wall, and said composition comprises that Hesperidin or hesperetin are as acceptable excipient, carrier or diluent on active component and the materia medica.
Can come useful in preparing drug formulations according to any conventional method.During preparation, active component preferably mixes with carrier or dilutes with carrier in preparation, perhaps is encapsulated in the carrier of form of capsule, sachet or other containers.If carrier is a diluent, it can be solid, semisolid or liquid substance, as carrier, excipient or the medium of active component.Therefore, preparation can be the dosage forms such as powder of tablet, pill, powder, sachets, elixir, suspensoid, Emulsion, solution, syrup, aerosol, soft hard gelatin capsule, aseptic parenteral solution, aseptic packaging.
The example of suitable carriers, excipient and diluent is lactose, glucose, sucrose, sorbitol, mannitol, starch, Radix Acaciae senegalis, alginate, gelatin, calcium phosphate, calcium silicates, cellulose, methylcellulose, microcrystalline Cellulose, polyvinylpyrrolidone, water, methyl hydroxybenzoate, nipasol, Pulvis Talci, magnesium stearate and mineral oil.Pharmaceutical preparation can comprise filler, anti-agglomerant, lubricant, wetting agent, flavoring agent, emulsifying agent, antiseptic etc. in addition.Compositions of the present invention can be mixed with the preparation of quick after delivering medicine to mammal, lasting or delayed release of active elements with any methods known in the art.
Pharmaceutical preparation of the present invention administration by all means comprises oral, transdermal, subcutaneous, vein and muscle administration.For the people, the typical daily dose of Hesperidin or hesperetin is about 0.1-100mg/kg body weight, is preferably 3-10mg/kg, and this dosage can single dose or the administration of many doses.
But the amount that it should be understood that the active component of actual administration should determine that described factor comprises the order of severity of disease to be treated, selected route of administration, each patient's age, sex and body weight and patient's symptom according to various correlative factors; Therefore, above-mentioned dosage never is to be used to limit the scope of the invention.
In addition, Hesperidin or hesperetin can be incorporated in the Foods or drinks, as additive or dietary supplement, are used to suppress the ACAT activity, suppress accumulation and/or prevention or the treatment hepatopathy of macrophage-lipid complex on arterial endothelium.Foods or drinks can comprise meat; Juice such as vegetable juice (for example Radix Dauci Sativae juice and Fructus Lycopersici esculenti juice) and fruit juice (for example orange juice, Sucus Vitis viniferae, pineapple juice, Sucus Mali pumilae and bananas juice); Chocolate; Snack; Confection; Pizza; The food of being made by flour is as bread, cake, soda cracker, cookies, cookies, noodles etc.; Chewing gum; Milk product is as milk, cheese, yoghourt and ice cream; Soup; Meat soup; Gruel, tomato sauce and sauce; Tea; Alcoholic beverage; Soda pop such as opening cola
And pepsi cola
The vitamin complex; And various health foods.
In the case, Hesperidin in the Foods or drinks or hesperetin content can be between 0.01-5% weight.Particularly, every 1000ml can comprise Hesperidin or the hesperetin of 200-10000mg according to beverage of the present invention.
As mentioned above, Hesperidin or hesperetin can be used as effective inhibition ACAT activity, suppress hepatopathy is accumulated and/or prevented or treat to macrophage-lipid complex on arterial endothelium non-drug toxicity.
Following examples are used for further illustrating the present invention, rather than limit its scope.
In addition, the solid percentage ratio in the solid in the following solid mixture, the liquid in the liquid and the liquid is respectively to calculate with wt/wt, vol/vol and wt/vol, and all reactions all are at room temperature to carry out, except as otherwise noted.Embodiment 1: extract Hesperidin from Pericarpium Citri Reticulatae
At room temperature dry mandarin orange (Cheju Island, Korea), citron (Jeollanamdo, Korea) and orange, (skin USA) is ground into the powder that particle diameter is 100-200 μ m then for California, CA for grapefruit and Fructus Citri Limoniae.The methanol that adds 50ml in above-mentioned each Pericarpium Citri Reticulatae powder of 500mg respectively extracted 6 hours down in 50 ℃ in water-bath then.Cool off resulting extract, filter then, in filtrate, add the volume of methanol to 50ml.
