생약학회지 Kor. J. Pharmacogn. 44(4) : 372 378 (2013) 한국약용식물의최종당화산물생성저해활성검색 (XI) 최소진 1 김영숙 1 송유진 1 김주환 2 김진숙 1 * 1 한국한의학연구원한약연구본부한의신약개발그룹, 2 가천대학교생명과학과 Screening of Korean Herbal Medicines with Inhibitory Activity on Advanced Glycation End Products Formation (XI) So Jin Choi 1, Young Sook Kim 1, Yoo Jin Song 1, Joo Hwan Kim 2, and Jin Sook Kim 1 * 1 Korean Medicine-Based Herbal Drug Development Group, Herbal Medicine Research Division, Korea Institute of Oriental Medicine, Daejeon 30-811, Korea 2 Department of Life Science, Gachon University, Seongnam 461-701, Korea Abstract In this study, the inhibitory effect on advanced glycation end products (AGEs) formation of 43 Korean herbal medicines has been evaluated. Among them, 16 Korean herbal medicines were showed to have significant effect (IC ; < µg/ml) compared to positive reference, aminoguandine (IC : 76.47±4.81 µg/ml). Especially, five herbal medicines, Rubus coreanus (leaves, IC : 4.49±0.03 µg/ml), Rubus coreanus (twigs, IC : 3.80±0.34 µg/ml), Ampleopsis brevipedunculata (stems, IC : 7.43±0.09 µg/ml), Lindera erythrocarpa (leave, IC : 8.14±0.20 µg/ml), and Lindera erythrocarpa (stems, IC : 3.69±0.14 µg/ ml) showed more potent inhibitory activity (approximately 9-20 fold) than the positive control aminoguanidine. Key words Advanced glycation end products (AGEs), Diabetic complications, Korean herbal medicines 당뇨합병증의원인으로는최종당화산물 (advanced glycation end products, AGEs) 의생성, polyol pathway flux 의증가및 protein kinase C 활성화등이주요발병기전으로알려져있다. 1-3) 그중최종당화산물은비가역적산물로생성된최종당화산물은혈당이정상으로회복되어도분해가되지않고혈액단백질이나여러조직에축적되어당뇨합병증을가속화한다. 4-7) 따라서생체내에서최종당화산물의생성을저해하거나이미생성된최종당화산물의단백질과의교차결합을억제또는절단하여당뇨합병증을예방하거나치료하기위해많은연구들이진행되고있다. 8-11) 기존연구에서한국, 중국, 베트남산천연물의에탄올추출물에서최종당화산물생성저해효능이있는후보군을발굴하였으며, 12-19) 1 형과 2 형당뇨동물모델에서최종당화산물저해에따른합병증특히망막증과 20) 신증이 21,22) 억제됨을확인하였다. 본연구에서는기존에보고된바없는한국에서자생하는약용식물 43 종의에탄올추출물에서최종당화산물생성저해활성을 in vitro 에서검색하였다. * 교신저자 (E-mail) : jskim@kiom.re.kr (Tel): +82-42-868-946 재료및방법 실험재료 약용식물은 2009 월 4 월부터 월그리고 20 년 1 월부터 2011 년 7 월까지전국에서채취되어, 가천대학교생명과학과김주환교수의감정을거친후실험재료로사용되었다 (Table I). 사용한실험재료의증거표본은한국한의학연구원한약연구본부한의신약개발그룹당뇨합병증연구팀표본실에보관중이다. 추출및시료조제 분쇄한시료 200 g 에 2L 의에탄올을넣고실온상태에서 3 일간 3 회추출하였다. 이를여과하여 40 o C 의수욕상에서감압농축을실시한후, 동결건조기에서건조하였다. 추출물은실험수행전에감압하에서 P 2 O 2 를이용하여 24 시간이상재건조한후 DMSO(Sigma, St. Louis, MO, USA) 에용해시켜 stock solution 을조제하였으며최종 DMSO 의농도가 0.2% 가되도록 1% TWEEN 80(Sigma, St. Louis, MO, USA) 용액으로희석하여사용하였다. 추출에이용한에탄올및그외시약은 1 급및특급시약을사용하였다. In vitro 에서최종당화산물생성저해실험 Vinson 과 Howard 23) 의방법을변형하여실험을실시하였다. 본실험 372
