박지훈등 항산화물질의임상적용 HMR 소는그자체의역할과더불어 c-jun N-terminal kinase (JNK), p38, extracellular signal related kinase (ERK) 등의미토겐활성화단백 질키나아제 (mitogen-associated ki

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1 항산화물질의임상적용 박지훈 권기량 pissn X eissn 충남대학교의학전문대학원생화학교실 Clinical Applications of Antioxidants Ji-Hoon Park, Gi Ryang Kweon Department of Biochemistry, School of Medicine, Chungnam National University, Daejeon, Korea Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are natural by-products of cellular physiological processes involving metabolism of compounds containing oxygen and nitrogen, respectively. Physiological defense mechanisms against ROS/RNS readily convert them into water or urea, but dysregulation of ROS/RNS production damages cells resulting in abnormal conditions such as uncontrolled growth or cell death. ROS/RNS are closely related to the development of a variety of diseases such as cancer, diabetes, neurodegeneration, vascular disease and chronic inflammation. Thus, it has been proposed that the removal of ROS/RNS may prevent or treat oxidative stress-induced diseases. Some antioxidant molecules are synthesized in the body, while others are obtained from food in the diet including fruits, vegetables, meat and even in natural water. In addition to the natural antioxidants, synthetic antioxidants have been modified from natural chemicals so as to increase bioavailability to target organs and increase stability in the air. In developing novel antioxidants for therapeutic use, some factors to consider are: 1) improved efficacy; 2) low side effects (comparatively clear mechanism); 3) competitive price and 4) improved convenience of dosing. In this review, we will discuss the issues mentioned above and the use of antioxidants in clinical application. Correspondence to: Gi Ryang Kweon 우 , 대전광역시중구문화로 226, 충남대학교의과대학생화학교실 Department of Biochemistry, School of Medicine, Chungnam National University, 226 Munhwa-ro, Jung-gu, Daejeon , Korea Tel: Fax: mitochondria@cnu.ac.kr Received 11 March 2013 Revised 26 April 2013 Accepted 30 April 2013 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Key Words: Reactive Oxygen Species; Reactive Nitrogen Species; Antioxidants; Clinical Trial 서론활성산소 (reactive oxygen species, ROS) 는산소의산화물로서매우큰반응성으로인하여세포내단백질, 지질뿐만아니라핵산과결합하여구조의변화를유발한다. 