Be Determination of Hesperidin Content in the extract that confirms as above to make, the described extract of 0.5 μ l is carried out high performance liquid chromatography (HPLC) analysis, wherein use Lichrosorb RP-8 post (5 μ m, 4 * 250mm), described chromatographic column is with 37% methanol pre-equilibration and remain under 30 ℃.Extract is with the flow velocity eluting of 37% methanol with 1.0ml/min.(Sigma Chemical Co. USA) is dissolved in the methanol, makes ultimate density be respectively 0.1,0.2,0.3,0.4 and 0.5mg/ml, and preparation standard solution carries out HPLC then and analyzes under identical condition thus with Hesperidin.Under 280nm, detect eluent, and calculate Determination of Hesperidin Content by the HPLC area under the curve that compares citrus peel extract and standard solution with the UV-VIS spectrophotometer.Content of hesperidin in the various citrus peel extracts (%) sees Table shown in the I.
Table I
Embodiment 2: the toxicity of oral administration Hesperidin or hesperetin
| Hesperidin (%) | |
| Orange | ????2.10 |
| Fructus Citri Limoniae | ????1.40 |
| Mandarin orange | ????2.10 |
| Grapefruit | ????- |
| Citron | ????0.80 |
Under the condition of 22 ± 1 ℃ temperature, 55 ± 5% humidity and periodicity of illumination 12L/12D, raise the female Mus of ICR (6) and the male Mus (6) of 7-8 age in week, specific pathogen free, female Mus weight is at 25-29g, and male Mus weight is at 34-38g.With feedstuff (Cheiljedang Co., Mus feedstuff) and water sterilization, feed to mice then.
Hesperidin or hesperetin are dissolved among the 0.5%Tween 80, to concentration be 100mg/ml, then this solution is administered orally to mice, consumption is a 0.2ml/20g mice body weight.Behind the described solution of administration, observe mice 10 days and write down side effect or the phenomena of mortality: after the administration 1,4,8 and 12 hour, then observed later on every 12 hours by following program.Write down the mice body weight change every day, to check the effect of Hesperidin or hesperetin.In addition, in the time of the 10th day, mice is put to death, and the macroscopy internal.
All mices all survive in the time of the 10th day, and the Hesperidin of 1000mg/kg dosage or hesperetin do not have toxicity.The postmortem result is, mice does not form the improper property of any pathology, and do not observe during 10 days inspection and lose weight.Therefore, can draw to draw a conclusion: Fructus Citri tangerinae Hesperidin or hesperetin do not have toxicity when being administered orally in animal.Embodiment 3: to animals administer Hesperidin or hesperetin
With body weight be at random 30 4 of 90-110g age in week the Sprague-Dawley rat (Taihanlaboratory animal center Korea) is divided into 3 diet groups.The rat of three groups is fed with three kinds of different high-cholesterol diet respectively, the AIN-76 laboratory animal feedstuff (ICN Biochemicals, Cleveland, the OH that promptly comprise 1% cholesterol, USA) (matched group), and 1% cholesterol adds 0.1% Hesperidin or hesperetin.Organize feeds utilized composition Table II as follows for three.
Table II
*: (Madison, WI U.S.A.) buy from TEKLAD Premier Co.
| Feed ingredient | Matched group | The Hesperidin group | The hesperetin group |
| Casein | ????20 | ????20 | ????20 |
| D, the L-methionine | ????0.3 | ????0.3 | ????0.3 |
| Corn starch | ????15 | ????15 | ????15 |
| Sucrose | ????49 | ????48.9 | ????48.9 |
| Cellulose powder * | ????5 | ????5 | ????5 |
| Mineral mixture * | ????3.5 | ????3.5 | ????3.5 |
| Vitamin mixtures * | ????1 | ????1 | ????1 |
| Adipokinetic hormone | ????0.2 | ????0.2 | ????0.2 |
| Semen Maydis oil | ????5 | ????5 | ????5 |
| Cholesterol | ????1 | ????1 | ????1 |
| Hesperidin | ???? | ????0.1 | ???? |
| Hesperetin | ????- | ????- | ????0.1 |
| Amount to | ????100 | ????100 | ????100 |
Unrestrictedly apparatus body feedstuff and water are fed rat totally 6 weeks, write down intake every day, weighed in per then 7 days, and the analytic record data.All rats all show the normal speed of growth, and are not having significant difference aspect food intake and the weight increase between three groups.Embodiment 4: T-CHOL, HDL-cholesterol and neutral lipid Determination on content in the blood plasma
Below measure to the influence of rat administering hesperidin or hesperetin plasma cholesterol and neutral lipid content.
