한국임상약학회지제 21 권제 2 호 Kor. J. Clin. Pharm., Vol. 21, No. 2. 2011 담즙산의생체활성물질로서의역할 방준석 1 이유정 2,3 정지훈 3 손의동 4# 1 가톨릭대학교서울성모병원, 2 숙명여자대학교임상약학대학원, 3 중앙대학교의과대학, 4 중앙대학교약학대학 (2011 년 3 월 8 일접수 2011 년 6 월 14 일수정 2011 년 6 월 15 일승인 ) Roles of Bile Acid as an Active Biological Substance Joon Seok Bang 1, Yu Jeung Lee 2,3, Ji Hoon Jeong 3, and Uy Dong Sohn 4# 1 Seoul St. Mary s Hospital, The Catholic University of Korea, Seoul 137-701, Republic of Korea 2 Graduate School of Clinical Pharmacy, Sookmyung Women s University, Seoul 140-742, Republic of Korea 3 College of Medicine and 4 College of Pharmacy, Chung-Ang University, Seoul 156-756, Republic of Korea (Received March 8, 2011 Revised June 14, 2011 Accepted June 15, 2011) The family of bile acids belongs to a group of molecular species of acidic steroids with very peculiar biological characteristics. They are synthesized by the liver from cholesterol through several complementary pathways and secreted into small intestine for the participation in the digestion and absorption of fat. The bile acids are mostly confined to the territories of the so-called enterohepatic circulation, which includes the liver, the biliary tree, the intestine and the portal blood with which bile acids are returned to the liver. In patients with bile acid malabsorption, the amount of primary bile acids in the colon is increased compared to healthy controls. Although the increase in the secondary bile acids including deoxycholic acid, is reported to have the potency to affect tumorigenesis in gastrointestinal tracts, there is no firm evidence that clinically relevant concentrations of the bile acids induce cancer. The list of their physiological roles, as well as that of the pathological processes is long and still not complete. There is no doubt that many new concepts, pharmaceutical tools and pharmacological uses of bile acids and their derivatives will emerge in the near future. Key words - bile acids, cholic acid, chenodeoxycholic acid, deoxycholic acid, malabsorption, cancer 지난수십년동안많은학자들에의하여담즙산 (bile acid) 의생리적, 약리적효과가입증되었고, 최근에는그화학구조와병리적현상의연관성을규명하는연구가진척되어담즙산이가진역할을재조명하려는관심과노력이증가하고있다. 이제까지알려진담즙산의기본적역할은지방의소화를돕는계면활성제로서의기능이지만, 근래이루어진다양한연구결과는담즙산이가진복합적인생물학적효능, 효과를부각시키고있다. 담즙산은담즙 (bile juice) 을구성하는주요유기물질로서소화기계중에서특히간과장관에서중요한생리적기능을담당하고있다. 