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1 ISSN (PRINT) ISSN (ONLINE) 약학회지제 61 권제 2 호 117~123 (2017) Yakhak Hoeji Vol. 61, No. 2 DOI /psk 종설 Short Report 금은화추출물이폐암치료제 gefitinib 의약물동태에미치는영향 구태성 서숙희 김성섭 * 충남대학교신약전문대학원 (Received February 20, 2017; Revised April 1, 2017; Accepted April 3, 2017) Effects of Lonicera japonica extract on the Pharmacokinetics of Gefitinib in Rats Tae-Sung Koo, Suk-Hee Seo, and Sung-Sub Kim* Graduate School of New Drug Discovery and Development, Chungnam National University, Korea Abstract The objective of this study was to estimate the potential herb drug interaction between gefitinib and Lonicera japonica (LJ) by evaluating changes in gefitinib pharmacokinetics following single and multiple oral doses of LJ in rats. Firstly, to determine basic pharmacokinetics of gefitinib, rat pharmacokinetics after 3, 10 and 30 mg/kg single intravenous and oral administration of gefitinib was executed. Secondly, single and 7-day repeated oral dose pharmacokinetics of gefitinib (10 mg/kg) after pretreatment with saline or LJ extract (500 mg/kg) were performed. In addition, the effect of fecal and urinary recovery after co-treatment with LJ and the inhibition of CYP3A4 by LJ was evaluated. Gefitinib showed dose-independent pharmacokinetics at intravenous and oral doses of 3 30 mg/kg and the pharmacokinetic parameters of gefitinib following single and multiple doses were not significantly affected by pretreatment with LJ extract. Fecal and urinary recovery of gefitinib was not significantly different between groups and LJ extract did not inhibit CYP3A4, main metabolic enzyme of gefitinib, activity until the concentration reached 300 μg/ml. These indicated that pharmacokinetics of gefitinib was not significantly affected by co-treatment with LJ extract. Keywords Lonicera japonica, Iressa, herb-drug interaction, pharmacokinetics Gefitinib( 상품명 Iressa ) 는최초로개발된표피성장인자수용체 (Epidermal growth factor receptor, EGFR) 의 tyrosine kinase 활성을선택적으로억제하는폐암치료약물이다. EGFR 은주로폐암이나유방암등의고형암에서과발현되어있으며, 세포복제와세포자멸사의억제, 암세포의혈관신생등을통하여암세포의성장에중요한역할을한다. 1) Gefitinib는 EGFR의 tyrosine kinase의활성을선택적으로저해함으로써 EGFR의인산화를차단하고이를통하여 EGFR의신호전달을막아암세포의증식을억제한다. 2) 기존의다른항암제들과달리 gefitinib는비소세포폐암에서도높은치료효과를나타내어, 기존의항암치 # Corresponding Author Sung-Sub Kim Graduate School of Drug Discovery and Development, Chungnam National University, Daejeon 34134, Republic of Korea Tel.: Fax.: sungsub@cnu.ac.kr 료에실패한비소세포폐암의유일한치료약물로주목받고있다. Gefitinib는기존의세포독성항암제에비해서상대적으로낮은독성을가졌다고알려져있지만, 피부발진, 설사, 오심, 구토, 식욕부진, 위염, 탈수, 간독성, 무력감, 결막염, 안검염, 간질성폐질환, 각막미란및속눈썹탈락등의여러부작용이보고되고있다. 