From the rat of above three groups, take blood sample, and with the HDL-cholesterol reagent that comprises glucose sulfuric ester (Sigma Chemical Co., Cat.No.352-3) separated plasma HDL composition therefrom.(Sigma Chemical Co. USA) measures T-CHOL and HDL-cholesterol concentration (Allain et al., Clin.Chem., 20,470-475 (1974)) with Sigma Diagnostic Kit Cat.No.352-100.(SigmaChemical Co. USA) measures neutral lipid concentration (Bucolo, G. and David, H., Clin.Chem., 19,476-482 (1973)) with Sigma Diagnostic Kit Cat.No.339-50.The results are shown in Table III, wherein, compare with control rats, the total plasma cholesterol concentration of rat descends 32% and 18% respectively in Hesperidin and the hesperetin raising group.
Table III
TG: triglyceride embodiment 5: (step 1) prepares microsome to Hesperidin and the hesperetin activity in ACAT suppresses
| The group lipid concentration | Matched group | The Hesperidin group | The hesperetin group |
| T-CHOL (mg/dl) | ??147.8±34.8 | ??131.6±29.7 | 125.1±15.6 |
| HDL-cholesterol (mg/dl) | ??22.2 | ??18.7 | 25.7 |
| HDL-cholesterol/T-CHOL (%) | ??15.7±5.3 | ??15±4.9 | 20±5.6 |
| TG(mg/dl) | ??99.2±18.9 | ??92.7±20.5 | 114.6±18.8 |
For determining that with Hesperidin or hesperetin raising rat to the active effect of ACAT, the preparation microsome is as the enzyme source from hepatic tissue.
At first, with three groups of rat sacrificed by decapitation among the embodiment 3, and take out liver.Respectively with the 1g liver at 5ml homogenate medium (50mM KH
2PO
4(pH7.4), 0.1 MEDTA, 2mM beta-mercaptoethanol) middle homogenize.Centrifugal described homogenate is 10 minutes under 4 ℃, 3000 * g, and centrifugal resulting supernatant 15 minutes under 40 ℃, 15000 * g obtains supernatant thus then.Supernatant is put into super centrifuge tube (Beckman), and,, then this precipitate is suspended in the homogenate medium of 3ml to obtain the microsome precipitate 100000 * g, 4 ℃ centrifugal 1 hour down, and under 4 ℃, 100000 * g centrifugal 1 hour.The precipitate that obtains thus is suspended in the 1ml homogenate medium.Measure Protein content in the gained suspension with the Lowry method, be adjusted to 4-8mg/ml then.The gained suspension is stored in the Deep-Frozen machine (Biofreezer, Forma Scientific Inc.).(step 2) ACAT experiment
1mg/ml cholesterol acetone soln with 6.67 μ l in acetone mixes with the 10%TritonWR-1339 (Sigma Co.) of 6 μ l, removes acetone by using nitrogen to evaporate then.Add distilled water in the mixture of gained, its amount is that the concentration adjustment with cholesterol is 30mg/ml.
Microsome solution that in the cholesterol aqueous solution that 10 μ l obtain, makes in the step 1 of the 0.6mM bovine serum albumin (BSA) of the 1M potassium dihydrogen phosphate (pH7.4) of interpolation 10 μ l, 5 μ l, 10 μ l and the distilled water (90 μ l altogether) of 55 μ l.In water-bath in this mixture of 37 ℃ of following precincubation 30 minutes.
With 10 μ l (1-
14C) oleoyl-CoA solution (0.05 μ Ci, ultimate density 10 μ M) is added in the mixture of precincubation, in water-bath in the mixture of 37 ℃ of following incubation gained 30 minutes.In this mixture, add the isopropyl alcohol of 500 μ l: heptane mixture (4: 1v/v), the heptane of 300 μ l and the 0.1 M potassium dihydrogen phosphate (pH 7.4) of 200 μ l, use vortex vigorous stirring mixture then, and at room temperature left standstill 2 minutes.
