大田大學校 韓醫學硏究所 論文集 171

第15卷 第2號 2006年 12月 30日

간경화 치료에 대한 중국 한의학의 연구 개요

호효평･손창규*
7)

Study on Traditional Chinese Medicine against Liver Fibrosis

East‐West Cancer Center, Dunsan Oriental Hospital of Daejeon
University,1136 Dunsan‐dong, Seo‐gu, Daejeon, 302‐122, South Korea
Xiao‐Ping Hu, Jang‐Woo Shin, Jung‐Hyo Cho, Chong‐Kwan Cho, Hwa‐Seung Yoo, Yeon‐Weol
Lee, Chang‐Gue Son*

간섬유화는 다양한 만성 간질환에 기인하는 간실질의 결합조직의 과도한 증식을 말하며, 간경화로 발전하는 중간과정이다.
중국과 한국에는 많은 간섬유화 환자가 있지만 현재까지 서양의학에서 간섬유화를 효과적으로 치료할 수 있는 치료법은 발견
되지 않고 있다. 최근 수년간 중국전통의학의 임상과 실험연구에서 많은 발전이 있었다. 전통의학이론을 바탕으로 활혈거어(活
血祛瘀), 익기(益氣)의 효능이 있는 한약제가 항섬유화 효능을 보였다. 전통중국의학에서 간섬유화에 대한 일반적인 치료는 유
효 성분, 단방 및 복방 처방의 세 부분으로 나뇐다. 우리는 중국전통의학에서 간섬유화의 효과적인 치료와 관련된 작용기
작을 소개하였다.

Key Words: Traditional Chinese Medicine (TCM), liver fibrosis, experimental and clinical, prevention and
treatment

Introduction: infection. Chronic hepatitis B always proceeds

as “hepatitis‐‐‐ fibrosis ‐‐‐ cirrhosis‐‐‐sometimes
High incidence of chronic hepatitis and its cancer”. In this process, progression to
related disease in China fibrosis or cirrhosis is critical step
According to the Asian Liver Center, 2 determining the clinical outcome; prevention
billion people of the world have been infected against its formation is a most important
with HBV, and 400 million people of them issue. Accordingly, many countries or
have chronic infections. On the other hand, pharmaceutical companies have investigates
China has the greatest burden of chronic the development of anti‐fibrotic or anti‐
infection of HBV and liver cancer. In China, cirrhotic drugs from natural resource. This
liver fibrosis is the major medical concern review aimed to survey and provide
because of the high level of hepatitis B viral information about herbal plant‐derived
experimental or clinical trials from China to
* 대전대학교 한의과대학 간계내과학교실
the Korean oriental doctors or scientists
· 교신저자 : 손창규 · E-mail : ckson@dju.ac.kr
· 채택일 : 2006년 12월 1일 working in this field.
172 大田大學校 韓醫學硏究所 論文集 第15卷 第2號

Single component from traditional Chinese current in rat hepatocytes. Tet could reduce
medicine liver cell damage and fibroses, and lower the
serum ALT, alkaline phosphatase (ALP) and
Tetrandrine (Tet) : Tetrandrine (Tet) is the total bilirubin (TB) [3]. So Tetrandrine is one
main alkaloid isolated from the lumpy root of of the effective component in traditional
Stephania tetrandra S. Moor (漢防己甲素). Its Chinese medicine.
molecular formula is C33H42N2O6 and its
chemical structure belongs to a dibenzy‐ Kwoninone : Kwoninone, a alkaloid isolated
isoquindine[1]. Modern pharmacological from Sophora Subpsostarata (苦蔘素). have the
studies have proved that Tet is a Ca2+ anti‐inflammation, antibacterial, antivirus,
antagonist, which acts mainly on the calcium potential immunomo‐dulating, anticarcinoma and
channel of cell to block the cross‐membrane multiple bioactivities. The kwoninone
transportation of calcium ions as well as their significantly inhibited fibroblastic proliferation,
intracellular distribution and utilization. In growth and expression of TGF‐β [4]. In rat
recent years, the actions of Tet in preventing model induced by CCl4 for 10 weeks, serum
and treating hepatofibrosis have gradually ALT, AST, TBA, and GGT are reduced in
attracted attention of more investigators. With pretreated and post‐treated kwoninone groups
the establishment of the technique of liver (P＜0.05, P＜0.01). And the protein expression
cell isolation and culture, and advance in of MMP‐2 was evident lower than control
technology of molecular biology, studies on group (P＜0.05, P＜0.01) [5]. By the clinical
the anti‐hepatofibrotic effects of Tet have study that efficacy of kwoninone in the
probed into the cellular, subcellular and treatment of hepatic fibrosis with hepatitis B
molecular levels [1]. In clinical study, 115 virus, serum of laminin (LN), HA, PⅢP, type
cases of chronic liver disease treated with Ⅳ collagen (Ⅳ‐C) have the remarkable
oral Tet for 6 months, their serum hyaluronic difference in the patients of liver fibrosis
acid (HA) and procollagen Ⅲ peptide (PⅢP) between treatment with kwoninone before and
levels were remarkably lower than those after. The rate of seronegative for HBsAg,
before treatment (P＜0.01). Among them, liver HbeAg and HBV‐DNA were 3.3%, 22.8% and
fibrosis disappeared in 14 (15.4%) cases, 20.0% respectively [6].
much reduced in 54 (58.1%) cases and
slightly reduced in 19 (20.4%) cases. In Salvianolic acid B (SalB): Salvianolic acid‐B
addition, there were reductions in (SalB) is one of the water‐soluble components
inflammatory cell infiltration and the number isolated from Salviae Miltiorrhizae Radix (丹
of Ito cells in the Tet treated patients, as 蔘). SalB had strong anti‐oxidant activity and
compared with the glucurone controls (P could inhibit the fibrilformation [7]. Salvianolic
＜0.001) [2]. Recently, in order to have a acid B protected the tetrachloride carbon
better understanding its hepatoprotective and (CCl4)‐induced fibrosis in rats, and reversed
antifibrotic effects, whole‐cell patch‐clamp dimethylnitrosamine (DMN)‐induced liver
technique was used to observe the effects of fibrosis in rats. It could prevent liver cell
Tet on Calcium release‐activated calcium injury, and inhibit proliferation of hepatic
 간경화 치료에 대한 중국 한의학의 연구 개요 173