세포대사에사용되는전체산소의 90-95% 는미토콘드리아에서 ATP를만들어내는과정에서소모되며, 이중 1-2% 는활성산소로전환된다 [1]. 일반적으로가장처음만들어지는활성산소의형태는초과산화물 (superoxide, O 2- ) 이며, 이는미토콘드리아의전자전달계중산화적인산화과정의복합체 I, III에서대부분생성된다. 또한초과산화물은세포질또는지질막에존재하는 NADPH 산화효소, 크산틴산화효소 (xanthine oxidase) 에의해서도생성된다. 이들은미토콘드리아와세포질에각각존재하는망간-초과산화물불균등화효소 (manganese superoxide dismutase, Mn-SOD) 와구리 / 아연초과산화물불균등화효소 (copper/zinc superoxide dismutase, Cu/Zn-SOD) 에의해과산화수소 (hydrogen peroxide, H 2O 2) 로전환되어세포바깥으로배출되기도한다. 최종적으로과산화수소는과산화수소분해효소 (catalase) 와과산화효소 (peroxidase) 에의해물과산소분자로분해되는데, 처리되지못한과산화수소의일부는전이금속인환원된상태의철을이용하는펜톤반응 (Fenton s reaction) 에의해활성산소중가장반응성이강한히드록실라디칼 (hydroxyl radical, OH - ) 로전환되어세포내소기관의손상을초래한다 (Fig. 1)[2]. 활성산 Hanyang University College of Medicine

2 박지훈등 항산화물질의임상적용 HMR 소는그자체의역할과더불어 c-jun N-terminal kinase (JNK), p38, extracellular signal related kinase (ERK) 등의미토겐활성화단백 질키나아제 (mitogen-associated kinase, MAPK) 뿐만아니라 nuclear factor-κb (NF-κB) 활성화도촉진한다. 이들은산화환원상태 에따라반응하는단백질인 apoptosis signal-regulating kinase 1 (ASK1) 에의해인산화되어질병의유발원인이되기도한다 [3,4]. 활성산소의생성과제거는매우유기적으로조절되지만세포내 에서수용할수있는역치한계를넘어서게되면변형된형태의단 백질의축적, 지질형태변형및핵산변형등을통해세포의사멸이 나세포의이상증식으로인해종양으로발전될수있다. 활성산소 의과잉생성은대부분의질병또는질환과관련되어있다고알려져 있으며, 그중특히허혈 / 재관류에의한조직손상, 대사증후군, 파 킨슨병, 알츠하이머병과같은퇴행성신경질환, 암, 심혈관질환, 노 화등과같은질병과의관련성에대한보고가계속되고있다 [5,6]. 인류가발전해온이래자연에서병을치료하기위한약재를찾는 노력은계속되어왔으며식물의잎, 과일, 동식물의추출물등다양 한재료에서부터화합물들을찾아내고그효능을밝혀왔다. 수많 은연구들을통해질병의진행에있어활성산소의중요성과항산화 Lipophilic antioxidants Hydrophilic antioxidants H2O Glutathione peroxidase Oxidases Fig. 1. Production of ROS/RNS and antioxidant system. NO, nitric oxide; SOD, superoxide dismutase. O2 - SOD H2O2 Fenton s reaction OH - Mitochondria DNA, protein, lipid Unregulated growth, cell death NO Catalase OONO - H2O 제의효능을입증해왔으며비타민 (vitamin), 카테킨 (cathechin), 플라보노이드 (flavonoid), 카로틴 (carotene), 커큐민 (curcumin) 등의항산화물질은건강보조식품으로뿐만아니라다양한질병을치료하기위한약제로시도되고있다 [7]. 이에천연항산화제에이어새로이합성된항산화물질이어떻게개발되고임상에적용되고있는지에대해고찰하고자한다. 본론 1. 천연항산화제의종류와임상에의적용현황 1) 비타민 (vitamin) 아스코르빈산 (ascorbic acid, vitamin C), 알파-토코페롤 (α-tocopherol, vitamin E), 엽산 (folic acid, vitamin B 9) 을비롯한비타민은수십여종이알려져있으며일부는인체내에서합성이가능하지만일부는음식물을통해섭취해야만한다. 