The supernatant of 200 μ l gained is put into scintillation vial, and add the scintillation solution (Lumac) of 4ml therein.(Wallacoy Finland) carries out radioactivate analysis to mixture with 1450 Microbeta liquid scintillation counters.Pmol number (pmoles/min/mg albumen) with the synthetic cholesterol acid ester of every mg albumen per minute calculates the ACAT activity.The results are shown in Table IV.
Table IV
| Group | ACAT activity (pmol/min/mg albumen) | To the active inhibition percent of ACAT |
| Matched group | ????806.2±105.2 | ????0 |
| 0.1% Hesperidin group | ????851.2±86.0 | ????19.2 |
| 0.1% hesperetin group | ????616.4±60.5 | ????23.5 |
From the result of Table IV as can be seen, the ACAT activity is lower than matched group 19.2% and 23.5% respectively in Hesperidin and the hesperetin group rat.Embodiment 6: (step 1) is to animals administer Hesperidin and hesperetin for the inhibitory action that in Hesperidin and hesperetin letting animals feed the speckle that is caused by macrophage-lipid complex is formed
Under the condition of 20 ± 2 ℃ temperature, 55 ± 5% relative humidity and periodicity of illumination 12L/12D, raise 24 weight be respectively 2.5-2.6kg 3 monthly age New Zealand white rabbit (YeonamHorticulture and Animal Husbandry College, Korea).Above-mentioned rabbit is divided into 4 groups, raises 4 kinds of different feedstuffs to the rabbit of 4 groups then, promptly be respectively: the RC4 feedstuff (Oriental Yeast Co., Japan) (matched group) that comprise 1% cholesterol; 1% cholesterol adds 1mg/kg Lovastatin (Merck, USA) (contrast groups); 1% cholesterol adds 0.1% Hesperidin; And 1% cholesterol add 0.1% hesperetin.The RC4 feedstuff comprises 7.6% moisture, 22.8% crude protein, 2.8% crude fat, 8.8% cinder, 14.4% crude fibre and 43.6% solubility does not have nitrogen material.Rabbit raised for 6 weeks, and can freely absorb feedstuff and water.Fatty streaks in (step 2) analyzing animal tremulous pulse
The rabbit of raising in the step 1 is killed, cut chest then.Position by 1cm on the active mixer amplification by variable reactance begins the aorta that downward resection length is about 5cm, removes paraaortic fat then.In the middle of the longitudinal axis, cut aorta, and nail onboard.Wet tremulous pulse is taken a picture, and following then according to Esper, people's such as E. method (J.Lab.Clin.Med., 121,103-110 (1993)) dyes to fatty streaks.
With anhydrous propylene glycol in 2 minutes, wash a part through cut can aorta 3 times, use the propylene glycol saturated solution dyeing 30 minutes of Oil Red O (ORO, Sigman Co.) then.Afterwards, in 3 minutes, wash aorta 2 times, to remove residual staining solution, the washing of reuse normal saline with 85% propylene glycol solution.Aorta is taken a picture, and tracking shot.With image analyzer (LEICA, Q-600, the Germany) area of mensuration pigmented section (fatty streaks zone), and the ratio (%) of calculating and total aorta area.
On the other hand, according to hematoxylin-eosin (H﹠amp; E) and Masson ' s trichrome staining aortal other parts are dyeed, examine under a microscope then, whether be accumulated in inner membrance, tube chamber middle part, elastic layer and middle level to confirm macrophage-lipid complex.
In addition, from rabbit, take blood sample, and measure T-CHOL and triglyceride according to the method identical with embodiment 4.
The results are shown in Table shown in the V.