3) 이러한 Gefitinib의다양한부작용을줄이고약물의약효를증대하기위한다양한방법들이시도되고있으며, 그가운데최근상대적으로독성이낮은천연물신약혹은기존한의약물과의동시투여연구가진행되고있다. 4) 금은화 (Lonicera japonica) 는항산화효과, 5) 항염증작용, 6) 항암작용, 7,8) 항균작용, 9) 중금속해독작용, 10) 간보호효과, 11) 장점막보호효과 12) 및아토피염에의한피부손상완화효과 13) 등의여러생리활성을가진것으로보고되어왔다. 금은화의여러효능중에서항암효과나폐손상억제효과등은 gefitinib와동시투여시약효의증대가예상되고, 장점막보호효과나피부손상완화, 간보호효과등은 gefitinib의부작용인간기능이상, 117

2 118 구태성 서숙희 김성섭 설사, 위염, 피부질환등을완화시킬수있을것으로기대된다. 약초등을약물과함께투여하면함께투여한약물의체내동태에영향을주어혈중농도의변화를일으켜약효나독성의변화를유발할수있다. Gefitinib는 Cytochrome450 3A4에의한대사를통해주로소실되는것으로알려져있는데, 14) 금은화가대사효소등에미치는효과가완전히알려지지않았기때문에, 금은화가 gefitinib의약동학에영향을미치는지는분명하지않다. 15,16) 본연구의목적은폐암을포함한다양한악성종양의치료제로빈번히사용되고있는대표적인 EGFR inhibitor 경구용항암제인 gefitinib와, 이의부작용감소에역할을할것으로기대되는한방제제인금은화의병용연구를위한허브-약물상호작용 (herbdrug interaction) 가능성을평가하는것이다. 따라서본논문에서는 gefitinib의약물의기초적특징인 CYP450 효소저해실험을실시하고, 실험동물에 gefitinib와금은화를병용투여한후약물동태학매개변수를산출하고, 이데이터를통해약물의흡수, 분포, 대사및배설등의약물동태학적특성을알아보고자한다. 실험방법실험약물및재료실험에사용된내부표준물질인 erlotinib( 순도 100%) 는 Sigma- Aldrich(St. Louis, MO, USA) 에서 gefitinib( 순도 >99%) 는 Santa Cruz Biotechnology(Dallas, TX, USA) 에서구매하였다. 금은화엑스산은동국대학교약학대학생약실험실 (Ilsan, Korea) 에서구하였다. Acetonitrile과 methanol은 HPLC 등급으로 Tedia (Fairfield, OH, USA) 에서구입하였고 formic acid는 Kanto Chemical(Tokyo, Japan) 에서구입하였다. 흰쥐에서의약동학시험실험동물은 Sprague Dawley계 7주령수컷흰쥐 (161~271 g) 를사용하였으며, 오리엔트바이오 (Seongnam, Korea) 에서공급받아동물실험을실시하였다. 실험동물은적당한온도및습도가유지되는동물실험실에서 1주일간순화시켜발육상태가양호한개체를실험에사용하였다. 사육조건은온도 25±2 o C, 습도 50±10% 및명암주기 12시간을유지하였다. 약물투여 14시간전물만공급하여절식하였으며, 약물투여후 4시간까지절식시켰다. 충남대학교의동물실험윤리위원회 ( 승인번호 : CNU-00398) 의승인을받아동물실험을수행하였다. 동물시험은다음의 4개의시험으로구분하여진행하였다. [ 시험I] DMSO, Tween80, PEG400, 1.43 N HCl 및식염수를각각 10%, 40%, 1%, 49% 조성으로혼합한용액에 gefitinib를 1.5, 5, 6mg/mL의농도로녹여조제한후, 정맥투여용보정틀 (Rodent restrainers, Natsume, Japan) 이나경구투여용니들 (Gavage needle) 을이용하여흰쥐의꼬리정맥이나경구로임상용량 250 mg 의체중환산값 (4.167 mg/kg) 과종간차이보정값 (25.83 mg/kg) 을포함하도록 3, 10, 30 mg/kg씩투여하였다 (n=4). [ 시험II] 경구투여용니들을이용하여 Saline( 대조군 ) 또는금은화 (300 mg/kg, 실험군 ) 를경구투여한후 5분후에 Gefitinib(10 mg/kg) 를경구투여하였다 (n=5). 금은화추출물의투여량은사람용량과동물독성연구에근거하여선택하였다. 쥐의신진대사과정이사람의신진대사과정보다빠르다는점을감안하여임상권장량인 2g/day( 33.3 mg/kg/day) 보다 5~10배높은 300 mg/kg 금은화추출물을투여했다. [ 시험III] [ 시험II] 와동일하게 7일간반복투여하였다 (n=5). [ 시험I, II, III] 모든쥐에서투여직전및투여후 5분 ( 정맥투여시만 ), 15분, 30분, 1시간, 3시간, 7시간, 10시간, 24시간에채혈용고정판 (NAIGAI-CFK-1S; As One, Osaka, Japan) 과 100 IU Heparin(Green cross, Youngin, Korea) 으로코팅한 1회용 1 ml Syringe(Korea vaccine, Seoul, Korea) 를사용하여경정맥에서 0.3 ml씩채혈하였다. 