Vol. 44, No. 4, 2013 373 Table I. List of the ethanol extracts of the herbal medicines Family name Scientific name Part used Agrimonia pilosa ( 짚신나물 ) Whole plants Vitaceae ( 포도과 ) Ampelopsis brevipedunculata ( 개머루 ) Stems Broussonetia kazinoki ( 닥나무 ) Leaves Broussonetia kazinoki ( 닥나무 ) Twigs Caragana sinica ( 골담초 ) Roots Papaveraceae ( 양귀비과 ) Chelidonium majus ( 애기똥풀 ) Whole plants Sterculiaceae ( 벽오동과 ) Corchoropsis tomentosa ( 수까치깨 ) Whole plants Cornaceae ( 층층나무과 ) Cornus officinalis ( 산수유 ) Fruits Fumariaceae ( 현호색과 ) Corydalis speciosa. ( 산괴불주머니 ) Whole plants Cudrania tricuspidata ( 꾸지뽕나무 ) Twigs, stems Cudrania tricuspidata ( 꾸지뽕나무 ) Leaves Saxifragaceae ( 범의귀과 ) Deutzia glabrata Kom. ( 물참대 ) Twigs, leaves, flowers Araliaceae ( 두릅나무과 ) Eleutherococcus senticosus ( 가시오갈피 ) Stems Araliaceae ( 두릅나무과 ) Eleutherococcus sessiliflorus ( 오갈피나무 ) Stems Theaceae ( 차나무과 ) Eurya japonica ( 사스레피나무 ) Leaves Balsaminaceae ( 봉선화과 ) Impatiens textori ( 물봉선 ) Aerial parts Indigofera kirilowii ( 땅비싸리 ) Twigs, leaves, flower Indigofera pseudotinctoria ( 낭아초 ) Whole plants Lythraceae ( 부처꽃과 ) Lagerstroemia indica ( 배롱나무 ) Leaves Lauraceae ( 녹나무과 ) Lindera erythrocarpa ( 비목나무 ) Leaves Lauraceae ( 녹나무과 ) Lindera erythrocarpa ( 비목나무 ) Twigs Magnoliaceae ( 목련과 ) Magnolia denudate ( 백목련 ) Flower buds Morus bombycis ( 산뽕나무 ) Stems (twigs) Morus bombycis ( 산뽕나무 ) Leaves Rutaceae ( 운향과 ) Orixa japonica ( 상산 ) Leaves Rutaceae ( 운향과 ) Orixa japonica ( 상산 ) Fruits Valerianaceae ( 마타리과 ) Patrinia scabiosaefolia ( 마타리 ) Aerial parts Valerianaceae ( 마타리과 ) Patrinia villosa ( 뚝갈 ) Aerial parts Phytolaccaceae ( 자리공과 ) Phytolacca Americana ( 미국자리공 ) Aerial parts Simaroubaceae ( 소태나무과 ) Picrasma quassioides ( 소태나무 ) Twigs, leaves Juglandaceae ( 가래나무과 ) Platycarya strobilacea ( 굴피나무 ) Leaves Prunus mume ( 매실나무 ) Leaves Prunus mume ( 매실나무 ) Twigs (1 year) Prunus mume ( 매실나무 ) Twigs Anacardiaceae ( 옻나무과 ) Rhus tricocarpa ( 개옻나무 ) Flowers Anacardiaceae ( 옻나무과 ) Rhus tricocarpa ( 개옻나무 ) Twigs Rubus coreanus ( 복분자딸기 ) Leaves Rubus coreanus ( 복분자딸기 ) Twigs Rubus crataegifolius ( 산딸기 ) Leaves Polygonaceae ( 마디풀과 ) Rumex crispus ( 소리쟁이 ) Roots Cruciferae ( 십자화과 ) Thlaspi arvense ( 말냉이 ) Whole plants Vicia villosa ( 벳지 ) Whole plants Wisteria floribunda ( 등 ) Stems