Table V
*M-L complex: macrophage-lipid complex
| The feedstuff group | T-CHOL (mg/dl) | Triglyceride (mg/dl) | M-L *Complex area (%) |
| Contrast | ????1143 | ????56 | ????35 |
| ?1mg/kg?Lovastatin Group | ????1210 | ????66 | ????5 |
| 0.1% Hesperidin group | ????1130 | ????40 | ????13.5 |
| 0.1% hesperetin group | ????1150 | ????41 | ????13 |
By Table V as can be seen, compare 1mg/ml Lovastatin with matched group
, the macrophage-lipid complex area that is accumulated on the arterial endothelium in 0.1% Hesperidin and the 0.1% hesperetin group significantly reduces.Therefore, confirm that Hesperidin and hesperetin can suppress the accumulation of macrophage-lipid complex on arterial endothelium.Particularly, obviously as can be seen, Hesperidin and hesperetin have the accumulation of macrophage-lipid complex and suppress active when being higher than the cholesterol blood concentration of 1100mg/dl, and described cholesterol concentration is much higher than the concentration of normal rabbit, promptly, about 50mg/dl.This results suggest has new mechanism to prevent atherosclerotic beginning, and this is synthetic with HMG-CoA reductase inhibitor blocking-up cholesterol, the ACAT inhibitor is blocked cholesterol absorption or CETP inhibitor blocking-up cholesterol shifts different.
Figure 1A, 1B and 1C have shown administration 1% cholesterol (matched group) respectively; 1% cholesterol adds 1mg/kg Lovastatin
(contrast groups); Add the tremulous pulse of the rabbit of 0.1% Hesperidin with 1% cholesterol.Shown in Figure 1A, 1B and 1C, on the arterial endothelium of the rabbit of administration 1% cholesterol, observe the macrophage-lipid complex of thick-layer, and add 1mg/kg Lovastatin at administration 1% cholesterol respectively
, and 1% cholesterol add the macrophage-lipid complex that does not almost have or only observe thinner layer on the arterial endothelium of rabbit of 0.1% Hesperidin.
Therefore, can draw to draw a conclusion: Hesperidin and hesperetin can suppress the accumulation of macrophage-lipid complex on arterial endothelium consumingly.Embodiment 7: (step 1) is to the Mus administering hesperidin to the prevention of hepatopathy for Hesperidin
(TaihanLaboratory Animal Center Korea) is equally divided into two feedstuff groups for the Sprague-Dawley rat of about 90-110g with 20 weight at random.The rat of these 2 groups feeds respectively with 2 kinds of different high cholesterol diets, promptly, comprise AIN-76 laboratory animal feedstuff (ICN Biochemicals, Clevand, OH, USA) (matched group) of 1% cholesterol; And 1% cholesterol add 0.02% Hesperidin.The composition of the feedstuff of 2 groups sees Table shown in the VI.
Table VI
*: available from TEKLAD Premier Co. (Madison, WI, USA)
| Feedstuff is formed and is divided | Matched group | 0.02% Hesperidin group |
| Casein | ????20 | ????20 |
| D, the L-methionine | ????0.3 | ????0.3 |
| Corn starch | ????15 | ????15 |
| Sucrose | ????39 | ????38.98 |
| Cellulose powder * | ????5 | ????5 |
| Mineral mixture * | ????3.5 | ????3.5 |
| Vitamin mixtures * | ????1 | ????1 |
| Adipokinetic hormone | ????0.2 | ????0.2 |
| Fat | ????15 | ????15 |
| Cholesterol | ????1 | ????1 |
| Hesperidin | ????- | ????0.02 |
| Amount to | ????100 | ????100 |
Unrestrictedly apparatus body feedstuff and water are fed rat totally 6 weeks, write down intake every day, weighed in per then 7 days, and the analytic record data.All rats all show the normal speed of growth, and are not having significant difference aspect food intake and the weight increase between two groups.(step 2) measures serum GOT and GPT concentration
Following mensuration administering hesperidin is to the effect of Hepar Mus function.
From the Mus of 2 groups, take blood, then according to method (Reitman, S. and J.S.Frankel, the Am.J.Clin.Pathol. of Reitman and Frankel, 28,56 (1956)) measure serum GOT (glutamic-oxaloacetic transaminase) and GPT (glutamic acid-acetone acid transaminase).GOT and GPT are synthetic in liver and heart, and are released in the blood when these organs are damaged.Therefore, GOT and GPT are the representative indexs of liver function, and on behalf of liver, high serum GOT and GPT concentration be subjected to major injury.
