KR100291143B1 - Acyl coa: cholesterol-o-acyltransferase inhibitory composition comprising naringin or naringenin - Google Patents
Acyl coa: cholesterol-o-acyltransferase inhibitory composition comprising naringin or naringenin Download PDFInfo
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- KR100291143B1 KR100291143B1 KR1019990051433A KR19990051433A KR100291143B1 KR 100291143 B1 KR100291143 B1 KR 100291143B1 KR 1019990051433 A KR1019990051433 A KR 1019990051433A KR 19990051433 A KR19990051433 A KR 19990051433A KR 100291143 B1 KR100291143 B1 KR 100291143B1
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- South Korea
- Prior art keywords
- cholesterol
- naringin
- naringenin
- acat
- activity
- Prior art date
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- 239000001606 7-[(2S,3R,4S,5S,6R)-4,5-dihydroxy-6-(hydroxymethyl)-3-[(2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyloxan-2-yl]oxyoxan-2-yl]oxy-5-hydroxy-2-(4-hydroxyphenyl)chroman-4-one Substances 0.000 title claims abstract description 33
- DFPMSGMNTNDNHN-ZPHOTFPESA-N naringin Chemical compound O[C@@H]1[C@H](O)[C@@H](O)[C@H](C)O[C@H]1O[C@H]1[C@H](OC=2C=C3O[C@@H](CC(=O)C3=C(O)C=2)C=2C=CC(O)=CC=2)O[C@H](CO)[C@@H](O)[C@@H]1O DFPMSGMNTNDNHN-ZPHOTFPESA-N 0.000 title claims abstract description 33
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Classifications
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2200/00—Function of food ingredients
- A23V2200/30—Foods, ingredients or supplements having a functional effect on health
- A23V2200/326—Foods, ingredients or supplements having a functional effect on health having effect on cardiovascular health
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2250/00—Food ingredients
- A23V2250/60—Sugars, e.g. mono-, di-, tri-, tetra-saccharides
Landscapes
- Life Sciences & Earth Sciences (AREA)
- Mycology (AREA)
- Health & Medical Sciences (AREA)
- Nutrition Science (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Food Science & Technology (AREA)
- Polymers & Plastics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Plant Substances (AREA)
Abstract
본 발명은 나린진(naringin) 또는 나린제닌(naringenin)을 포함하는 아실 코에이: 콜레스테롤-O-아실트랜스퍼레이즈(acyl CoA: cholesterol-O-acyltrans ferase, ACAT) 활성 저해제 조성물에 관한 것으로, 본 발명의 조성물은 의약용 및 식품용 조성물을 포함한다. 본 발명의 조성물은 동물체내의 ACAT 활성을 저해하여 혈중 저밀도 지단백질(LDL) 콜레스테롤을 감소시키므로 각종 심혈관계 질환의 예방 및 치료제로서 유용하게 사용될 수 있다.The present invention relates to an acyl coay: cholesterol-O-acyltransferase (ACAT) activity inhibitor composition comprising naringin or naringenin. The composition includes medicinal and food compositions. The composition of the present invention can be usefully used as a prophylactic and therapeutic agent for various cardiovascular diseases since it inhibits ACAT activity in the animal and reduces blood low density lipoprotein (LDL) cholesterol.
Description
본 발명은 나린진(C27H32O14, 분자량 580.53) 및 나린제닌(C15H12O5, 분자량 272.25)을 포함하는 아실 코에이: 콜레스테롤-O-아실트랜스퍼레이즈(ACAT) 저해제 조성물에 관한 것이다.The present invention relates to an acyl coei: cholesterol-O-acyltransferase (ACAT) inhibitor composition comprising naringin (C27H32O14, molecular weight 580.53) and naringenin (C15H12O5, molecular weight 272.25).