374 Kor. J. Pharmacogn. 에서는 mg/ml 의우혈청알부민 (bovine serum albumin, Sigma) 을 0.2 M phosphate buffer(ph 7.4) 에용해시키고, 0.2 M 의 fructose 와 glucose 를처리하였다. 이때 0.2 M phosphate buffer 에 0.02% sodium azide 를넣어반응기간동안박테리아의생성을방지하였다. 이반응액에추출물또는최종당화산물생성저해제인 aminoguanidine 을넣은후 37 o C 에서 7 일동안반응시켰다. 배양후에는 spectrofluorometric detector(bio-tek, Synergy HT, USA) 를이용하여형광도를측정하였다 (Ex: 3, Em: 4 nm). IC 값은 n=3 으로하여계산되었다. 결과및고찰 최근청년당뇨환자의증가와함께평균수명이연장됨에따라당뇨환자의합병증문제가심각하게대두되고있다. 만성당뇨로인한망막증, 실명, 신경병증, 족부궤양, 신 증및신장이식등국가재정뿐만아니라환자및가족의삶의질을매우부정적인영향을끼치고있다. 그러나아직당뇨완치제도개발이안되었으며합병증약개발또한요원한상태이다. 24,) 따라서최근에는천연물을이용하여당뇨합병증의요인중의하나인최종당화산물의생성을억제하는약물의검색을위해많은연구들이진행되고있다. 한국산생약을대표적인최종당화산물의억제제인 aminoguanidine 26,27) 은독성문제가제기되어임상 3 상에서중단되었다. 본연구팀은최종당화산물생성을강력하게억제하는천연물소재를발굴하기위하여많은천연소재들의효능을검색발표하였다. 12-19) 본연구에서도국내에서자생하는약용식물 43 종의에탄올추출물을이용하여최종당화산물생성저해효능을측정하였다. 양성대조약물인 aminoguanidine 의 IC 값 (76.47±4.81 µg/ml) 을근거로하여, 추출물이 IC < µg/ml 이면효능이있다고판단하였다. Table II 에서보여주는것 Table II. Inhibitory activity of the ethanol extracts of the herbal medicines on AGEs formation in vitro Family name Scientific name Part used Conc. (µg/ml) Inhibition (%) IC (µg/ml) Vitaceae ( 포도과 ) Papaveraceae ( 양귀비과 ) Sterculiaceae ( 벽오동과 ) Cornaceae ( 층층나무과 ) Fumariaceae ( 현호색과 ) Saxifragaceae ( 범의귀과 ) Agrimonia pilosa ( 짚신나물 ) Ampelopsis brevipedunculata ( 개머루 ) Broussonetia kazinoki ( 닥나무 ) Broussonetia kazinoki ( 닥나무 ) Caragana sinica ( 골담초 ) Chelidonium majus ( 애기똥풀 ) Corchoropsis tomentosa ( 수까치깨 ) Cornus officinalis ( 산수유 ) Corydalis speciosa. ( 산괴불주머니 ) Cudrania tricuspidata ( 꾸지뽕나무 ) Cudrania tricuspidata ( 꾸지뽕나무 ) Deutzia glabrata Kom. ( 물참대 ) Whole plants Stems 2..3±0.30 40.03±0.61 60.29±0.62 9.22±0.83 30.63±0.44 70.93±0.96 18.22±0.27 7.43±0.09 Leaves 7 41.98±0.78 >7 Twigs 7 44.30±1.4 >7 Roots 7 16.16±2.1 >7 Whole plants -3.9±2.64 2.03±4.11 3.28±3.79 > Whole plants 7 33.27±3.9 >7 Fruits 7 1.83±1.13 >7 Whole plants Twigs, stems Leaves Twigs, leaves, flowers 12.21±3. 14.43±4.97 28.43±1. 1.17±1.19 34.66±0.4 60.86±1.72 18.04±1.24 32.±3.37 49.±0.47 20.39±1.9 37.3±2.1 8.98±1.89 > 39.92 > 39.92
Vol. 44, No. 4, 2013 37 Table II. Continued Family name Scientific name Part used Conc. (µg/ml) Inhibition (%) IC (µg/ml) Araliaceae ( 두릅나무과 ) Araliaceae ( 두릅나무과 ) Theaceae ( 차나무과 ) Balsaminaceae ( 봉선화과 ) Lythraceae ( 부처꽃과 ) Lauraceae ( 녹나무과 ) Lauraceae ( 녹나무과 ) Magnoliaceae ( 목련과 ) Rutaceae ( 운향과 ) Rutaceae ( 운향과 ) Valerianaceae ( 마타리과 ) Valerianaceae ( 마타리과 ) Phytolaccaceae ( 자리공과 ) Simaroubaceae ( 소태나무과 ) Juglandaceae ( 가래나무과 ) Eleutherococcus senticosus ( 가시오갈피 ) Eleutherococcus sessiliflorus ( 오갈피나무 ) Eurya japonica ( 사스레피나무 ) Impatiens textori ( 물봉선 ) Indigofera kirilowii ( 땅비싸리 ) Indigofera pseudotinctoria ( 낭아초 ) Lagerstroemia