The result shows that the GOT of Hesperidin group and GPT concentration hang down about 30% and 10% respectively than matched group.(step 3) is used the experiment of rabbit
Same steps as in the repeating step 1, but use 30 weight to be respectively 3 monthly age New Zealand white rabbit (the Yeonam Horticulture and Animal Husbandry College of about 2.5-2.6kg, Korea) replace Mus, feed described rabbit respectively with 3 kinds of different feedstuffs then, promptly, comprise the RC4 feedstuff (matched group) of 1% cholesterol; 1% cholesterol adds 1mg/kg Lovastatin
(contrast groups); And 1% cholesterol add 0.1% Hesperidin.
Afterwards, from rabbit, separate liver, and the pathological study of carrying out as described below.
Intramuscular injection of ketamine (75mg/kg) anesthesia rabbit, hara kiri then.Hardened color of perusal liver and degree, and will from rabbit, fix more than 24 hours with 10% neutral buffered formalin by isolating liver.The water thorough washing is through fixed liver, and substep is embedded in the paraffin then with 70%, 80%, 90% and 100% ethanol dehydration.With microtome the liver that embeds is cut into the thickness of 4 μ m, and dyes with hematoxylin and eosin.Make dyed liver sample be transparence with dimethylbenzene, fix, use microscopic examination then, to confirm existing of damage with permount.
On behalf of administration 1% cholesterol (matched group), 1% cholesterol, Fig. 2 A, 2B and 2C add 1mg/kg Lovastatin respectively
(contrast groups) and 1% cholesterol add the microscopic features of the rabbit liver of 0.1% Hesperidin.Shown in Fig. 2 A and 2B, the hepatocyte of matched group and contrast groups is for arranging brokenly and increase, and wherein deposits a large amount of fat.On the contrary, shown in Fig. 2 C, the hepatocyte of Hesperidin group is normal, and does not observe the deposition of fat.This result shows that Hesperidin suppresses the generation of fatty liver consumingly, and hepatocyte is not had toxic and side effects.(step 4) end user's experiment
To man's administering hesperidin of 55 years old totally 68 days, and before the beginning administration, measure GOT, GPT and γ GTP respectively during 45 and 68 days (the 45th and 68 day) after (the 0th day) and the administration with the dosage of 10mg/g.Consequently, comparing during with the 0th day, the serum GOT concentration in the time of the 45th and 68 day reduces by 17% respectively.Comparing during with the 0th day, the serum GPT concentration in the time of the 45th and 68 day reduces by 15% and 19% respectively.And, comparing during with the 0th day, the serum r GTP concentration in the time of the 45th and 68 day reduces by 25% and 51% respectively.Surprisingly, comparing during with the 0th day, serum r GTP concentration reduced more than 50% in the time of the 68th day.This result shows that Hesperidin or hesperetin have potent liver protective effect to hepatopathy such as hepatitis, fatty liver and alcoholic fatty liver.
On the other hand, with 6mg/kg every day dosage to male's oral administration Hesperidin of 56 years old totally 30 days, this male habitually drinks the alcoholic beverage of 100cc every day, then before administration after (the 0th day) and the administration 30 days (the 30th day) measure serum r GTP concentration.Consequently, the initial serum r GTP concentration in the time of the 0th day is 129 IU/1, and the concentration the 30th day the time is reduced to 69 IU/1, has reached normal range.This result confirms that Hesperidin or hesperetin have high activity to prevention alcoholic fatty liver and hepatitis interstitialis chronica.Embodiment 9: the food that comprises Hesperidin or hesperetin
Following manufacturing comprises the food of Hesperidin or hesperetin.(1) makes tomato sauce and sauce
Hesperidin or hesperetin are added in tomato sauce or the sauce, and its amount is for 0.01-5wt%, to obtain more wholesome tomato sauce or sauce.(2) make wheat flour food
Hesperidin or hesperetin are added in the wheat flour food, and its amount is 0.01-5wt%, and uses this mixture to make bread, cake, cookies, soda cracker and noodles, to obtain more wholesome food.(3) make soup and gravy
Hesperidin or hesperetin are added in soup and the gravy, and its amount is for 0.01-5wt%, to obtain more wholesome soup and gravy.(4) make the beef end
Hesperidin or hesperetin are added in the beef end, and its amount is for 0.01-5wt%, to obtain more wholesome beef end.(5) make milk product
Hesperidin or hesperetin are added in the milk, and its amount uses this milk to make various milk product such as butter and ice cream for 0.01-5wt% then.