관상동맥성 심혈관 질환은 현재 모든 사망원인의 30% 이상을 차지하고 있으며 미국, 유럽 등 선진국에서는 심각한 문제가 되고 있다. 한편 개발도상국에서도 식생활의 서구화, 운동부족 등의 영향을 받아 심장병이 증가하고 있는 추세에 있다. 혈중 콜레스테롤의 양이 높을 경우 혈관벽에 지방과 더불어 대식세포(macrophage), 포말세포(foam cell) 등이 생성 침착되고 플라크(plaque)를 형성하여 혈액순환을 저해하는 동맥경화증세가 오기 쉬운 것으로 알려져 있다(Ross, R., Nature, 362, 801-809(1993)). 혈중 콜레스테롤의 양을 줄이는 방법으로는 콜레스테롤의 흡수를 억제하는 방법이 있다. ACAT는 인체조직 속에서 콜레스테롤을 콜레스테릴 에스터로 전환시켜주는 효소이다. 실험적이나 임상학적인 동맥경화 현상에서 대식세포(macrophage)나 평활근(smooth muscle) 세포 유래 포말세포들의 형성은 아주 중요한 인자이다. 포말세포들은 ACAT 작용에 의해 형성되고 혈액 속의 LDL에 의해 운반되는 콜레스테롤 에스터를 많이 함유하고 있다. 동맥 혈관 벽에 있는 포말세포들은 ACAT 활성의 증가와 더불어 발견되는 경우가 많기 때문에, ACAT 저해제는 동맥경화 예방제가 될 가능성이 높다. 또한 간 속의 ACAT 활성을 저해 할 경우 혈액속에 유통되는 LDL-콜레스테롤 수준을 낮출 수 있을 것이다(Witiak, D. T. and D. R. Feller(eds), Anti lipidemic Drugs: Medicinal, Chemical, and Biochemical Aspects, Elsevier, pp159-195(1991)).Coronary cardiovascular disease currently accounts for more than 30% of all deaths and is a serious problem in developed countries such as the United States and Europe. Meanwhile, in developing countries, heart disease is on the rise due to westernization of diet and lack of exercise. If the amount of cholesterol in the blood is high, macrophage, foam cells, etc. are formed and deposited in the blood vessel walls, and plaques are formed, and atherosclerosis, which inhibits the blood circulation, is known to be prone to occur. Ross, R., Nature, 362, 801-809 (1993)). Reducing the amount of cholesterol in the blood is a way to suppress the absorption of cholesterol. ACAT is an enzyme that converts cholesterol into cholesteryl esters in human tissues. The formation of macrophage or smooth muscle cell-derived foam cells is an important factor in experimental and clinical atherosclerosis. Foam cells contain large amounts of cholesterol esters formed by ACAT and carried by LDL in the blood. Because foam cells in the arterial vessel walls are often found with increased ACAT activity, ACAT inhibitors are likely to be protective agents of atherosclerosis. Inhibition of ACAT activity in the liver may also lower the level of LDL-cholesterol in the blood (Witiak, DT and DR Feller (eds), Anti lipidemic Drugs: Medicinal, Chemical, and Biochemical Aspects, Elsevier, pp159-195 (1991)).
혈중 콜레스테롤의 양을 줄이는 다른 방법으로는 지단백질간에 콜레스테롤 전이를 매개하는 콜레스테롤 에스터 전달 단백질(cholesterol ester transfer protein, CETP)의 작용을 억제하거나 간에서 콜레스테롤 생합성에 관련하는 효소인 3-하이드록시-3-메틸글루타릴 조효소 A(HMG-CoA) 환원효소의 작용을 억제하는 방법이다. 본 발명자들은 비교적 안전할 것으로 생각되는 생약재, 식품재료, 과채류 등에 풍부한 물질들의 약리활성물질 탐색연구를 수행하였다.Other ways to reduce the amount of cholesterol in the blood include 3-hydroxy-3-, an enzyme that inhibits the action of cholesterol ester transfer protein (CETP) that mediates cholesterol transfer between lipoproteins or is involved in cholesterol biosynthesis in the liver. A method of inhibiting the action of methyl glutaryl coenzyme A (HMG-CoA) reductase. The present inventors conducted research on pharmacologically active substances of substances rich in herbal medicines, food ingredients, fruits and vegetables that are considered to be relatively safe.