indica ( 배롱나무 ) Lindera erythrocarpa ( 비목나무 ) Lindera erythrocarpa ( 비목나무 ) Magnolia denudate ( 백목련 ) Morus bombycis ( 산뽕나무 ) Morus bombycis ( 산뽕나무 ) Orixa japonica ( 상산 ) Orixa japonica ( 상산 ) Patrinia scabiosaefolia ( 마타리 ) Patrinia villosa ( 뚝갈 ) Phytolacca Americana ( 미국자리공 ) Picrasma quassioides ( 소태나무 ) Platycarya strobilacea ( 굴피나무 ) Prunus mume ( 매실나무 ) Stems 7 46.1±0.22 >7 Stems 7 3.31±2.89 >7 Leaves 34.16±2.21 4.80±1.08 3.17±0. 40.69±0.69 Aerial parts 7 29.06±1.88 >7 Twigs, leaves, flowers 17.94±1.8 30.71±2.01 67.24±0.71 17.9 Whole plants 7 43.06±2.70 >7 Leaves Leaves 2. Twigs 1 2. 18.2±0.43 41.69±0.08 67.±1.29 18.26±0.62 3.24±1.21 9.32±0.21 27.97±1.43 42.09±1. 9.7±1.21 16.4±0.37 8.14±0.20 3.69±0.14 Flower buds 7 31.20±0.6 36.94±2.06 Stems (twigs) 17.24±0.8 41.78±0.23 64.89±0.1 17.31±0.04 Leaves 7 43.09±1.90 >7 Leaves Fruits 8.20±1.44.74±1.98 43.37±0.84 4.62±4.03 22.21±3.79 46.±2.3 > > Aerial parts 7 23.39±1.07 >7 Aerial parts 7 20.4±1.27 >7 Aerial parts 7 21.±2.8 >7 Twigs, leaves 7 20.38±4.63 >7 Leaves 7 37.±1.07 >7 Leaves 7 26.8±2.94 >7
376 Kor. J. Pharmacogn. Table II. Continued Family name Scientific name Part used Conc. (µg/ml) Inhibition (%) IC (µg/ml) Anacardiaceae ( 옻나무과 ) Anacardiaceae ( 옻나무과 ) Polygonaceae ( 마디풀과 ) Cruciferae ( 십자화과 ) Prunus mume ( 매실나무 ) Prunus mume ( 매실나무 ) Rhus tricocarpa ( 개옻나무 ) Rhus tricocarpa ( 개옻나무 ) Rubus coreanus ( 복분자딸기 ) Rubus coreanus ( 복분자딸기 ) Rubus crataegifolius ( 산딸기 ) Rumex crispus ( 소리쟁이 ) Thlaspi arvense L. ( 말냉이 ) Vicia villosa Roth ( 벳지 ) Twigs (1 year) Twigs 28.49±0.6 48.96±0.96 62.22±0.48 16.39±0.4 4.76±0.88 6.77±0.20 32.7±0.37 16.67±0.19 Flowers 7 46.62±0.74 >7 Twigs 7 39.42±1.39 >7 Leaves 1 2. Twigs 1 2..1±1.96 23.91±0.61 6.98±0.37 32.28±1.86 47.16±4..13±2.04 4.49±0.03 3.80±0.34 Leaves 7 41.37±1.12 >7 Roots Whole plants Whole plants 20.22±0.31 44.97±2.20 83.23±1.03 3.41±0.61 8.77±2.39 19.±0.74-2.4±1.43 4.67±1.07 14.7±0.36 Wisteria floribunda Stems 7 24.89±3.13 >7 ( 등 ) Aminoguanidine 76.47±4.81 IC values were calculated from the dose inhibition curve. 28.67 > > 과같이 16 종의식물추출물에서 IC < µg/ml 로최종당화산물생성저해효능을보였고, 그중에서 종의추출물 Rubus coreanus 의잎 (4.49±0.03 µg/ml) 과가지 (3.80±0.34 µg/ ml), Ampleopsis brevipedunculata 의줄기 (7.43±0.09 µg/ml), Lindera erythrocarpa 의잎 (8.14±0.20 µg/ml) 과줄기 (3.69± 0.14 µg/ml) 은 IC 가 µg/ml 이하로 aminoguanidine 보다약 9-20 배이상의우수한효능이있음을알수있었다. 