But, when making cheese, Hesperidin or hesperetin are added in the cohesion lactoprotein; And when making yoghourt, then Hesperidin or hesperetin are added in the cohesion lactoprotein that obtains after the fermentation.Embodiment 10: the beverage (1) that comprises Hesperidin or hesperetin is made vegetable juice
200-10000mg Hesperidin or hesperetin are added in 1000ml Fructus Lycopersici esculenti or the Radix Dauci Sativae juice, to make more wholesome vegetable juice.(2) make fruit juice
200-10000mg Hesperidin or hesperetin are added in 1000ml Fructus Mali pumilae or the Sucus Vitis viniferae, to make more wholesome fruit juice.(3) make soda pop
200-10000mg Hesperidin or hesperetin are added into 1000ml coca cola
Or pepsi cola
In, to make more wholesome soda pop.
Though invention has been described with reference to above-mentioned specific embodiments, it should be understood that those skilled in the art also can carry out various improvement and variation within the scope of the invention, and scope of the present invention limited by following claims.
Claims (27)
Applications Claiming Priority (8)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1019970055578A KR19990034089A (en) | 1997-10-28 | 1997-10-28 | Acylcoay: Cholesterol-Ortho-Acyltransferase Inhibitor Compositions Including Hesperidin or Hesperetin |
| KR1019980010888A KR19990076178A (en) | 1998-03-28 | 1998-03-28 | Composition for the prevention and treatment of liver disease, including hesperidin |
| KR1998/10888 | 1998-03-28 | ||
| KR1019980012411A KR19990079683A (en) | 1998-04-08 | 1998-04-08 | Functional health food containing citrus rind powder or rind extract |
| KR1998/12411 | 1998-04-08 | ||
| KR1019980013283A KR19990080214A (en) | 1998-04-14 | 1998-04-14 | Functional drink containing health extract of citrus peel |
| KR1998/13283 | 1998-04-14 | ||
| KR1997/55578 | 1998-04-14 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1278170A true CN1278170A (en) | 2000-12-27 |
| CN1124133C CN1124133C (en) | 2003-10-15 |
Family
ID=27483239
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN98810701A Expired - Fee Related CN1124133C (en) | 1997-10-28 | 1998-10-20 | Hesperidin and hesperetin as inhibitor of acyl coa-cholesterol-o-acyltransferase, inhibitor of macrophage-lipid complex accumulation on the arterial wall and preventive agent |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP1063988A1 (en) |
| JP (1) | JP2001520993A (en) |
| CN (1) | CN1124133C (en) |
| CA (1) | CA2307890A1 (en) |
| WO (1) | WO1999021549A1 (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100546576C (en) * | 2006-06-15 | 2009-10-07 | 安徽医科大学 | Application of hesperetin derivative in preparation of anti-inflammatory immune drugs |
| TWI450960B (en) * | 2006-01-23 | 2014-09-01 | Suntory Holdings Ltd | Food or beverage and its manufacturing method |
| CN104688756A (en) * | 2013-12-09 | 2015-06-10 | 中国药科大学 | Pharmaceutical composition and its use in preparation of drug for treating alcoholic liver injury |
| CN114832007A (en) * | 2021-02-01 | 2022-08-02 | 健茂生物科技股份有限公司 | Composition for reducing cholesterol and preparation method thereof |
| CN114832041A (en) * | 2021-02-01 | 2022-08-02 | 健茂生物科技股份有限公司 | Composition with liver protection effect and preparation method thereof |
| CN115607538A (en) * | 2022-09-26 | 2023-01-17 | 浙江工商大学 | Application of hesperetin in preparation of medicine for inhibiting and/or treating wheat allergy |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20020006953A1 (en) * | 1999-11-05 | 2002-01-17 | Carla R. McGill | Modification of cholesterol concentrations with citus phytochemicals |