나린제닌은 오렌지, 귤 등의 감귤류에 존재하는 천연물 나린진에서 배당체를 제거하여 얻어진 물질로, 쥐에 투여하였을 때 0.5 내지 1% 농도에서 혈중 콜레스테롤 농도를 강하시킨다는 보고가 있다(일본 특허 공개 제 08-283154 호(1996. 10. 29)). 그러나, 상기 문헌에서는 나린진과 같은 배당체가 포함된 천연물은 콜레스테롤 강하에 효과가 없다고 보고하였다. 또한, 혈중 콜레스테롤의 양은 동물 체내에서 많은 조절을 통해 통제되는데, 상기 문헌에서는 혈중 콜레스테롤 강하가 일어나는 구체적인 기작에 대해서는 언급하고 있지 않다.Naringenin is a substance obtained by removing glycosides from naringin, a natural product present in citrus fruits such as oranges and tangerines, and when administered to rats, naringenin has been reported to lower blood cholesterol concentrations at a concentration of 0.5 to 1%. 283154 (October 29, 1996). However, the literature reported that natural products containing glycosides such as naringin have no effect on cholesterol lowering. In addition, the amount of cholesterol in the blood is controlled through a lot of regulation in the animal body, which does not mention the specific mechanism by which blood cholesterol drop occurs.
본 발명자들은 감귤류의 과일중에 있는 바이오플라보노이드가 인체에 유익한 많은 종류의 활성을 가지고 있는 것을 안 후, 이들이 동맥경화증에 관련된 콜레스테롤 대사 특히 콜레스테롤 생합성 관련 효소(예컨대, HMG-CoA 환원효소)나 콜레스테롤 흡수에 관련된 효소(예컨대, ACAT 또는 CETP) 등의 활성과 관련이 있는지를 확인하고자 연구를 계속한 결과, 나린진과 나린제닌이 ACAT 활성을 억제한다는 사실을 발견하여 본 발명을 완성하였다.The present inventors have found that bioflavonoids in citrus fruits have many types of activity beneficial to the human body, and therefore they are responsible for cholesterol metabolism, especially cholesterol biosynthesis-related enzymes (eg, HMG-CoA reductase) or cholesterol absorption related to atherosclerosis. As a result of continuing the study to determine whether related enzymes (eg, ACAT or CETP) and related activities, the present invention was completed by finding that naringin and naringenin inhibit ACAT activity.
본 발명의 목적은 나린진 또는 나린제닌을 포함하는 아실 코에이: 콜레스테롤-O-아실트랜스퍼레이즈(ACAT) 활성 저해용 약학 조성물을 제공하는 것이다.An object of the present invention to provide a pharmaceutical composition for inhibiting acyl coay: cholesterol-O-acyltransferase (ACAT) activity containing naringin or naringenin.
본 발명의 다른 목적은 나린진 또는 나린제닌을 포함하는 ACAT 활성 저해용 식품 또는 음료 조성물을 제공하는 것이다.Another object of the present invention to provide a food or beverage composition for inhibiting ACAT activity comprising naringin or naringenin.
본 발명에서는 나린진 또는 나린제닌을 활성 성분으로서 약학적으로 허용되는 담체와 함께 포함하는 아실 코에이: 콜레스테롤-O-아실트랜스퍼레이즈(ACAT) 활성 저해용 약학 조성물이 제공된다. 또한, 나린진 또는 나린제닌을 포함하는 ACAT 저해용 식품 조성물 및 음료 조성물이 제공된다.In the present invention, there is provided a pharmaceutical composition for inhibiting acyl coei: cholesterol-O-acyltransferase (ACAT) activity comprising naringin or naringenin as an active ingredient together with a pharmaceutically acceptable carrier. Also provided are food compositions and beverage compositions for inhibiting ACAT comprising naringin or naringenin.
나린진 또는 나린제닌은 감귤류로부터 추출하거나 공지된 합성 방법에 의해서도 합성할 수 있다. 본 발명에서 감귤류란 탕헤르오렌지(tangerine), 오렌지, 레몬, 그레이프프루트, 유자 또는 탱자 등을 말한다. 감귤류에 들어있는 플라보노이드는 과일의 성숙기에 따라 또는 과일의 종류에 따라 각각 활성 성분의 비율이 변할 수 있으며, 이들의 추출 방법은 메르크 인덱스(Merck Index) 등의 문헌 및 특허 등에 다수 공개되어 있다.Naringin or naringenin can be extracted from citrus fruits or synthesized by known synthetic methods. Citrus fruits in the present invention refers to tangerine, orange, lemon, grapefruit, citron or tanza. Flavonoids contained in citrus fruits may vary in active ingredient ratio depending on the maturity of the fruit or the type of fruit, and their extraction methods are disclosed in the literature and patents such as the Merck Index.