stellate cells (HSC) and collagen production in There were dose‐ and time‐effective
vitro. [8‐12]. SalB could inhibit A‐beta relationships of Danshen on anti‐lipid
aggregation and fibril formation, as well as peroxidation of mitochondria of hepatic
directly inhibit the cellular toxicity of aged A‐ fibrosis in rats. Danshen improved liver
beta towards PC12 cells [13]. In clinical tissue injuries and reduced the magnitude of
study compared with the IFN‐gamma group, fibrosis in rats with CCl4 and DMN
four serological fibrotic markers significant (dimethylnitrosamine)‐induced hepatic fibrosis
improved and score of liver ultrasound [17]. Danshen decreased the hypoxanthine
imaging was lower in SalB group. IFN‐gamma and MDA (malondialdehyde) levels in the liver
showed certain side effects (fever and tissue [18]. Danshen appears a marked
transient decrease of leukocytes, occurrence hepatoprotective effect and with few side‐
rates were 50 % and 3.23 %), but SalB effects. Based on the traditional medical
showed no side effects [14]. From these theory, hepatoprotective function of Danshen
study, we known that SalB is one of the as above could be interpreted due to its
effective component for inhibition the fibril effect at improving blood circulation and
formation and has no side‐effect. promoting regeneration of liver cells.

Other single component widely used in Astragali Radix (Root Astragali; Huang Qi)
China : Amygdalin，Schisandra spenanthera， (黃芪): Astragali Radix is the dried root of
Cucurbitacin B, Oleanolic acid etc, have been Astragalus membranaceus (Fisch.) Bunge (膜莢
proved to have the active effect on anti‐ 黃芪) and Astragalus mongholicus Bunge
fibrosis. (Fabaceae)（蒙古黃芪）; family Leguminosae(豆
科). It is mainly produced in inner Mongolia,
Single description of traditional Chinese Shanxi, Gansu and Heilongjiang provinces of
medicine China [19]. Primarily, the active constituents
of Astragali Radix consist of polysaccharides
Danshen（Salvia Miltiorrhizae Radix）(丹蔘): and flavonoids [20]. Astragalus membranaceus
Danshen is the root of Salvia miltiorrhiza. (AM) has been widely used for treating liver
Danshen has been used infrequently in ancient diseases in traditional Chinese medicine. The
Chinese medicine. Yet it has become an effect of AM of on hepatocarcinogenesis
important herb in modern Chinese clinical induced by diethylnitrosamine(DEN), two‐thirds
practice. Danshen inhibited ET‐1‐induced partial hepatectomy, and 2‐acetylaminofluorene
depletion of intracellular calcium, which had (2‐AAF) (DEN‐PH‐AAF) was evaluated using
no correlations with the influx of extracellular glutathione S‐transferase placenta form (GST‐
calcium. Danshen also inhibited KCl‐induced P) as marker. The formation of GST‐P‐
influx of calcium, indicating its characteristic positive foci and the expression of GST‐P
of blocking voltage‐operated Ca2+ channel protein and mRNA caused by DEN‐PH‐AAF
[15]. In another study, Danshen decreased were reduced in the treatment groups, which
[Ca2+] in activated HSCs, which may be one clearly suggests that AM is effective in
of important ways to block liver fibrosis [16]. delaying DEN‐PH‐AAF‐induced
174 大田大學校 韓醫學硏究所 論文集 第15卷 第2號

hepatocarcinogenesis [21]. Astragalus collagenous and reticular fibers as well as in