이들대부분은우리가주로섭취하는쌀, 육류, 계란, 야채등에많이포함되어있으며, 이들중특정비타민의결핍과관련된증세들이잘알려져있을뿐만아니라과잉섭취시발생하는부작용에대한연구도많이되어있다. 아스코르빈산은수용성으로세포내항산화물질인글루타티온 (glutathione) 에의해환원형태로존재하며과산화수소와같은활성산소를제거하는역할을한다 [8]. 또한 2-산소화효소 (dioxygenase) 외몇몇효소는기질을환원시키기위하여아스코르빈산을보조기질로필요로한다 [9]. 지용성비타민인토코페롤은활성산소에의한세포막의산화를억제하며아스코르빈산과같은다른항산화물질에의해다시환원되어재사용된다 [10]. 이러한천연물유래비타민들은오랫동안음식물을통해섭취되어왔기에비교적안전하고쉽게임상실험에적용되어왔으며일부에서그효과를검증받고있다 (Table 1)[7]. 2) 카테킨 (catechin) 카테킨은페놀고리구조를가진천연물질로서 (-)-epigallocatechin-3-gallate (EGCG), (-)-epicatechin-3-gallate (ECG), (-)-epigallocatechin (EGC) 그리고 (-)-epicatechin (EC) 등이알려져있으며녹차잎의주성분인 EGCG는녹차한잔에 mg이포함되어있다. 녹차는 5,000년이상인류와함께해왔으며특유의페놀고리와고유의작용기로인한항산화효과로여러가지이로운효과들이있는것으로알려져있다. 카테킨은항암작용 ( 암세포의사멸 Table 1. Antioxidants and the Clinical Applications to the Diseases Vitamins Diseases Ascorbic acid (Vitamin C) α-tocopherol (Vitamin E) Folic acid (Vitamin B9) Coronary heart disease, hypertension, type 2 diabetes, sepsis, myeloma, neurodegenerative diseases Coronary heart disease, atherosclerosis, Parkinson s disease, Alzheimer s disease, type 2 diabetes Stroke, cardiovascular diseases, depression 131

3 HMR Ji-Hoon Park, et al. Clinical Applications of Antioxidants 과전이억제 ), 혈관세포의보호, 체중감소, 신경세포보호등의기능이알려져있으며이들에대한임상시험이진행중이거나일부에서긍정적인결과를확인하였다 [11]. 3) 커큐민 (curcumin) 커큐민은심황 (turmeric) 이라는식물의성분으로 카레 의주성분이라고잘알려진화합물이다 년에염료로발견되어 1910 년구조가밝혀지고합성이가능하게되었다. 지질친화성이높고활성산소뿐만아니라 1,1-diphenyl-2-picryl-hydrazyl (DPPH), 2,2 -azino-bis (3-ethylbenzthiazoline-6-sulphonic acid) (ABTS) 등과같은라디칼과반응성을가져지질산화를효과적으로억제할수있는것으로밝혀졌다 [12]. 항산화능력에중요한작용기는양쪽의페놀고리구조보다가운데위치한메틸렌기가중요한것으로알려졌으며, 조건에따라산화촉진제로도작용하여암세포의사멸을유도할수있음이밝혀졌다 [13] 년까지 1,500여건의특허와 56 여건의임상시험에대한보고가있으며, 지속적인연구가진행되고있다. 활성산소와활성질소에대한반응성이있는것으로알려져있으며간에서의대사속도가빨라섭취후 1시간이내에체외로배출된다. 현재까지활성산소또는활성질소와관계있는것으로알려진질병들에대한임상시험이진행중이거나일부에서긍정적인결과를확인하였다 [14]. 4) 레스베라트롤 (resveratrol) 레스베라트롤은적포도주의성분중하나로서 French Paradox 라고하는심혈관질환의유병률과적포도주의섭취의역관계성에대한역학조사결과에서처음으로주목받기시작했다 [15]. 레스베라트롤은그자체의항산화능력과질산화물 (nitric oxide, NO) 생성증가를통해혈관을확장시킴으로써심장의재관류손상과부정맥을억제하는것으로확인되었다 [16]. 그외에도 Akt, ERK1/2 등의활성화를통해 NAD(P)H: quinone oxidoreductase (NQO1), heme oxygenase-1 (HO-1) 과같은활성산소의처리에관련된효소들이 anti-oxidant response element (ARE) 를통해발현증가됨이확인되었다 [17]. 