나린진 또는 나린제닌은 ACAT 활성을 저해하며, 쥐의 혈중 콜레스테롤 감소현상도 일부는 ACAT활성 저하에 기인한다고 볼 수 있다. 현재까지 연구된 독성시험 결과, 나린진 또는 나린제닌은 1000 mg/kg의 용량으로 쥐에게 경구투여하였을 때 독성이 거의 없는 것으로 밝혀졌다. 또한, 나린진 또는 나린제닌은 간을 비롯한 장기의 기능에 어떠한 부작용도 나타내지 않는다.Naringin or naringenin inhibit ACAT activity, and some of the decrease in blood cholesterol in rats may be due to a decrease in ACAT activity. Toxicity studies studied to date have shown that naringin or naringenin is virtually nontoxic when administered orally to rats at a dose of 1000 mg / kg. In addition, naringin or naringenin show no adverse effects on the function of organs, including the liver.
ACAT의 활성을 저해하기 위하여, 나린진 또는 나린제닌을 유효성분으로서 약제학적으로 또는 식품첨가물로서 허용되는 담체와 혼합하여 ACAT 활성 저해제 조성물을 제조할 수 있다. 이 조성물은 통상적으로 사용되는 부형제, 붕해제, 감미제, 활택제, 향미제 등을 추가로 포함할 수 있으며, 통상적인 방법에 의해 정제, 캅셀제, 산제, 과립, 현탁제, 유화제, 시럽제, 액제 또는 비경구 투여용 제제와 같은 단위 투여형 또는 수회 투여형 약제학적 제제로 제형화될 수 있다.In order to inhibit the activity of ACAT, naringin or naringenin may be mixed with a carrier that is pharmaceutically or as an acceptable food additive as an active ingredient to prepare an ACAT activity inhibitor composition. The composition may further include conventionally used excipients, disintegrants, sweeteners, lubricants, flavoring agents and the like, and may be prepared by tablets, capsules, powders, granules, suspensions, emulsifiers, syrups, solutions or by conventional methods or It may be formulated in a unit dosage form or in multiple dosage form pharmaceutical preparations, such as preparations for parenteral administration.
본 발명의 나린진 또는 나린제닌을 유효성분으로 함유하는 ACAT 저해제 조성물은 목적하는 바에 따라 비경구 투여하거나 경구 투여할 수 있으며, 하루에 체중 1 ㎏당 0.001 내지 10 g, 바람직하게는 0.1 내지 1 g의 양을 1 내지 수회에 나누어 투여할 수 있다. 특정 환자에 대한 투여용량 수준은 환자의 체중, 연령, 성별, 건강상태, 식이, 투여시간, 투여 방법, 배설율, 질환의 중증도 등에 따라 변화될 수 있다.The ACAT inhibitor composition containing naringin or naringenin of the present invention as an active ingredient can be parenterally or orally administered as desired, and 0.001 to 10 g, preferably 0.1 to 1 g per kg of body weight per day. The amount can be administered in one to several portions. Dosage levels for a particular patient may vary depending on the patient's weight, age, sex, health condition, diet, time of administration, method of administration, rate of excretion, severity of the disease, and the like.
나린진 또는 나린제닌은 또한 ACAT 활성을 억제할 목적으로 식품 또는 음료에 첨가될 수 있다. 건강보조식품용 개발을 위하여 나린진 또는 나린제닌을 첨가할 수 있는 식품으로는, 예를 들어, 각종 식품류, 육류, 음료수, 초코렛, 스넥류, 과자류, 피자, 라면, 기타 면류, 껌류, 아이스크림류, 알콜음료류, 비타민 복합제, 건강보조식품류 등이 있다.Naringin or naringenin may also be added to foods or beverages for the purpose of inhibiting ACAT activity. Examples of foods to which naringin or naringenin may be added for the development of dietary supplements include, for example, various foods, meats, beverages, chocolates, snacks, snacks, pizzas, ramen noodles, other noodles, gums, ice creams, alcohols. Beverages, vitamin complexes and dietary supplements.