장미과의 R. coreanus( 복분자딸기 ) 의열매는 tumor necrosis factor-a(tnf-a), interleukin 6(IL-6) 분비를억제하고, nitric oxide(no) 의생산감소와 inducible nitric oxide synthases (inos), cyclooxygenase-2(cox-2) 와같은염증유발단백질의발현을억제하여항알레르기, 항염작용을한다고보고되었고, 28,29) 열매, 잎, 뿌리의추출물의항산화, 미백, 주름개선효과가보고되었다. 30) R. coreanus 의물추출물, 에탄올추출물은돌연변이억제효과가뛰어나고, Hep3B 와 Hela cell 의성장을억제한다고보고되었다. 31) R. coreanus 의줄기와잎에서분리한 tannins 가항산화작용을한다고보고되었다. 32) 포도과에속하는 A. brevipedunculata( 개머루 ) 는메탄올추출물이환원력이강하고, 리놀산과산화와플라스미드 DNA 산화를억제시키고, 33) 2,2-diphenyl-1-picrylhydrazyl (DPPH) 라디칼에대한산화능이강해항산화효과가있으며, 암세포에대한증식억제효과를나타낸다고보고되었다. 34) 마우스에서사염화탄소에의해유도된간독성을억제시켜간기능을회복시켜주는효과가있다고보고되었다. 3) 또한병원성미생물에대해항균작용을한다고보고되었다. 36) 녹나무과인 L. erythrocarpa( 비목나무 ) 가사람면역결핍바이러스타입 1(HIV-1) 단백질분해효소에대해억제효과를가지는것으로보고되었다. 37) 또한 lipopolysaccharide(lps) 로유도된대식세포에서 NO, inos 와 COX-2 을억제하여항염작용을한다고보고되었다. 38) 일본에서는위장약과신경
Vol. 44, No. 4, 2013 377 통의진통제로사용되고있으며, 39) L. erythrocarpa의잎은항균활성을한다고보고되었다. 40) 또한산화스트레스가유도된 H9c2의 apoptosis를억제하여항산화작용을한다고보고되었다. 41) 위언급된 종의약용식물은최종당화산물생성억제효능이보고된바없으며, 양성대조약물보다 9-20배이상최종당화산물생성억제효능이우수한것으로확인되었으므로, 전임상실험을통해 in vivo효능확인이필요하다고생각된다. 본연구결과는국내약용식물로부터안전하고효능이좋은최종당화산물생성저해제후보를발굴하기위한기초자료로활용될수있으며, 당뇨에의해나타나는합병증치료제개발의기반을구축하는데기여할수있을것이다. 결 기원이확인된국내산약용식물 43 종의에탄올추출물이 in vitro 에서최종당화산물생성저해효능이검색되었다. 그결과 16 종이양성대조군인 aminoguanidine 보다우수한효능이있음을확인하였고, 특히복분자딸기의잎 (IC : 4.49±0.03 µg/ml) 과가 (IC : 3.80±0.34 µg/ml), 개머루줄기 (IC : 7.43±0.09 µg/ml), 비목나무잎 (IC : 8.14±0.20 µg/ml) 과줄기 (IC : 3.69±0.14 µg/ml) 등 종의추출물은양성대조군 (aminoguanidine: IC : 76.47±4.81 µg/ml) 보다 9-20 배억제효능이우수하므로당뇨합병증예방및치료제로개발될가능성이있다. 사 본연구는한국한의학연구원기관고유사업 (K12040, K13040) 의지원으로수행되었으며이에감사드립니다. 론 사 인용문헌 1. Sakurai, T. and Tsuchiya, S. (1988) Superoxide production from nonenzymatically glycated protein. FEBS Lett. 236: 406-4. 2. Shinohara, R., Mano, T., Nagasaka, A., Sawai, Y., Uchimura, K., Hayashi, R., Hayakawa, N., Nagata, M., Makino, M., Kakizawa, H., Itoh, Y., Nakai, A. and Itoh, M. (1998) Effects of thyroid hormone on the sorbitol pathway in streptozotocininduced diabetic rats. Biochim. Biophys. Acta 14: 77-86. 3. Bucala, R., Cerami, A. and Vlassara, H. (199) Advanced glycosylation end products in diabetic complications. Diabetes Rev. 3: 8-268. 4. Larkins, R. G. and Dunlop, M. E. (1992) The link between hyperglycaemia and diabetic nephropathy. Diabetologia 3: 499-4.. Ahmed, N. (200) Advanced glycation endproducts-role in pathology of diabetic complications. Diabetes Res. Clin. Pract. 67: 3-21. 6. Yokozaw, T., Nakagawa, T. and Terasawa, K. (2001) Effects of oriental medicines on the production of advanced glycation endproducts. J. Trad. Med. 18: 7-112. 