레스베라트롤은효모, 꼬마선충, 초파리등의수명을연장시킨다는보고가있었으나, 대부분의진핵생물에서는수명연장과는관계없이 sirtuin 단백질량을증가시켜미토콘드리아의기능을증진시키고당대사흐름을개선시킬수있다고알려졌다 [18,19]. 다양한연구를통해레스베라트롤이수명을연장시킬수있을거란기대는깨졌지만, 여전히건강한삶을위해 sirtuin 단백질량을조절하는것이중요하고레스베라트롤이도움을줄수있다는보고들은계속되고있다. 또한레스베라트롤은여전히암의발병, 심혈관질환, 당뇨병, 뇌질환등에대한치료제로서의가능성을가지고실험들이진행되고있다. 2. 합성항산화제의종류와특징 1) 글루타티온유도체글루타티온은글루탐산, 시스테인, 글리신세개아미노산의중합체로매우환원성이뛰어난설프하이드릴기 (sulfhydryl group) 를통해두개의글루타티온분자가수소분자두개를내어놓으며하나의글루타티온이황화물 (glutathione disulfide, GSSG) 을형성한다. 글루타티온은직접활성산소와결합하기도하지만글루타티온과산화효소 (glutathione peroxidase, GPx) 또는글루타티온 S-전이효소 (glutathione S-transferase, GST) 등을통해기질을환원시키고자신은산화되어 GSSG형태로전환된다. 산화형태의 GSSG는글루타티온환원효소 (glutathione reductase) 에의해 NADPH를사용하여 GSH로환원되어재이용된다. 글루타티온은세포내에 1-10 mm 정도의농도를유지하고있으며혈액내에도 μm 정도가존재하고있다 [20,21]. 세포내에서높은농도를유지하고있으며계속재사용될수있음에도글루타티온은세포막을투과하는능력이매우낮기때문에세포내로글루타티온을효율적으로주입시키려는노력이계속되고있다. 그중에틸에스테르화를통해세포내수송률을높이는방법이이용되거나, 글루타티온합성에필요한물질인시스테인의공급을증가시킴으로세포내에서글루타티온의신생합성을돕는방법등이이용되고있다 [22,23]. N-아세틸시스테인 (N-acetylcysteine, NAC) 의경우, 그자체의타이올기 (thiol group, -SH) 로항산화능력을갖기도하지만글루타티온합성단계의속도결정단계에중요한시스테인공급원으로작용하여세포내의글루타티온의농도를높여준다 [24]. NAC은아세트아미노펜에과다투여에의한급성간독성에대한치료제로임상에서사용되고있으며, 그외바이러스나약물에의해유발되는급성간독성모델에대한적용도시도되고있다 [25]. 2) 마이토퀴논 (mitoquinone) 미토콘드리아전자전달계사슬의전자주개 / 받개인유비퀴논 (ubiquinone, coenzyme Q) 은매우효율적인항산화물질이다. 마이토퀴논은유비퀴논의낮은수용성을극복하고세포내로의원활한유입을위하여지용성작용기인 triphenylphosphonium (TPP) 양이온과결합시킨물질이다 [26]. TPP 양이온은 in vitro뿐만아니라 in vivo에서도미토콘드리아에특이적으로이동하는것으로알려져있다 [27]. 마이토퀴논은 TPP에의한고유의양전하로인해막전위차에의존적으로세포질및미토콘드리아막을투과하여미토콘드리아내막에고농도로존재하게된다. 산화적인산화과정에서 2번째복합체인숙신산염탈수소효소 (succinate dehydrogenase) 에의해항산화능력을갖는퀴놀형태로전환되지만, 유비퀴논처럼 3번째복합체에의해다시산화되지는못한다. 퀴놀형태로전환된마이토퀴논은초과산화물뿐만아니라퍼옥시나이트라이트 (peroxynitrite, OONO - ) 도직접제거하지만과산화수소와의반 132

4 박지훈등 항산화물질의임상적용 HMR 응성은거의없다. 실험동물인 C57BL/6 에마이토퀴논 (500 μm) 을 20-28주동안구강투여했을때운동성, 산소소모량등생리적인변화는없었으며, 조직내에서특히미토콘드리아내에서유의할만한유전자발현량의차이는보이지않았다 [28]. 마우스를이용한실험에서마이토퀴논은허혈 / 재관류심장손상, 니트로글리세린에의한혈관내피세포손상, lipopolysaccharide (LPS) 등으로유발한패혈증, 아드리아마이신 (adriamycin) 에의한심장손상등을억제하였다. 임상 1상시험에서는 80 mg (1 mg/kg) 의마이토퀴논투여 1시간후혈장내농도가 ng/ml로좋은약동학적결과를보여주었고, 파킨슨병과 C형간염에대한임상시험결과에서는 C형간염시험에서만유의한간손상억제효과를보여주었다 [29]. 미토콘드리아는세포내에서활성산소를가장많이생성하는기관으로서다양한질병이미토콘드리아유래활성산소와밀접한연관이있는바, 미토콘드리아를표적으로하는항산화물질은적응증이무궁무진하다할수있다. 이에마이토퀴논은특정소기관으로이동할수있는항산화제로매우큰관심을받았으나퀴논구조의특성상하나의전자를받은상태인세미퀴논형태가되면전자를내어주려는성질로인해산화촉진제로서작용할수있어오히려정상세포의호흡을억제하거나세포사멸을유도할수도있어사용에주의를요하고있다 [30]. 