이하 본 발명을 다음과 같은 실시예에 의하여 더욱 상세하게 설명하고자 한다. 단, 다음의 실시예는 본 발명을 예시하기 위한 것일 뿐, 본 발명의 범위가 이것들 만으로 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following Examples are only for illustrating the present invention, but the scope of the present invention is not limited to these.
실시예 1: 실험동물의 식이 조성과 나린진 및 나린제닌의 동물투여실험Example 1 Dietary Composition of Animals and Animal Administration of Naringin and Naringenin
3주령의 스프라그 다울리(Sprague-Dawley) 흰쥐 30마리를 충북 음성군의 대한실험 동물센터로부터 구입하여 1주간 제일제당 실험동물 사료로 사육하고, 4주령(체중: 90∼110g)이 되었을 때, 난괴법(randomized block design)에 의해 3 개의 그룹으로 나누었다. 세 그룹의 쥐들에게 각각 세가지의 서로 다른 고콜레스테롤 식이, 즉, 정상식이(AIN-76 실험동물 식이)에 1% 콜레스테롤(대조군); 1% 콜레스테롤 및 0.1% 나린진; 그리고 1% 콜레스테롤 및 0.1% 나린제닌이 각각 함유된 식이를 섭취시켰다. 세 그룹에게 섭취시킨 식이의 조성은 하기 표 1에 나타나 있다.30 Sprague-Dawley rats of 3 weeks of age were purchased from the Korean Experimental Animal Center in Negative Chungcheongbuk-do and were bred for 1 week in experimental animal feed, and at 4 weeks of age (90-110 g), Divided into three groups by randomized block design. Three groups of rats each had three different high cholesterol diets, namely 1% cholesterol (control) in normal diet (AIN-76 experimental animal diet); 1% cholesterol and 0.1% naringin; A diet containing 1% cholesterol and 0.1% naringenin was taken. The composition of the diets ingested in the three groups is shown in Table 1 below.
모든 식이들은 고콜레스테롤식이(1%, wt/wt)에 해당하고, 나린진 및 나린제닌은 미국의 시그마사(Sigma Chemical company, St. Louis, Mo)로부터 구입하였으며, 실험용 흰쥐의 실험실 식이인 AIN-76 식이 조성 중 셀룰로즈, 미네랄 혼합물 및 비타민 혼합물 성분은 미국의 테크라드 프리미어사(TEKLAD premier, Madison, Wisconsin)로부터 구입하였다.All diets correspond to a high cholesterol diet (1%, wt / wt), naringin and naringenin were purchased from Sigma Chemical company, St. Louis, Mo. AIN-, the laboratory diet of rats. Cellulose, mineral and vitamin mixture components in the 76 dietary composition were purchased from TEKLAD premier, Madison, Wisconsin, USA.
모든 식이군의 쥐들에게 6주동안 해당 식이를 물과 함께 자유로이 섭취하도록 하였으며, 식이섭취량을 매일 기록하고 7일마다 체중을 측정하였다. 동물사육이 종료된 후 사육일지의 자료를 분석한 결과, 식이 섭취량과 체중증가에 있어서는 3개군간 유의적인 차이가 없었으며 정상적인 성장을 보였다.All dietary rats were given free diet with water for 6 weeks. The dietary intake was recorded daily and weighed every 7 days. After the animal breeding was completed, the data on the breeding journal showed that there was no significant difference between the three groups in terms of dietary intake and weight gain and showed normal growth.
실시예 2: 실험동물의 혈중 총콜레스테롤, HDL-콜레스테롤 및 중성 지질 함량Example 2: Blood Total Cholesterol, HDL-Cholesterol, and Neutral Lipid Content in Experimental Animals
측정Measure
실험 식이의 투여가 흰쥐의 혈중 콜레스테롤 및 중성지질 함량에 미치는 영향을 다음과 같이 조사하였다.The effects of experimental diet on blood cholesterol and triglyceride content in rats were investigated as follows.