채혈한혈액은즉시원심분리기 (Smart-15; Hanil, Korea) 를이용하여 17,000 g에서 10 분간원심분리하여혈장을취하였다. 모든시료는분석전까지 20 o C에냉동보관하였다. [ 시험IV] [ 시험II] 와동일하게투여후대사케이지 (Rat Metabolic Cage; Daejong, Seoul, Korea) 에넣은후뇨는투여후 0-2, 2-4, 4-10, 10-24시간동안분변은 0-12, 12-24시간동안시료를모았다 (n=4). 24시간후기벽에묻어있는뇨를증류수로씻어내고이를포함한모든시료를 20 o C 에냉동보관하였다. 전처리방법및약물농도분석생체시료중 gefitinib의농도는 Chahbouni 등이발표한액체크로마토그래피 -질량분석기 (high performance liquid chromatographytandem mass spectrometry, HPLC-MS/MS) 법을 17) 일부변경하여분석하였다. 혈장중단백질을제거하기위해냉동보관된공혈장 50 μl에 10 ng/ml의농도로조제한내부표준물질 50 μl와 150 μl의 0.1% formic acid가포함된 acetonitrile을가하고 10 분간섞어준후, 17,000 g에서 10분간원심분리하였다. 분리된상징액 150 μl를분석용 vial에옮긴후 5μL를 HPLC에주입하였다. 뇨시료의전처리는혈액시료의전처리와동일한방법을사용하였다. 분변시료에 50% methanol 50 ml를가하고, multi-tube vortexer를이용하여 14시간이상균질화를실시한후얻은균질화된분변액을혈액시료전처리방법과동일하게전처리하였다. 전처리한생체시료는 Agilent 1200 series HPLC system (Agilent Technologies, Santa Clara, CA, USA) 과 API 4000 QTRAP hybrid triple quadrupole/linear ion trap mass spectrometer(ab Sciex, Foster City, CA, USA) 를사용하여정량하였다. Zorbax XDB-C18 Column(3.5 μm, mm, Agilent, USA) 을사용하였고, 0.1% Formic acid in DW (A) 와 J. Pharm. Soc. Korea

3 금은화추출물이폐암치료제 gefitinib 의약물동태에미치는영향 % Formic acid in acetonitrile (B) 을이동상으로 0.3 ml/min의기울기분리 (Gradient) 조건으로약물을 5분동안분리하였다. 용매의비율은 1분까지 95:5으로유지후선형적으로증가시키고 분동안은 5:95로유지한후다시감소시켜 3 5분동안 95:5로유지하였다. 분리된약물의검출은 Triple quadrupole mass spectrometry를이용하여양이온전기분무이온화 (positive electrospray ionization, ESI+) 방식의 Multiple reaction monitoring (MRM) 모드에서수행하였다. Gefitinib는 m/z 에서, 내부표준물질인 Erlotinib는 m/z 에서정량하였다. 분석시의상대오차 (relative error) 와변이계수 (coefficient of variation) 는 15% 미만으로생물시료분석법가이드라인기준을충족하였다. 18) 약동학매개변수분석흰쥐의각개체별혈중약물농도-시간곡선을 WinNonlin software( 버전 4.2, Pharsight Co., Cary, NC, USA) 을이용하여 non-compartmental analysis로분석하였다. 흰쥐의시간별혈중농도로부터사다리꼴공식 (Trapezoidal rule) 에의해혈중농도-시간곡선하면적인 (Total area under the plasma concentration time curve from zero to infinity) 값과 AUMC (Area under the moment curve) 를계산한후, 계산된 AUMC 를 로나누어약물의평균잔류시간 (Mean residence time, MRT) 을구하였다. 각혈중농도의소실기로부터소실속도상수 (K el ) 을계산한후이로부터반감기 ( ) 를계산하였다. 청소율 (CL) 은투여량 / 로부터, 정상상태의분포용적 (V ss ) 은 MRT CL로부터각각구하였다. 19) CYP inhibition 금은화의 CYP 효소에의한대사저하를측정하기위해, 금은화추출물 (20, 60, 200, 600 mg/ml) 과음성대조군 (DMSO) 및양성대조군 (CYP1A2, 2C9, 2C19, 2D6 및 3A4의강한저해제인 10 μm α-naphthoflavone, 10 μm sulfaphenazole, 100 μm amitriptyline, 10 μm quinidine 및 10 μm ketoconazole) 의 CYP 저해정도를평가하였다. 1 M potassium phosphate dehydrogenize 용액과 luciferinfree water 및 human CYP450 enzyme의각 isozyme(p450- Glo, Promega, Madison, WI, USA) 을해당기질들과 96-well plate에순차적으로가했다. 