3) 초과산화물불균등화효소 (superoxide dismutase, SOD)/ 과산화수소분해효소 (catalase) 유사제금속포르피린 (metalloporphyrin) 은헴 (heme) 구조와같은보결분자단 (prosthetic group) 으로헤모글로빈, 마이오글로빈, 산화질소합성효소 (nitric oxide synthase), 사이토크롬산화효소 (cytochrome oxidase), 사이토크롬 P450 시스템 (cytochrome P450 system) 그리고사이클로옥시지네이즈 (cyclooxygenase) 등에존재하고있다. 이들은자연계에존재하는형태로다음과같은장점을가진다. (1) 체내에서거부감이적다. 즉, 면역반응을거의유발하지않으며작은분자량으로인해세포내로의투과도가높다. (2) 합성과변형이용이하다. (3) 포르피린구조는매우안정한형태이며전이금속과의결합력이매우좋아구조그대로세포내로유입되어작용할수있다 [31]. 이와비슷한형태로살렌 (salen) 구조가있으며전이금속과반응성이좋은포르피린과유사한특성을가져합성항산화제로다양한종류가개발되고있다. 이들은초과산화물불균등화효소의기능과유사하게세포내에서초과산화물을산소와과산화수소로분해하며몇몇형태의망간-포르피린 / 망간-살렌은과산화수소를물과산소로분해하는과산화수소분해효소의기능과유사하여초과산화물불균등화효소 / 과산화수소분해효소유사제 (SOD/catalase mimics) 로불리운다. 대표적인약물로는 EUK-8, -134, -189, MnTBAP, Tempol 등이있으며, 현재까지임상에서탁월한성과는보이지못하고있지만 다양한동물실험모델에서효과를보이고있다 [31]. 4) 네크록스 (NecroX) 인돌 (indole) 은방향성유기화합물로서벤젠고리 (benzene ring) 와피롤고리 (pyrolle ring) 의결합된구조를가지고있으며자연계에존재하는대표적인인돌구조를가진물질에는트립토판, 멜라토닌등이있다 [32]. 네크록스계열약물은인돌구조를기반으로다양한작용기를적용하여효능및수용성을높이거나체내흡수율과체외배출율을증가시킨합성물질이다. 천연물만큼의안전성은아직확인되지않았으나마우스, 랫등의실험동물에장기투여시에도특별한기관이상을초래하지않았으며, 10 μm 미만농도의 in vitro 실험에서저온노출또는과량의활성산소에의한세포괴사 (necrosis) 를억제하는것으로확인되었다. 네크록스는세포수준에서활성산소종및활성질소종의생성을억제할수있음을 DCF- DA, DHR123 등의형광시약을이용하여확인하였으며, 다른어떤효소의도움없이도특정라디칼의반응성을억제하였다 [33]. 비글견 (beagle dog) 에네크록스를혈관으로투여후간으로유입되는혈관을막았다풀어주는허혈재관류간손상 in vivo 모델에서네크록스는혈액내간효소수치를정상으로유지시켰으며, 간조직의세포괴사를효과적으로억제함을확인하였다 [34]. 간세포내에서과량의활성산소생성과세포괴사가발생하는 in vivo 모델인아세트아미노펜과량투여모델에서도네크록스는간기능을효과적으로보호함을확인하였다. 이때에는활성산소, 활성질소뿐만아니라주로아세트아미노펜의대사중간체인 N-acetyl-para-benzoquinone imine (NAPQI) 과직접결합함으로써아세트아미노펜에의한간의손상을억제하였다 [35]. 종합적으로네크록스의주된기능은활성산소, 활성질소그리고몇몇라디칼들과반응하며, 과다한활성산소발생으로인한세포괴사를효과적으로억제하는것으로생각되며, 현재 NecroX-7 이심근경색을대상으로임상 1상시험진행중이다. 5) 그외의합성항산화물질 Trolox 는비타민 E의유도체로물에쉽게녹을수있는형태로변형한물질이며, 혼합물의항산화능력을측정하기위한표준법으로 Trolox 를기준으로하는 trolox equivalent antioxidant capacity (TEAC) 방법을사용하기도한다. 정상세포에서외부자극으로인해유발되는세포사멸을억제하거나, 암세포의증식을 in vitro에서억제한다는보고들이나오고있으나아직임상에적용되고있지는않다. Erdosteine 은타이올기 (thiol group, R-SH) 를갖는화합물로서세포내에서대사되면황화수소기 (-SH) 가노출되어뮤코다당류분해기능과자유라디칼과반응능력을갖게된다. 흡연등으로인해유발되는만성폐쇄성폐질환 (chronic obstructive pulmonary dis