세 식이군의 쥐들로부터 혈액 시료를 채취하고, 이로부터 덱스트란-설페이트를 포함한 HDL-콜레스테롤 시약(Sigma Chemical Co. Cat. No. 352-3)을 이용하여 혈장 HDL 분획을 분리하였다. 총 콜레스테롤과 HDL-콜레스테롤 농도는 시그마사의 총 콜레스테롤 키트(Cat. No. 352-100)를 사용한 효소발색법(Allain et al., Clin. Chem., 20, 470-475(1974))에 의해 측정하였다. 중성 지질 농도는 시그마 진단 키트(Cat. No. 339-50)를 사용하여 측정하였다(Bucolo, G. and David, H., Clin. Chem., 19, 476-482(1973)). 그 결과는 하기 표 2에 나타나 있는데, 혈장 총 콜레스테롤 농도는 나린진 투여군에서 대조군에 비해 32% 감소하였고, 나린제닌 투여군에서는 대조군에 비해 18% 감소하였다.Blood samples were taken from three dietary rats, and plasma HDL fractions were isolated from the HDL-cholesterol reagent (Sigma Chemical Co. Cat. No. 352-3) including dextran-sulfate. Total cholesterol and HDL-cholesterol concentrations were measured by enzymatic coloration using Sigma's Total Cholesterol Kit (Cat. No. 352-100) (Allain et al., Clin. Chem., 20, 470-475 (1974)). It was. Neutral lipid concentrations were measured using Sigma Diagnostic Kit (Cat. No. 339-50) (Bucolo, G. and David, H., Clin. Chem., 19, 476-482 (1973)). The results are shown in Table 2 below, the plasma total cholesterol concentration was reduced by 32% compared to the control group in the naringin administration group, 18% compared to the control group in the naringenin administration group.
실시예 3: 나린진 및 나린제닌 투여가 ACAT 효소 활성에 미치는 영향Example 3: Effect of Naringin and Naringenin Administration on ACAT Enzyme Activity
(단계 1) 마이크로좀의 제조(Step 1) Preparation of the microsome
세 그룹의 흰쥐들을 희생시켜 간을 적출하였다. 1 g의 간 조직을 5 ml의 용액 1(0.1 M 인산칼륨(pH 7.4), 0.1 mM EDTA 및 10 mM β-머캅토에탄올)을 이용하여 균질화하였다. 이 균질액을 4℃에서 3,000xg 로 15분 동안 원심분리하였다. 상층액을 새로운 튜브로 옮기고, 4℃에서 15,000xg로 15분 동안 다시 원심분리하였다. 상층액을 5 ml 초원심분리 튜브(Beckman)로 옮기고, 4 ℃에서 100,000xg 로 1 시간 동안 원심분리하였다. 상층액을 버리고, 펠렛을 3 ml의 용액 1 로 현탁시킨 후, 이 용액을 4℃에서 100,000xg로 1 시간 동안 원심분리하였다. 상층액을 버리고, 펠렛을 1 ml의 용액 1 로 현탁시켰다. 현탁액중의 단백질 농도를 로우리(Lowry) 등의 방법으로 측정하고, 단백질 농도를 4 내지 8 mg/ml로 조절하였다. 이 현탁액을 딥 프리저(deep freezer)에 보관하였다.Liver was harvested at the expense of three groups of rats. 1 g of liver tissue was homogenized with 5 ml of solution 1 (0.1 M potassium phosphate pH 7.4, 0.1 mM EDTA and 10 mM β-mercaptoethanol). This homogenate was centrifuged at 3,000 × g for 15 minutes at 4 ° C. The supernatant was transferred to a new tube and centrifuged again at 15,000 × g at 4 ° C. for 15 minutes. The supernatants were transferred to 5 ml ultracentrifuge tubes (Beckman) and centrifuged at 100,000 × g at 4 ° C. for 1 hour. The supernatant was discarded and the pellet was suspended with 3 ml of solution 1, then the solution was centrifuged at 4Ox at 100,000xg for 1 hour. The supernatant was discarded and the pellet suspended in 1 ml of solution 1. The protein concentration in the suspension was measured by Lowry et al. And the protein concentration was adjusted to 4-8 mg / ml. This suspension was stored in a deep freezer.
(단계 2) ACAT 활성 측정(Step 2) ACAT Activity Measurement
아세톤에 1 mg/ml의 농도로 용해된 콜레스테롤 용액 6.67 ㎕를 아세톤중의 10% 트리톤(Triton) WR-1339 6 ㎕와 혼합하고, 질소가스를 이용하여 아세톤을 증발시킨 후, 10 ml 부피당 300mg의 콜레스테롤이 포함되도록 증류수를 가했다.6.67 μl of cholesterol solution dissolved in acetone at a concentration of 1 mg / ml was mixed with 6 μl of 10% Triton WR-1339 in acetone, and acetone was evaporated using nitrogen gas. Distilled water was added to contain cholesterol.