600 rpm으로 5초간교반하고, 37 o C 에서 20분동안 pre-incubation 시켰다. 그후, NADPH regenerating system 용액을가하여반응을시작하였다. 37 o C에서 20 분간반응후 luciferin detection reagent 를넣고실온에서 20분동안안정화시켰다. 분석은 Varioskan flash multimode reader(thermo fisher scientific, San Jose, CA, USA) 를이용하여측정하였다. 대조시료의발광대비금은화추출물이처리된 시료의발광정도를저해도 (inhibition, %) 로환산하여값을산출하였다. 실험결과 흰쥐에 gefitinib를 3, 10, 30 mg/kg의용량으로정맥주사및경구투여한후혈중 gefitinib의시간별농도변화를 Fig. 1 및 2에나타내었다. 약물동태학매개변수 (PK parameters) 는 Table 1 및 2에나타내었다. 3, 10, 30 mg/kg로정맥투여시곡선하면적 ( ) 값은각각 4.657, , μg h/ml였으며, 청소율 (CL) 은 0.781, 0.951, ml/h/kg이었다. 반감기 ( ) 는 9.572, 6.343, h, 분포용적 (V ss ) 은 6.584, 5.618, ml/ kg으로계산되었다. CL, 및분포용적을 one-way ANOVA Fig. 1 Mean plasma concentration time curves of gefitinib after single intravenous injection to rats ( : 3 mg/kg, : 10 mg/kg, : 30 mg/kg). Fig. 2 Mean plasma concentration time curves of gefitinib after single oral administration to rats ( : 3 mg/kg, : 10 mg/ kg, : 30 mg/kg). Vol. 61, No. 2, 2017

4 120 구태성 서숙희 김성섭 Table I Pharmacokinetic parameters of gefitinib after 3, 10 and 30 mg/kg intravenous injection to rats (n = 4) PK parameters Intravenous injection 3 mg/kg 10 mg/kg 30 mg/kg (h) 0.229± ± ±0.172 (µg/ml) 1.351± ± ±4.839 (h) 9.572± ± ±0.823 (µg h/ml) 4.266± ± ±9.043 (µg h/ml) 4.657± ± ±9.572 CL (ml/h/kg) 0.781± ± ±0.357 V ss (ml/kg) 6.584± ± ±1.475, maximum plasma concentration;, terminal half-life, area under the plasma concentration time curve from time zero to last;, area under the plasma concentration time curve from time zero to infinity; V ss, volume of distribution at steady state; CL, elimination clearance Table II Pharmacokinetic parameters of gefitinib after 3, 10 and 30 mg/kg oral administration to rats (n = 4) PK parameters Oral administration 3 mg/kg 10 mg/kg 30 mg/kg (h) 2.875± ± ±3.000 (µg/ml) 0.273± ± ±0.634 (h) 6.463± ± ±0.657 (µg h/ml) 1.644± ± ±2.664 (µg h/ml) 1.724± ± ±2.611 F (%) ± ± ±8.580, maximum plasma concentration;, terminal half-life;, area under the plasma concentration time curve from time zero to last;, area under the plasma concentration time curve from time zero to infinity; F, bioavailability 의 tukey s multiple comparison test를이용하여통계처리하였을때각각은유의적인차이를보이지않았다 (P >0.05) (Table 1). 흰쥐에경구로 3, 10, 30 mg/kg 로투여실험했을때 값은각각 1.724, 5.479, μg h/ml였으며, 최고혈중농도 ( ) 값은 0.273, 0.882, μg/ml였다. 는 6.463, 4.807, h, 생체이용률 (BA) 은각각 , , % 로나타났다. 