5 HMR Ji-Hoon Park, et al. Clinical Applications of Antioxidants ease, COPD) 에효과가있다 [36]. 3. 치료제로서항산화물질의개발과전망활성산소와질병의연관성에대한보고및항산화물질의효능에대한논문은한해에도 2만여편이상출간되고있다. 항산화물질은인류의진화와함께생활속어디에나존재해왔으며, 우리도모르는사이음식을통해섭취된다. 하지만가공및가열식품의발달로인해많은항산화물질이파괴되어음식을통한섭취만으로는부족하게되었고, 결국추가적으로섭취해야만체내에서필요한양을충족시킬수있다. 이러한항산화물질은세포내에서산화-환원반응을조절하기도하며세포생장및외부자극에대한반응에필수적인요소로알려져있다. 나아가몇몇항산화물질은영양보충제로서의역할뿐만아니라암세포의증식을억제하거나또는정상적인세포의기능을보호하는것으로밝혀져치료제로서의역할도중요시되고있다 [37-39]. 임상시험은크게네단계의과정을거쳐진행된다. 1단계에서는 명의건강한지원자를대상으로다양한농도의약물을주입한후약물의대사과정이나배출과정을관찰하며안전성을평가한다. 2단계와 3단계에서는각각 명, 1,000-2,000명의환자를대상으로하여전반적인약물투여방법에대한프로토콜의정립과효능및안전성을평가한다. 마지막으로시장에진출후약물의장기적인효과및부작용을관찰한다 (4단계, post-marketing surveillance)[40]. 대부분의항산화제가유효농도범위내에서는비교적안전하며 1단계의임상시험은쉽게통과하는경향이있으나, 기존의처치법 (gold-standard treatment) 에비해효과가떨어지는경우가많다. 또한활성산소의생성이세포의기능손상을유발하는경우도있지만세포신호전달물질로도이용됨으로써단순히활성산소의생성을억제하는기능만으로임상시험의 2단계, 3단계의장벽을넘기가쉽지않다. 몇몇연구자들은항산화제의임상시험중도탈락의원인으로잘못된디자인, 시험의질, 샘플의균질성, 질병의진행상태, 농도, 처치시점, 식이와의연관성그리고유전자변형등의이유를제시하고있다 [31,41]. 급발성으로진행되는질병보다만성적으로진행되는질병에서항산화제의임상탈락률이높으며, 이를통해이미활성산소에의한손상이진행된후에는항산화제의역할자체가적을것으로예측된다. 몇가지임상시험결과를살펴보면항산화제의효능에대한의구심이생기기도한다. 1992년부터 2004년까지실시된 45세이상의여성 39,876 명을대상으로한 10년간의임상시험에서는 600 IU의비타민 E를하루간격으로복용토록한후심혈관질환과종양의발병률을관찰하였다. 그결과, 속임약 (placebo) 군대비비타민 E 복용군에서심혈관질환과종양의발병률에통계적유의성이없었다 [42]. 또한, 프랑스인 13,017 명을대상으로비타민 C, E, 베타-카로틴등의항산화제를 7.5년동안투여하였지만심혈관질환의발병률에 는영향을미치지않았다 [43]. 암의발병률에있어서도 세사 이의 20,071 명의남성을대상으로이틀에한번 50 mg 의베타 - 카로 틴을 12 년간투여하였을때암의발병률이나심혈관질환으로인한 사망에영향을미치지는않았다 [44]. 그럼에도불구하고, 항산화물질이신약으로서매력을가지는이 유는활성산소또는자유라디칼이질병의진행과노화에영향을 미치는것에대해부정할수없으며, 몇몇조사에서는긍정적인결 과를확인하였기때문이다. 조사대상을좀더세분화하여활성산 소의발생이극대화되었을것으로생각되는그룹 ( 제 2 형당뇨환자 중항산화물질인합토글로빈의유전적이상을가진그룹 ) 의조사 결과, 비타민 E 의투여가심근경색증, 뇌졸중, 심혈관계질환으로 인한사망률을유의하게감소시켰다 [ 투여군 2.2% 대비속임약군 4.7% (p = 0.01)][45]. 또한비흑색종피부암 (nonmelanoma skin cancer) 환자 1312 명을대상으로매일셀레늄 (selenium) 200 μg 을 투여하고약 2 년후재발률을살펴보았을때폐, 대장에서의재발 에는효과가없었지만전립선에서의재발에는통계적유의성을확 인할수있었다 [46]. 위결과에서보듯, 항산화물질이동물실험결과에서기대한만 큼의효과를보이지않거나그결과에대한논란의여지가있지만 현재도항산화물질의효능을극대화하기위하여기존에알려진다 양한형태의항산화물질뿐만아니라에틸에스테르화글루타티온, 마이토퀴논과같은변형된형태의물질들도속속개발되고있으며, 부작용은최대한줄이고화합물의안전성과표적특이성그리고 체내흡수율등을증가시킨이상적인형태의치료물질로서항산화 물질의개발이계속되고있다 (Fig. 2). Fig. 2. Structures of antioxidant molecules. EGCG, (-)-epigallocatechin-3-galate; MitoQ, Mitoquinone