하지만, 일부불용성담즙산은간과장에서세포의세포사멸 (apoptosis) 및괴사 (necrosis) 를유발하는병리현상에도중요한역할을담당하는것으로여겨지고있다. 1) 담즙산은크게 1차성과 2차성으로구분되는데, 1차성담즙산은 Correspondence to : 손의동중앙대학교약학대학약물학교실서울특별시동작구흑석동 221 Tel: +82-2-820-5614, Fax: +82-2-826-8752 E-mail: udsohn@cau.ac.kr 간세포 (hepatic cell) 에서지용성물질인콜레스테롤을원료로모핵에수용성기를첨가함으로써생성되며, 최종적으로지용성이자수용성을띠는양성물질로합성된다. 인체내에서생성되는 1차성담즙산으로는 cholic acid (CA) 와 chenodeoxycholic acid (CDCA) 가있으며, 2차성담즙산은 CA와 CDCA가위장관내부에서장내세균에의해변화된형태이며장관으로부터재흡수되어간으로이동하는, 이른바장간순환 (enterohepatic circulation) 을한다. 2차성담즙산도다양한생리활성을지니는데, 매우소량만이존재하는 ursodeoxycholic acid (UDCA) 는간기능개선이라는약리적효과가입증되어간질환치료제로써응용되고있다. 2) 담즙산의비수용성이증가하는것은담즙산의유효성과독성에크게영향을미치는요소이다. 담즙산은화학적으로산성을띠는 steroid 구조인데모핵에결합하는치환기에따라상이한구조의담즙산류로변하고고유한생리적, 병리적, 약리적활성을나타낸다. 즉, 모핵의어떤부분이어느정도, 어떤방향으로수산화되는지에따라수용성이정해지고그안전성과유효성까지결정된다. 3) 최근연구에따르면, 일부의담즙산은자유라디칼 (free-radical) 을억제하는효과때문 49
50 Kor. J. Clin. Pharm., Vol. 21, No. 2, 2011 Fig. 1. Pathways of bile acid biosynthesis in the human liver. The neutral and alternative pathways of bile salt biosynthesis are initiated by cholesterol 7α-hydroxylase (CYP7A1) and mitochondrial sterol 27-hydroxylase (CYP27A1), respectively. Sterol 12α-hydroxylase (CYP8B1) determines the ratio of CA to CDCA synthesized. In humans, the neutral pathway is the major procedure under normal physiological conditions. StAR D1 (steroidogenic acute regulatory protein D1); 27OH-C (27-hydroxycholesterol); 25OH-C (25-hydroxycholesterol); SULT2B1b (hydroxycholesterol sulfotransferase 2B1b); CYP7B1 (oxysterol 7α-hydroxylase); BAL (bile acid CoA ligase); BAT (bile acid CoA: amino acid N-acyltransferase). 에약리적또는임상치료적으로의의가있으나, 다른담즙산은오히려세포에산화적스트레스 (oxidative stress) 를유발하여염증및발암가능성을나타낸다고보고하였다. 따라서, 본글에서는담즙산의기능과관련된최근의상반된연구결과를발췌, 정리함으로써담즙산이가진생리활성물질로서의다양한역할을고찰하였다. 담즙산담즙산은간에서 cholesterol을원료로다양한효소가관여하는세가지경로를통하여주로 CA와 CDCA 같은 1차담즙산으로생합성된다 (Fig. 1). 4) 합성된담즙산은간에서분비되기이전에 glycine이나 taurine과포합하여수용성이증가된 C-24 amide 형태로배출되는데, 5) 포합담즙산은약 100 mm의농도로담낭에저장되며섭취된지방이소장근위부에도달하면소화를돕기위하여위장관내부로분비되지만, 6,7) 그양이매우적어생리적, 병리적효과측면에서는큰영향을미치지못한다. 8) 장관내부로분비된담즙산은소장중에서도특히회장 (ileum) 에서지방의체내흡수에중요한역할을한다. 9) 담즙산은매우안정한고리모양의 steroid 핵과잔기로이루어지며모핵의다양한위치가수산화되면화합물의용해도와생화학적특성도변한다. 특히, 수산화기의개수에따라 mono-, di-, tri-hydroxyl 담즙산이존재하며, 이수산화잔기에다시아미노산이결합하면 포합담즙산 을형성하는데, 인체에서는대부분 glycine이나소량의 taurine이결합한다. 