투여량으로보정한 /Dose, /Dose 및다른약동학변수들은유의적인차이를보이지않았다 (P >0.05) (Table 2). Gefitinib(10 mg/kg) 와생리식염수또는금은화 (300 mg/kg) 의투여간격을 5분으로하는단회경구병용투여후의혈중 gefitinib의시간별농도변화를 Fig. 3에나타내었다. 대조군과실험군에서 값은각각 4.815, μg h/ml였으며, 값은각각 0.779, μg/ml였다. 는 4.655, h로나타났다. 7일간반복병용투여후의시간별농도변화는 Fig. 4 에나타내었다. 대조군과실험군에서 값은 및 μg h/ml으로나타났고, 값은각각 0.546, μg/ ml이였다. 는 3.643, h로나타나유사한값을보였다. Student s t-test 를이용하여통계처리하였을때, 단회시험과 Fig. 3 Mean plasma concentration-time profiles of gefitinib after single oral administration of gefitinib (10 mg/kg) to rats pretreated with saline (5 ml/kg, control, ) or Lonicera japonica extract (300 mg/kg, ). 반복시험모두에서대조군과실험군간 와 는유의성있는차이를보이지않았다 (P > 0.05) (Table 3, 4). 생리식염수또는금은화 (300 mg/kg) 를경구투여한뒤 5분후 J. Pharm. Soc. Korea

5 금은화추출물이폐암치료제 gefitinib 의약물동태에미치는영향 121 Fig. 4 Mean plasma concentration-time profiles of gefitinib after oral administration of gefitinib (10 mg/kg) to rats pretreated with saline (5 ml/kg, control, ) or Lonicera japonica extract (300 mg/kg, ) for seven consecutive days. Table III Non-compartmental pharmacokinetic parameters of gefitinib after oral administration of gefitinib (10 mg/kg) to rats pre-treated with saline or Lonicera japonica (LJ) extract (300 mg/kg) (n = 5) PK Parameters Oral administration Gefitinib + Saline Gefitinib + LJ (h) 1.188± ±1.190 (µg/ml) 0.779± ±0.427 (h) 4.655± ±0.577 (µg h/ml) 4.655± ±0.408 (µg h/ml) 4.815± ±0.440, maximum plasma concentration;, terminal half-life;, area under the plasma concentration time curve from time zero to last;, area under the plasma concentration time curve from time zero to infinity 에 gefitinib(10 mg/kg) 를경구투여하고 24시간까지배출된뇨중회수된약물의양은각각 μg, μg으로 0.024%, 0.024% 의회수율을보였다. 동일기간분변중회수된약물의양은대조군과실험군각각 μg, μg으로 8.165%, 6.111% 의회수율을보였다. 대조군과실험군간의뇨및분변의회수율은유의적인차이를보이지않았다 (P > 0.05) (Table 4). 약물의 oxidative metabolism에관여하는효소인 cytochrome P450 중 major 5종에대한금은화의저해능을평가한결과, CYP1A2, 2C9, 2C19, 2D6, 3A4에대해금은화추출물의 IC 50 값은각각 >600 (1213.0), 182.4, 464.8, 531.2, >600 (806.5) μg/ ml이었다. 5종의양성대조군모두 95% 이상의저해를나타내어 Table VI Non-compartmental pharmacokinetic parameters of gefitinib after oral administration of gefitinib (10 mg/kg) to rats pre-treated with saline or Lonicera japonica (LJ) extract (300 mg/kg) for seven consecutive days (n = 5) PK parameters Oral administration Gefitinib + Saline Gefitinib + LJ (h) 2.600± ±2.748 (µg/ml) 0.546± ±0.180 (h) 3.643± ±1.188 (µg h/ml) 4.560± ±1.786 (µg h/ml) 4.773± ±1.676, maximum plasma concentration;, terminal half-life;, area under the plasma concentration time curve from time zero to last;, area under