10 ㎕의 상기에서 얻은 콜레스테롤 수용액, 10 ㎕의 1 M 인산 칼륨(pH 7.4), 5 ㎕의 0.6 mM 우 혈청 알부민(BSA), 10 ㎕의 단계 1에서 얻은 마이크로좀 및 55 ㎕의 증류수를 혼합하였다(총 90㎕). 혼합물을 37℃에서 30 분 동안 수욕(waterbath)에서 예비 반응시켰다.10 μl of the aqueous solution of cholesterol obtained above, 10 μl of 1 M potassium phosphate (pH 7.4), 5 μl of 0.6 mM bovine serum albumin (BSA), 10 μl of the microsome obtained in step 1 and 55 μl of distilled water were mixed. (90 μl total). The mixture was pre-reacted in a waterbath at 37 ° C. for 30 minutes.
방사능 표지된 올레일-CoA와 올레일-CoA를 혼합하여 제조된 10 ㎕의 올레일-CoA 용액(0.3 mg/ml)을 예비 반응된 혼합물에 가하고, 생성된 혼합물을 37℃에서 30 분동안 수욕에서 반응시켰다. 여기에 500 ㎕의 이소프로판올:헵탄=4:1(v/v) 용액, 300 ㎕의 헵탄 및 200 ㎕ 의 0.1M 인산 칼륨(pH 7.4)을 가하고, 볼텍스(vortex)로 격렬하게 혼합한 후, 상온에서 2분 동안 방치하였다.10 μl of oleyl-CoA solution (0.3 mg / ml) prepared by mixing radiolabeled oleyl-CoA and oleyl-CoA was added to the pre-reacted mixture, and the resulting mixture was water bathed at 37 ° C. for 30 minutes. Reaction at To this was added 500 μl of isopropanol: heptane = 4: 1 (v / v) solution, 300 μl of heptane and 200 μl of 0.1 M potassium phosphate (pH 7.4), followed by vigorous mixing with vortex, followed by room temperature. It was left for 2 minutes at.
200 ㎕의 상층액을 신틸레이션 병에 넣고, 신틸레이션 액(Lumac 사 제품) 4 ml를 섞어 신틸레이션 계수기(scintillation counter)로 방사선량을 측정하였다. ACAT 효소 활성은 측정된 방사선량으로부터 시간당 방사선량을 계산하여 피코몰/분/mg 단백질 단위로 나타내었다. 그 결과는 표 3과 같다.200 μl of the supernatant was placed in a scintillation bottle, and 4 ml of scintillation solution (manufactured by Lumac) was mixed and the radiation dose was measured by a scintillation counter. ACAT enzyme activity was expressed in picomolar / min / mg protein by calculating the radiation dose per hour from the measured radiation dose. The results are shown in Table 3.
표 3에서 볼 수 있는 바와 같이, 0.1% 나린진 투여시, 쥐의 간 속의 ACAT 활성도는 21% 감소하였다. 또한, 0.1% 나린제닌 투여는 ACAT 활성을 33% 감소시켰다.As can be seen in Table 3, administration of 0.1% naringin reduced ACAT activity in rat liver 21%. In addition, administration of 0.1% naringenin reduced ACAT activity by 33%.
실시예 4: 나린진의 경구독성실험Example 4 Oral Toxicity of Naringin
7-8 주령의 특정 병원체 부재(specific pathogens free) ICR 마우스로서 체중 25-29 g의 암컷 6마리와 체중 34-38 g의 숫컷 6 마리를 온도 22±1 ℃, 습도 55±5 %, 조명 12L/12D의 동물실내에서 사육하였다. 마우스는 실험에 사용되기 전 1 주일 정도 순화시켰다. 실험동물용 사료(주식회사제일제당, 마우스 및 랫드용) 및 음수는 멸균한 후 공급하였으며 자유섭취시켰다.Specific pathogens free of 7-8 weeks of age, 6 females weighing 25-29 g and 6 males weighing 34-38 g, temperature 22 ± 1 ° C, humidity 55 ± 5%, illumination 12L / 12D was bred in the animal room. Mice were allowed to acclimate for about a week before being used for the experiment. Feed for experimental animals (for Cheil Jedang Co., Ltd., mice and rats) and drinking water were supplied after sterilization and free ingestion.