6 박지훈등 항산화물질의임상적용 HMR 결론 REFERENCES 활성산소는정상적인세포에서산소의산화물로자연스럽게생성되는부산물이지만미토콘드리아의기능이상이나산화효소 (oxidases) 등에의해과량이생성되는경우, 또는활성산소를제거하는효소들의기능이상으로인해제대로처리되지않으면결국세포기능소실과세포사멸을초래한다. 다양한질병과활성산소와의연관성에대한많은연구가있었기에항산화물질의효능에대한관심또한클수밖에없다. 하지만이러한물질들이항산화능력을보이는것이외에세포내의신호전달체계를조절한다거나농도에따라활성산소제공자로서역할을할수있다는연구결과들이발표되고있어아직항산화물질을모든질병에대한치료제로서이용하기엔어려운상황이다. 또한성공적으로임상시험을통과하기위해서는몇가지조건을충족시켜야한다. 첫째, 기존에사용되고있는약물에비해부작용이적고효능이우수해야한다. 둘째, 가격경쟁력이있어야한다. 셋째, 투여방법이용이해야한다 ( 구강 > 피하 > 정맥주사 ). 이상의조건들을만족해야임상시험을통과할수있는충분조건이되는데대부분의항산화제는현재각각의질병에사용되고있는기존약물 (gold-standard treatment) 에비해앞서언급한조건들을충족시키지못하는경우가대부분이다. 또한활성산소가질병을유발하는필수조건인지에대한논의도계속되고있어항산화제의효능에대한의문은여전히남아있다. 반면항산화물질의효능을지지하는많은연구자들은항산화제가임상에서기대한만큼의효능을보이지못하는것에대해다음과같은이유를제시하고있다. 1) 활성산소제공자로서작용할수있어높은농도를투여할경우치명적일수있어충분한양의항산화물질을투여하지못하는경우 ; 2) 자연계에존재하는항산화물질과다른형태 ( 이성질체 ) 의저가의합성비타민의이용 ( 예를들어, 자연계에 8가지의이성질체가존재한다면임상시험에서는 1가지의이성질체만으로시험을진행 ); 3) 약물의농도와임상시험의기간이적절하지않음. 질병의유발이수년에서수십년에걸쳐일어나는퇴행성질환의경우임상시험기간이효과를확인하기에상대적으로짧을수도있음 ; 4) 잘못된환자군의이용. 질병의진행상태나발병원인의개인차가심한경우상반된효과를보일수있음 [41,47]. 이는잘디자인된임상시험에서항산화물질의효능을확인한것에미루어보아항산화물질이만병통치약은아니지만잘디자인된실험군내에서는기대한효과를보일수있음을알수있다 [48,49]. 결론적으로, 앞으로많은연구들을통하여기존의항산화물질을개량하고잘계획된임상시험을통해동물실험에서의긍정적결과들을사람에게적용시킬수있다면암, 당뇨병, 뇌질환등난치성질환들을치료할수있는좋은도구가될수있을것으로기대된다. 1. Bartz RR, Piantadosi CA. Clinical review: oxygen as a signaling molecule. Crit Care 2010;14: Preiser JC. Oxidative stress. JPEN J Parenter Enteral Nutr 2012;36: Runchel C, Matsuzawa A, Ichijo H. Mitogen-activated protein kinases in mammalian oxidative stress responses. Antioxid Redox Signal 2011;15: Pan JS, Hong MZ, Ren JL. Reactive oxygen species: a double-edged sword in oncogenesis. World J Gastroenterol 2009;15: Alfadda AA, Sallam RM. Reactive oxygen species in health and disease. J Biomed Biotechnol 2012;2012: Valko M, Leibfritz D, Moncol J, Cronin MT, Mazur M, Telser J. Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol 2007;39: Devasagayam TP, Tilak JC, Boloor KK, Sane KS, Ghaskadbi SS, Lele RD. Free radicals and antioxidants in human health: current status and future prospects. J Assoc Physicians India 2004;52: Ortega R. Importance of functional foods in the Mediterranean diet. Public Health Nutr 2006;9: Arrigoni O, De Tullio MC. Ascorbic acid: much more than just an antioxidant. Biochim Biophys Acta 2002;1569: Herrera E, Barbas C. Vitamin E: action, metabolism and perspectives. J Physiol