the plasma concentration time curve from time zero to infinity Table V Excretion of gefitinib after oral administration of gefitinib (10 mg/kg) to rats pretreated with saline or Lonicera japonica (LJ) extract (300 mg/kg) in rats (n = 4) Gefitinib + Saline Gefitinib + LJ Amount (µg) %Recovery Amount (µg) %Recovery Urine 0.47± ± ± ±0.01 Feces ± ± ± ±1.56 %Total 8.19± ±1.57 recovery 내부기준에적합하였다 (Fig. 4). 고 본논문에서는폐암치료제인 gefitinib와천연물금은화간의잠재적인약물상호작용을평가하였다. 기본적인 gefitinib의약동학특성을알아보기위해 3, 10, 30 mg/ml의농도로정맥및경구투여시험을진행하였을때 MCKillop 등이보고한것처럼정맥투여시와경구투여시모두에서장간순환의전형적인패턴인더블피크가혈중농도그래프 Figure 1, 2에서관찰되었다. 20) 정맥투여시 CL,, V ss 값은유의적인차이를나타내지않았고, 경구투여시, 투여량으로보정한, 값또한용량에따른유의적인차이를나타내지않았다. 이는 gefitinib가 3 30 mg/kg 에서용량비의존적인약물동태 (Dose-independent pharmacokinetics) 를보임을의미한다. Gefitinib(10 mg/kg) 와생리식염수또는금은화 (300 mg/kg, 실험군 ) 의투여간격을 5분으로하는단회경구병용투여실험결과, 대조군과실험군에서각각,, 는유의한차이가없었다. 이는 gefitinib의대사에관여하는주요효소인 CYP3A4가각각의농도에서금은화추출물에의해현저하게저 찰 Vol. 61, No. 2, 2017

6 122 구태성 서숙희 김성섭 Fig. 5 The CYP inhibition of Lonicera japonica extract (20, 60, 200 and 600 µg/ml) from the luminescent assay (a) CYP1A2, (b) CYP2C9, (c) CYP2C19, (d) CYP2D6, and (e) CYP3A4, respectively. 해되지않았고, 따라서 gefitinib의 CYP 주요대사가금은화에의해영향을받지않는다는것을보여준 CYP inhibition 결과와상통한다. 또한, 7일간반복병용투여에의한실험에서도, 대조군과실험군에서 는유사한값을보였고, 투여량으로보정한 및 에서유의성이없는것을확인하였다. 따라서, gefitinib의약물동태는단회및 7일간의금은화추출물과의병용투여시에영향을받지않는다는것을알수있었다. 생리식염수 ( 대조군 ) 또는금은화 (300 mg/kg, 실험군 ) 를경구투여한후 5분후에 gefitinib(10 mg/kg) 를경구투여한후대사케이지에서 24시간까지모아진뇨와분변을분석한결과, 대조군과실험군간유의한차이가없다는것을확인했다. 이는 gefitinib의배설또한금은화의병용투여로인해영향을받지않았다는것을의미한다. Gefitinib은비소세포폐암치료의첫번째선택요법으로고려된다. 따라서 gefitinib과관련된부작용을줄이기위한병용요법에대한많은연구가있었다. Gefitinib와허브제품에대한여러가지약동학상호작용연구에서 gefitinib와인삼, 버섯, 셀레늄사이에는유의적인상호작용이있음이밝혀졌다. 21,22) 금은화는항암효과나폐손상억제효과를가지고있기때문에 gefitinib 의폐암치료효과를증가시킬것으로기대된다. 또한장점막보호효과나피부손상완화, 간보호효과등은 gefitinib의부작용을완화시킬수있을것으로기대된다. 금은화추출물을 gefitinib과단일및다중투여투여했을때, gefitinib 경구약물 동태는유의한변화가관찰되지않았다. 차후 gefitinib의부작용감소와효능향상을평가하기위해서는추가의임상연구가수행되어야하지만이결과들은금은화를 gefitinib의보조요법제로사용할수있음을시사한다. 결론폐암치료제인 gefitinib와천연물인금은화의병용투여로인해약물동태학적상호작용을평가한결과, gefitinib의약물동태는금은화의단회및반복병용투여로인해유의한영향을받지않음을확인하였다. 감사의말씀본연구는충남대학교의학술연구비지원을받아수행되었으며이에감사드립니다. References 1) Grünwald, V. and Hidalgo, M. : The epidermal growth factor receptor: a new target for anticancer therapy. Curr. Probl. Cancer 26, 114 (2002). 2) Pao, W., Miller, V. A. and Kris, M. G. : Targeting the epidermal J. Pharm. Soc. Korea

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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,