나린진을 0.5% 트윈 80을 용매로 하여 100 mg/ml 농도로 조제한 후, 마우스 체중 20 g 당 0.2 ml씩 경구투여하였다. 시료는 1회 경구투여하였으며 투여 후 10 일 동안 다음과 같이 부작용 또는 치사 여부를 관찰하였다. 즉, 투여당일은 투여 후 1시간, 4시간, 8시간, 12시간 뒤에, 그리고 투여 익일부터 10일째까지는 매일 오전, 오후 1회 이상씩 일반증상의 변화 및 사망동물의 유무를 관찰하였다. 또한, 투여 10일째에 동물을 치사시켜 해부한 후 육안으로 내부 장기를 검사하였다. 투여당일부터 1일 간격으로 체중의 변화를 측정하여 나린진에 의한 동물의 체중 감소 현상을 관찰하였다.Naringin was prepared at a concentration of 100 mg / ml using 0.5% Tween 80 as a solvent, followed by oral administration of 0.2 ml per 20 g of mouse body weight. Samples were administered orally once and observed for side effects or lethality for 10 days after administration. That is, on the day of dosing, changes in general symptoms and the presence or absence of dead animals were observed at least once in the morning, at least 1 pm, 4 hours, 8 hours, 12 hours, and the next day until the 10th day of administration. In addition, the animals were killed and dissected at 10 days of administration, and the internal organs were visually examined. Changes in body weight were measured at daily intervals from the day of administration to observe the weight loss of animals caused by naringin.
본 실험은 나린진에 대하여 경구경로에서의 급성독성의 정도를 파악함으로써 일반약리 및 약효시험에서의 가용 약용량에 대한 정보를 제공하고 독성에 대한 기초 자료를 도출함을 목적으로 실시하여 아래와 같은 결과를 얻었다.The purpose of this experiment was to provide information on available drug doses in general pharmacology and drug efficacy tests and to derive basic data on toxicity by identifying the degree of acute toxicity in oral routes of naringin. Got it.
급성 경구독성의 경우는 나린진 1,000 mg/kg의 약용량에서 10일동안 치사동물이 관찰되지 않았다. 10일 후 생존동물에 대한 부검을 실시한 바, 특별한 병변 육안 소견이 없었으며, 투여 익일부터 10일간 어떠한 체중의 감소 없이 정상적인 체중의 증가가 관찰되었다.In acute oral toxicity, no lethal animals were observed for 10 days at the dose of 1,000 mg / kg naringin. An autopsy of the surviving animals was performed 10 days later, and there were no gross lesions, and normal body weight gain was observed without any weight loss for 10 days from the day after the administration.
결론적으로, 나린진은 상기의 농도로 경구투여시 독성이 관찰되지 않았다.In conclusion, naringin was not toxic upon oral administration at the above concentrations.
하기 제제예는 본 발명의 제제를 예시하는 것일 뿐 발명의 범위를 한정하는 것은 아니다.The following formulation examples are merely illustrative of the formulation of the present invention and do not limit the scope of the invention.
제 제 예My example
다음의 성분들을 이용하여 경질 젤라틴 캅셀을 제조하였다:Hard gelatin capsules were prepared using the following ingredients:
양(mg/캅셀)Amount (mg / capsule)
활성 성분(나린진) 20Active Ingredients (Naringin) 20
건조 전분 160Dry starch 160
스테아르산 마그네슘 20Magnesium Stearate 20
총 200 mg200 mg total
나린진 또는 나린제닌을 포함하는 ACAT 활성 저해제 조성물은 동물체내의 ACAT 활성을 저해하여 혈중 저밀도 지단백질(LDL) 콜레스테롤을 감소시키므로 각종 심혈관계 질환의 예방 및 치료제로서 유용하게 사용될 수 있다.ACAT activity inhibitor composition comprising naringin or naringenin can be usefully used as a prophylactic and therapeutic agent for various cardiovascular diseases since it inhibits ACAT activity in the animal to reduce blood low density lipoprotein (LDL) cholesterol.
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