10) 간은소수성을가진 cholesterol이나불용성화합물을수산화및포합과정을통해친수성을가진담즙산으로전환시키고, 일부의담즙산을황산화물로변환시켜신장을통한배설이가능하도록돕는다 (Fig. 2). 1차담즙산의농도를결정하는것은 cholesterol이담즙산으로전환되는과정에작용하는 cholesterol-7α-hydroxylase 라는효소이다. 10) 설치류를사용한실험에따르면, CA가주로내인성 (endogenous) cholesterol로부터생성되는반면, CDCA는식이로섭취된 cholesterol로부터합성된다고알려졌다. 11,12) 간은담즙산을주로친수성물질로변환시키는데반하여장내에서식하는박테리아는담즙산의수용성을증가시킨잔기들을탈포합하여모핵의탈수산화를촉진함으로써 deoxycholic acid (DCA), lithocholic acid (LCA), ursodeoxycholic acid (UDCA) 등과같은 2차성담즙산을생성한다 (Table 1). 담즙산의장간순환포합된담즙산은간세포 (hepatic cell) 사이에분포한미세관으로유입되어담낭에일시저장되었다가담관을통해소장내부로분비된다. 인체가취침등음식물의위장관유입이
담즙산의생체활성물질로서의역할 51 Fig. 2. Pathways for production of bile acids from cholesterol: chemical structure of the major bile acids present in bile juice and feces. Table 1. Names and kinetics of individual bile acids in humans Common name Type Synthesis Pool size (mg) Daily synthesis (mg) Cholic acid (CA) Primary Synthesized from 500 ~ 1,500 180 ~ 360 Chenodeoxycholic acid (CDCA) Primary cholesterol by liver 500 ~ 1,400 100 ~ 250 Deoxycholic acid (DCA) Secondary Produced in intestine from 200 ~ 1,000 Lithocholic acid (LCA) Secondary action of microorganisms on primary bile acids 50 ~ 100 Total 1,250 ~ 4,000 280 ~ 610 중단된동안에는간에서생성된담즙산의약절반은담낭에저장되고나머지절반은소장으로분비된다. 이때소장으로분비된담즙산은능동또는수동수송시스템에의하여간으로회수되었다가소장으로재분비되는과정을반복하다가대부분이담낭에저장된다. 위장관으로지방질이유입되면, 저장된담즙산이소장내부로분비되고소화효소로서기능을마친직후장에남아있던 95% 의담즙산은주로회장에서능동수송에의하여재흡수되어장간순환을반복한다. 13,14) 담즙산의장간순환과정이원활해지려면관련된세포들이효율적으로담즙산을수송해야한다. 장의상피세포막에는소장내부에남아있는담즙산을세포내부로능동적으로흡수하는 ASBT 수송체 (apical bile salt transporter) 가존재한다. 이수송체는두개의나트륨이온과한개의담즙산분자를 동시에운반한다. 15) ASBT 수송체에의해장상피세포내부로흡수된담즙산은이종단백의이중체로구성된 OSTa/ OSTb 수송체 에의해세포의기저부를경유하여간문맥으로이동한다. 이수송체는음이온을교환하는수송체로알려져있으나, 명확한음이온의형태는아직알려지지않았으며, 16) 향후지속적인연구가필요한분야이다 (Fig. 3). 대부분의담즙산이지방질의소화에관여한후, 회장원위부에서재흡수되는장간순환을하는데성인남자의경우 1 일 4~10회정도반복된다. 한편, 소장으로분비된 CA와 CDCA의소량은대장까지도달하는데, 그곳에서식하는미생물에의해탈수산화되고더욱소수성을지닌 2차담즙산 (deoxycholic acid, DCA와 lithocholic acid, LCA) 류로각각변환된다 (Fig. 4). 이러한 2차담즙산도대장에서재흡수되어
52 Kor. J. Clin. Pharm., Vol. 21, No. 2, 2011 Fig. 3. Schematic representation of the entero-hepatic circulation of bile acids The organs [A] and cell types and transporters [B] that are involved in the entero-hepatic circulation of bile acids are presented. ASBT (apical sodium-dependent bile acid transporter); BA (bile acid); BAEP (bile acid export pump); IBABP (ileal bile acid binding protein); NTCP (sodium-dependent taurocholate protein); OATP (organic anion transporter); tasbt (truncated form of ASBT) 간문맥을통해간으로회귀하는장간순환을한다. 