| FR2841472B1 (en) | 2002-06-28 | 2006-02-24 | Agronomique Inst Nat Rech | NUTRITIONAL OR THERAPEUTIC COMPOSITION CONTAINING THE HESPERIDINE COMPOUND OR ONE OF ITS DERIVATIVES |
| ES2627847T3 (en) | 2004-07-23 | 2017-07-31 | Suntory Holdings Limited | Material immersed in alcohol, food or drink that uses it and method to produce it |
| WO2006067925A1 (en) * | 2004-12-24 | 2006-06-29 | Kabushiki Kaisha Hayashibara Seibutsu Kagaku Kenkyujo | Hepatic function remedial agent |
| EP2368442B1 (en) | 2005-07-27 | 2014-12-17 | Symrise AG | Use of hesperetin for enhancing the sweet taste |
| JP2007112806A (en) * | 2006-11-27 | 2007-05-10 | Kao Corp | Body fat burning accelerator |
| JP2009007256A (en) * | 2007-06-26 | 2009-01-15 | Kao Corp | NADH / NADPH oxidase inhibitor |
| TWI715172B (en) * | 2019-08-28 | 2021-01-01 | 健茂生物科技股份有限公司 | Composition in suppressing body fat accumulation |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4150038A (en) * | 1977-05-16 | 1979-04-17 | Dynapol | Conversion of hesperidin into hesperetin |
| JPS54154569A (en) * | 1978-05-20 | 1979-12-05 | Lotte Co Ltd | Chewing gum for sports |
| ATE87204T1 (en) * | 1987-12-10 | 1993-04-15 | Tsumura & Co | ANTI-RETROVIRAL DRUG. |
| EP0347864A3 (en) * | 1988-06-24 | 1992-04-01 | Andries Johannes Cornelus Strydom | Anti-atherogenic agents |
| JPH04295428A (en) * | 1991-03-22 | 1992-10-20 | Dai Ichi Seiyaku Co Ltd | Antiallergic agent |
| WO1994023717A1 (en) * | 1993-04-20 | 1994-10-27 | The Procter & Gamble Company | Methods of using hesperetin for sebum control and treatment of acne |
| JPH0725761A (en) * | 1993-07-09 | 1995-01-27 | Kureha Chem Ind Co Ltd | Cartilage protectant |
| JPH08283154A (en) * | 1995-04-12 | 1996-10-29 | Nippon Shinyaku Co Ltd | Lipid metabolism improver |
| JP3557711B2 (en) * | 1995-04-12 | 2004-08-25 | 日本新薬株式会社 | Foods and manufacturing methods effective for improving lipid metabolism |
-
1998
- 1998-10-20 JP JP2000517707A patent/JP2001520993A/en active Pending
- 1998-10-20 CN CN98810701A patent/CN1124133C/en not_active Expired - Fee Related
- 1998-10-20 EP EP98951777A patent/EP1063988A1/en not_active Withdrawn
- 1998-10-20 CA CA002307890A patent/CA2307890A1/en not_active Abandoned
- 1998-10-20 WO PCT/KR1998/000324 patent/WO1999021549A1/en not_active Ceased
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TWI450960B (en) * | 2006-01-23 | 2014-09-01 | Suntory Holdings Ltd | Food or beverage and its manufacturing method |
| CN100546576C (en) * | 2006-06-15 | 2009-10-07 | 安徽医科大学 | Application of hesperetin derivative in preparation of anti-inflammatory immune drugs |
| CN104688756A (en) * | 2013-12-09 | 2015-06-10 | 中国药科大学 | Pharmaceutical composition and its use in preparation of drug for treating alcoholic liver injury |
| CN114832007A (en) * | 2021-02-01 | 2022-08-02 | 健茂生物科技股份有限公司 | Composition for reducing cholesterol and preparation method thereof |
| CN114832041A (en) * | 2021-02-01 | 2022-08-02 | 健茂生物科技股份有限公司 | Composition with liver protection effect and preparation method thereof |
| CN115607538A (en) * | 2022-09-26 | 2023-01-17 | 浙江工商大学 | Application of hesperetin in preparation of medicine for inhibiting and/or treating wheat allergy |
Also Published As
| Publication number | Publication date |
|---|---|
| EP1063988A1 (en) | 2001-01-03 |
| CA2307890A1 (en) | 1999-05-06 |
| WO1999021549A1 (en) | 1999-05-06 |
| CN1124133C (en) | 2003-10-15 |
| JP2001520993A (en) | 2001-11-06 |
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