Biochem 2001;57: Mak JC. Potential role of green tea catechins in various disease therapies: progress and promise. Clin Exp Pharmacol Physiol 2012;39: Ak T, Gulcin I. Antioxidant and radical scavenging properties of curcumin. Chem Biol Interact 2008;174: Chen WF, Deng SL, Zhou B, Yang L, Liu ZL. Curcumin and its analogues as potent inhibitors of low density lipoprotein oxidation: H-atom abstraction from the phenolic groups and possible involvement of the 4-hydroxy- 3-methoxyphenyl groups. Free Radic Biol Med 2006;40: Grynkiewicz G, Slifirski P. Curcumin and curcuminoids in quest for medicinal status. Acta Biochim Pol 2012;59: Renaud S, de Lorgeril M. Wine, alcohol, platelets, and the French paradox for coronary heart disease. Lancet 1992;339: Hung LM, Chen JK, Huang SS, Lee RS, Su MJ. Cardioprotective effect of resveratrol, a natural antioxidant derived from grapes. Cardiovasc Res 2000;47: Kelkel M, Jacob C, Dicato M, Diederich M. Potential of the dietary antioxidants resveratrol and curcumin in prevention and treatment of hematologic malignancies. Molecules 2010;15: Kaeberlein M, McDonagh T, Heltweg B, Hixon J, Westman EA, Caldwell SD, et al. Substrate-specific activation of sirtuins by resveratrol. J Biol Chem 2005;280: Pearson KJ, Baur JA, Lewis KN, Peshkin L, Price NL, Labinskyy N, et al. Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending life span. Cell Metab 2008; 8: Meister A, Anderson ME. Glutathione. Annu Rev Biochem 1983;52: Jones DP, Carlson JL, Mody VC, Cai J, Lynn MJ, Sternberg P. Redox state of glutathione in human plasma. Free Radic Biol Med 2000;28: Levy EJ, Anderson ME, Meister A. Transport of glutathione diethyl ester into human cells. Proc Natl Acad Sci U S A 1993;90: Dringen R, Hamprecht B. N-acetylcysteine, but not methionine or 2-oxothiazolidine-4-carboxylate, serves as cysteine donor for the synthesis of 135

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Journal of Life Science 2011, Vol. 21. No μ μ

Journal of Life Science 2011 Vol. 21. No. 8. 1120~1126 ISSN : 1225-9918 DOI : http://dx.doi.org/10.5352/jls.2011.21.8.1120 μ μ μ α β Journal of Life Science 2011, Vol. 21. No. 8 1121 μ μ 1122 생명과학회지 2011,