17) 담즙산의흡수장애약반세기전에시작된연구들로부터담즙산의흡수는공장 (jejunum) 보다는회장 (ileum) 에서농도구배 (concentration gradient) 에역행하는능동수송에따른다는가설이세워졌고이후동물실험을통하여회장의능동수송기전이담즙산의재흡수에중요함이규명되었다. 18) 이후많은연구로부터다수의질병이담즙의정상적인재흡수과정에문제가발생한것과관련있음이밝혀졌다. 질병기전과관련된담즙산의흡수장애는원인에따라크게세가지로구분된다. 첫번째유형은, 담즙의장-간이동에있어장관내부에문제가발생한경우이다. 한임상연구에서는회장원위부절제술 (distal ileal resection) 후에발생하는설사의원인이담즙산의흡수장애였다는결과가보고되었고, 19) 또다른연구에서는회장절제술후설사로고통받는환자에게담즙산을흡착하는 cholestyramine을처방하면설사의횟수가감소한다는효과를보여줌으로써담즙산의흡수에작용하는회장의역할이입증되었다. 담즙산의흡수장애를진단하는방법으로써 sodium-taurocholate 14 C를정맥주사한뒤대변에서방출되는방사선의양을측정하는방법이사용되는데, 정상인의경우 20% 이하가배출되지만흡수장애가있는환자의경우는 50% 이상이 24시간내에배출되는것으로알려졌다. 20) 특히, 회장상피부분에문제가발생한크론씨병 (Crohn s disease) 을 가진환자나, 여성암 (gynecological cancer) 에대한방사선치료의부작용으로회장이손상된경우 21) 에도담즙산의흡수장애가자주관찰되었는데, 이것은정상인에비하여담즙산의 turnover 비율이증가했기때문이라고밝혀졌다. 22) 두번째유형은, 임상형태학적으로정상의소화기관을보유했지만담즙산의흡수장애가발생한경우인데, 이를 특발성담즙산흡수장애 (idiopathic bile acid malabsorption, IBAM) 라부른다. 이질병이처음알려졌을때는흔치않은경우라여겨졌으나, 연구결과답즙산흡수장애의 30% 이상이그원인을알수없는특발성인것으로나타났다. 23) 또한, 과민성대장증후군 (irritable bowel syndrome, IBS) 으로잦은설사로인한고통을호소하는환자를대상으로진행한메타분석에서도 IBAM이 IBS의주요원인이라고밝혀졌다. 24) 마지막으로, 담즙산의흡수장애가장질환이외의질환과연관된경우를세번째유형으로분류한다. 담즙산의흡수장애를초래하는질환으로는담낭절제술후가족성 amyloid증, 다발성신경병증, 25) 낭성섬유증, 췌장기능부족, 26) 근긴장성이영양증등을예로들수있다. 27) 담즙산의흡수저하는과량의담즙산이소장을거쳐대장까지이동하는것과상통하므로이경우대장이과도한담즙산에노출됨으로써임상적으로병리적현상을유발할가능성이높아진것이라고여겨진다. 담즙산의체외배출건강한정상인의생리적대변에서검출되는총담즙산은
담즙산의생체활성물질로서의역할 53 Fig. 4. Pathway for production of bile acids from cholesterol. 3mg/g 정도로매우고농도이며, 대변과함께배설되는체액으로부터검출된담즙산의농도는최소 98에서 393 µm까지다양하다. 28,29) 대변을원심분리한후대변액으로부터채취한총담즙산의농도는대략 350 µm이검출되는데, 30) 대장폴립 (polyp) 증을가진환자의경우는대변액중의총담즙산농도가 184~1579 µm로다소높게나타난다. 29) 대장에서는소량의담즙산이물에용해된상태로존재한다. 대부분의담즙산은 ph 7.0 이하에서불용성인 DCA 혹은지방산과인지질같은극성지방과결합한형태로존재하거나, 미생물과음식물찌꺼기에흡수된형태로존재한다. 31-34) 설사등음식물의장내체류시간이짧아진경우는 2차성담즙산의비율이 CA, CDCA와거의동일해지고수용성담즙산이녹아있는대변수층의담즙산농도가 mili-molar 범위이상으로증가한다. 대체로대변내담즙산농도는식이습관에따라서대변양의변화와는무관한것으로알려지며, 대장에머무는시간이길수록불용성 2차담즙산의농도는증가한다. 35) 담즙산과암대변속담즙산의농도와암발생간의연관성연구는주로결장선종으로부터시작되었다. 고지방식이섭취에대응하여담즙산의분비량이증가하면위장관암종의발생률이증가한다는역학적보고가있으며, 36) 동물을이용한실험에서회장과우측결장을우회하도록수술하여담즙산의부하를좌측결장에집중시켰을경우종양발생률이정상적으로담즙산에노출된대조군에비해현저히높았다는보고가있다. 