7. Huebschmann, A. G., Vlassara, H., Regensteiner, J. G. and Reusch, J. (2006) Diabetes and advanced glycoxidation end products. Diabetes Care 29: 1420-1432. 8. Rahbar, S. and Figarola, J. L. (2003) Novel inhibitors of advenced glycation endproducts. Arch. Biochem. Biophys. 419: 63-79. 9. Wilkinson-Berka, J. L., Kelly, D. J., Koerner, S. M., Jaworski, K., Davis B., Thallas, V. and Cooper, M. E. (2002) ALT-946 and aminoguanidine, inhibitors of advanced glycation, improve severe nephropathy in the diabetic transgenic (mren-2) 27 rat. Diabetes 1: 3283-3289.. Peppa, M., Brem, H., Cai, W., Zhang, J. G., Basgen, J., Li, Z., Vlassara, H. and Uribarri, J. (2006) Prevention and reversal of diabetic nephropathy in db/db mice treated with alagebrium (ALT-711). Am. J. Nephrol. 26: 430-436. 11. Yang, S., Litchfield, J. E. and Baynes, J. W. (2003) AGE breakers cleave model compounds, but do not break maillard crosslinks in skin and tail collagen from diabetic rats. Arch. Biochem. Biophys. 412: 42-46. 12. Jang, D. S., Lee, Y. M., Kim, Y. S. and Kim, J. S. (2006) Screening of Korean traditional herbal medicines with inhibitory activity on advanced glycation end products (AGEs) formation. Kor. J. Pharmacogn. 37: 48-2. 13. Lee, Y. M., Kim, Y. S., Kim, J. M., Jang, D. S., Kim, J. W., Yoo, J. L. and Kim, J. S. (2008) Screening of Korean herbal medicines with inhibitory activity on advanced glycation end products (AGEs) formation (II). Kor. J. Pharmacogn. 39: 223-227. 14. Jeong, I. H., Kim, J. M., Jang, D. S., Kim, J. H., Cho, J. H. and Kim, J. S. (2009) Screening of Korean herbal medicines with inhibitory activity on advanced glycation end products (AGEs) formation (III). Kor. J. Pharmacogn. 40: 382-387. 1. Kim, J. M., Kim, Y. S., Kim, J. H., Yoo, J. M. amd Kim, J. S. (2009) Screening of herbal medicines from China and Vietnam with inhibitory activity on advanced glycation end products (AGEs) formation (IV). Kor. J. Pharmacogn. 40: 388-393. 16. Kim, Y. S., Choi, S. H. Kim, J. H. and Kim, J. S. (2011) Screening of herbal medicines from China with inhibitory activity on advanced glycation end products (AGEs) formation (V). Kor. J. Pharmacogn. 42: 46-3. 17.Lee, Y. M., Kim, Y. S., Kim, J. H. and Kim, J. S. (2011) Screening of herbal medicines from China with inhibitory activity on advanced glycation end products (AGEs) formation (VI). Kor. J. Pharmacogn. 42: 161-168. 18. Choi, S. J., Kim, Y. S., Song, Y. J., Lee, Y. M., Kim, J. H. and
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