37) 암발생과연관된주요한원인물질로는 DCA 같은 2 차성담 즙산이지목되는데, 38) 혈장 DCA 농도가증가하면, 토끼, 햄스터, Guinea pig, rat의장관세포가 2차성담즙산에더많이노출된다는것이밝혀졌다. 39) 임상적으로도종양발생을촉진할잠재성은 2차담즙산이 1차담즙산보다높을것으로예상된다. 일부연구자는요로결석증과혈청및배설물의 DCA 농도사이에병리적연관성을발견하였으며, 40) 위장관선종이있는환자의혈액이나대변에서정상인대비고농도의 2차담즙산이검출되었다는보고가있으나피험자의수가적어서담즙산과암발생간의관련성을확정하려면추가연구가필요하다. 41) 담즙산이암을유발하는병리적기전으로는, 고지방성음식물을소화시키기위해과량분비된담즙산에위장관이노출됨으로써어떠한발암기전이작동하였을것으로예상한다. 몇몇실험결과, DCA 및 LCA와같은 2차담즙산이위장관상피세포의증식과사멸, 그리고유전변이를일으켜암을유발한다고제시되어있다. 이와는상반되게, 일부세포주를이용한실험에서는 2차담즙산중에서 DCA가세포사멸촉진효과를나타낸것은여러경로의세포사멸기전에 DCA가어떠한기능을담당하기때문이라고주장한다. 42) 세포사멸에관련된담즙산의역할은소수성정도와연관성이높은데, 담즙산의소수성이증가할수록세포사멸작용도증가한다고여겨진다. 따라서비포합된, 즉소수성이큰 DCA 등이암발생과연관성이높을것으로예상되는데, 이는소수성이큰담즙산이수동확산기전을통해장관상피세포안으로잘흡수되기때문이다. 한편, 담즙산의세포사멸기능과관련된기전으로는, 미토콘드리아에서 cytochrome C의방출을촉진하여미토콘드리아세포막의투과성이증가된결과로세포사멸이유도되었기때문이라고생각한다. 43) DCA에의해세포사멸이증가되면조직내상피세포가 DCA에의한세포사멸에대하여저항성을증가시켜변형된세포가선택적으로살아남는결과를초래한다. 상피세포의저항성이증가하는과정에는산화질소 (nitric oxide) 가부분적으로연관되어있으며 glutathione-s-transferase도 DCA에대한저항성을증가시키는것으로여겨진다. 44,45) 이렇게담즙산의작용이반복적으로지속되면담즙산에노출된조직에선종이발생한다고판단된다. 담즙산과암의임상적연관성다수의 in vitro 및 in vivo 실험으로부터담즙산과암발생과의인과성이제기되었음에도불구하고이에대한근거자료로써활용될만한명확한임상연구의결과는의외로희소하다. 일부대규모역학연구로부터담즙산의발암성이제시되었고, 총 1,226명의환자를대상으로한 20여개의임상연구결과를종합한최근의메타분석에따르면, DCA와 LCA 같은 2차성담즙산의장내분비량과대장암의발생율사이에는아무런통계학적유의성이없었고, 암발생가능성이낮다고여기는 1차담즙산 CDCA가오히려대장암의병인으로서더중요하다고결론짓고있다. 46)
54 Kor. J. Clin. Pharm., Vol. 21, No. 2, 2011 고농도담즙산에노출된인체세포에서암발생이촉진되는지를가장명확히규명할수있는방법은일부시험대상자를담즙산에과다노출시킨후, 대장암의유병률을직접측정하는전향적임상연구가효과적이겠지만이는연구윤리적측면에서실효성이없는방안이다. 대신장내분비된담즙산의흡수불량증이란질병을보유함으로써결장점막이고 농도의담즙산에자주노출되는환자들을간접적으로 ( 후향적으로 ) 평가하면담즙산과암과의연관성에대한임상적판단이용이해진다. 그러나, 이렇게 특별성담즙산흡수불량증 을가진환자의대장암유병률을평가했을때, 담즙산과암과의임상적연관성에통계적유의성이없었다는보고가있다. 이연구는 1975년 ~1983년기간에총 838명의환자를대상으로 417명은정상대조군으로, 421명은부분적회장우회술에의해고농도의담즙산에노출된실험군으로배정하여두군간암발생률을후향적으로평가한것이다. 평균 14.7 년이라는환자추적기간 ( 범위 : 12.2~20년 ) 동안에대조군에서는총 58건 (13.9%) 의암이발생하였고, 시험군에서는총 61 건 (14.5%) 의암이발생한것으로집계되었다 (p=0.99). 암환자중대조군에서총 8건 (1.9%) 의결장직장암이발생하였고시험군에서는 10건 (2.4%) 이발생함으로써, 두집단간암발생에서도유의한차이가발견되지않았다 (p=0.69). 47) 그리고, 비록대장이고농도의담즙산에노출되더라도연구대상이었던 421명피험자의경우에보유한질병의치료후 15년까지결장직장암발생률의증가가없었다고결론지었다. 48) Crohn s disease는장내상피세포에문제가발생하여담즙의흡수가불가능해진경우로써환자의대장은고농도의담즙산에쉽게노출된다. 따라서이병을가진환자에서의대장암발병률을조사하면담즙산노출과암발생과의연관성을간접적으로판단할수있다. Crohn s disease에이환된 374명을 17년동안총누적인원 6,569명을대상으로진행한대규모역학연구로부터연구기간동안 8명에서총 9개의위장관계암종 ( 결장직장암 4건, 소장암 4건, 위암 1건 ) 이발견되었다. 그러나, 결장직장암 (colo-rectal cancer) 의발병위험성이대조군보다높지않았고, 대부분의위장관계암종이염증에영향을받은점막부위에서발생하여고농도의담즙산노출에의해암발생이촉진되었다는결론을제시하지못하였다. 49) 결 수십년간많은연구를통해담즙산은단순히소화작용에만필요한계면활성제뿐만아니라체내에서다양한생리적, 병리적현상에중요역할을담당하는물질로서밝혀졌다. 근래에는많은학자들이담즙산의화학적구조에따라병리적발병원인물질혹은약리적활성을지닌물질로서의가능성을제시하고있다. 담즙산의생체활성작용을돕는생리현상은장간순환이며, 이것이불완전할때초래되는담즙산의 론 흡수장애로부터조직세포가담즙산에과도하게노출되면일부질병의원인이된다. 특히담즙산의과다노출에의한암발생가능성에대한가설은 in vitro및 in vivo실험들을통해규명하려는시도가계속되고있으며, 한편으로대규모임상역학조사혹은메타분석을시행한결과등에서도그통계적연관성에대하여신뢰할만한데이터는아직없다. 담즙산특유의물리-화학적그리고생물학적특징들을면밀히연구하면신규약물의개발에유용할것이며, 천연약제또는반합성약물개발의기초가될수있으므로향후약리학및임상약학분야에서담즙산과담즙산유도체의역할규명연구가부각되리라고예견한다. 참고문헌 1. Attili AF, Angelico M, Cantafora A, et al., Bile acid-induced liver toxicity: relation to the hydrophobic-hydrophilic balance of bile acids. Med Hypotheses. 1986; 19(1): 57-69. 2. Paumgartner G, Beuers U: Ursodeoxycholic acid in cholestatic liver disease: mechanisms of action and therapeutic use revisited. Hepatology 2002; 36(3): 525-31. 3. Thomas C, Pellicciari R, Pruzanski M, et al., Targeting bileacid signalling for metabolic diseases. Nat Rev Drug Discov 2008; 7(8): 678-93. 4. Huang L, Sun Y, Zhu H, et al., Synthesis and antimicrobial evaluation of bile acid tridentate conjugates. Steroids. 2009; 74(8): 701-6. 5. Kullak-Ublick GA, Stieger B, Meier PJ. Enterohepatic bile salt transporters in normal physiology and liver disease. Gastroenterology 2004; 126(1): 322-42. 6. Perwaiz S, Tuchweber B, Mignault D, et al., Determination of bile acids in biological fluids by liquid chromatographyelectrospray tandem mass spectrometry. J Lipid Res 2001; 42(1): 114-9. 7. Krishnamurthy GT, Brown PH. Comparison of fatty meal and intravenous cholecystokinin infusion for gallbladder ejection fraction. J Nucl Med 2002; 43(12): 1603-10. 8. Javitt NB. Cholesterol, hydroxycholesterols, and bile acids. Biochem Biophys Res Commun. 2002; 292(5): 1147-53. 9. Redinger RN. The coming of age of our understanding of the enterohepatic circulation of bile salts. Am J Surg 2003; 185(2): 168-72. 10. Hofmann AF. The continuing importance of bile acids in liver and intestinal disease. Arch Intern Med 1999; 159(22): 2647-58. 11. Ayaki Y, Tsuma-Date T, Endo S, et al., Role of endogenous and exogenous cholesterol in liver as the precursor for bile acids in rats. Steroids 1981; 38(5): 495-509.
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