injection on CCl4―ethanol―induced hepatic repairing the structure of hepatic tissues [26].
fibrosis remarkably decreased serurn HA and Taoren is one of the safe and effective
LN levels (P<0．05) and liver MDA level (P traditional medicine for inhibition the liver
<0．01)，but increased the activity of liver fibrosis.
SOD (P<0．01)． Astragalus injection also
decreased fibrosis formation and expression Cordyceps Sinensis (Dongchongxiacao) (冬蟲
of LN． The mechanism is possibly associated 夏草): Cordyceps Sinensis is a well‐known
with the action of antioxidant and the plant that has been used in traditional Chinese
expression of decreasing LN [22]. The medicine to restore energy, promote
change of fibrogenesis serum markers before longevity, stimulate the immune system, and
and after astragalus injection in patients with to improve quality of life. Ancient records
chronic hepatitis, in astragalus injection claim that it is beneficial for the heart,
patients, TGF—β1, HA is high in serum circulatory system, liver, kidneys, respiratory
compared with the control group. Astragalus system, and sex organs in TCM. An
injection have the effect of decrease the interesting study was done in China, where 70
fibrogenesis serum markers on the patients of patients with chronic hepatitis B and post
chronic hepatitis [23]. hepatic cirrhosis were treated either with
Cordyceps or with another herbal combination
Semen Persicae (Taoren) (桃仁): Taoren is of proven effectiveness against liver disease,
the seed of Prunus davidiana Subovoid, whose main ingredient was the medicinal
smaller but thicker, about 0.9 cm long, 0.7 cm Mushroom Ganoderma applanatum. A
wide and 0.5 cm thick. TaoRen extract can significant clinical response was seen in 68%
significantly counteract hepatic fibrosis caused of the Cordyceps patients and in 57% of the
by CCl4 by promoting the dissolution of Ganoderma patients. Result shows Cordyceps
collagen as well as of fibronectin. Taoren can is a bit better at treating this type of liver
significantly reduce the formation of fibrous disease than is the Ganoderma applanatum,
septa composed of collagenous fibers and which is a type of Reishi [27]. Another study
reticular fibers, thus stimulating the recovery on the effects of cordyceps sinensis and its
of hepatic tissues [24]. Taoren has mechanism in liver fibrosis, colchicine was
suppressive effects on fibroblast growth in in‐ used as control therapy. They were both able
vitro cell cultivation. Furthermore, it can to markedly reduce serum PC III level, and
suppress the proliferation of inflammatory reduce I, III, IV collagen deposition in liver
cells and fibroblast hyperplasia in subjects of tissue, and then prevent the formation of
experimental trabeculae dissection [25]. pseudo‐lobule and cirrhosis. Both Cordyceps
Taoren acted on hepatic fibrosis induced by sinensis and colchicine had satisfactory effect
CCl4, through promoting the degradation of on hepatic fibrosis. They can inhibit
collagens type I, II, IV, VI and fibronectin. proliferation and transition of hepatic fat‐
Taoren has proved helpful in markedly storing cells (desmin‐positive cells), so as to
reducing the fibrous septa composed of both reduce collagen synthesis and deposition in
 간경화 치료에 대한 중국 한의학의 연구 개요 175

liver. Cordyceps sinensis is a useful anti‐ were given by FFBJRGP as high，moderate,

fibrotic drug in chronic liver diseases also has and low dosage respectively. The results
no side‐effect whereas colchicine always has showed the reduction in TIMP‐1 and TIMP‐2，
some side‐effect [28]. obviously up‐regulated expression of MMPs in
protein and mRNA levels, and suppression of
Other single description widely used in SC and TGF‐alpha expression comparing to
China: Traditional Chinese herbs activating control group. ECM degradation was generally
blood circulation to dissipate blood stasis such parallel to the changes in MMPs [30]. For
as Angelica sinensis (DangGui 當歸), clinical evaluation of the chronic hepatitis B
Ligusticum chuanxiong (川芎), Red Peony Root with liver fibrosis, the parameters of fibrosis
（ChiShao赤勺藥), Safflower（HongHua 紅花), level such as hyaluronic acid（HA），laminin
Rhizoma Sparganii （SanLeng 三棱) and （LN），collagen IV were observed.
Curcuma phaeocaulis Valeton (EZHU 莪朮) , 96patients with abnormal parameters of
have the effect of anti‐fibrosis. Also, fibrosis level were randomly divided into two
according to a theory of Liver‐discharging and groups. 48patients were treated by FFBJRGP
Qi‐regulating formulae (疎肝理氣), Bupleurum and the control group treated by
chinense DC. (ChaiHu柴胡), Glycyrrhiza Fufandanshengpian. The parameters of fibrosis
uralensis Fisch (GanCao甘草), Poria cocos level such as HA，LN，IV‐C were greatly
（Schw.）(FuLing茯苓) and Magnolia officinalis improved in treatment group（P<0.01），and
Rehd. et Wils (HouPu厚樸) have effects for liver function was improved in treatment
liver fibrosis，as well widely used in China. group（P<0.05）[31]. The results suggested
that FFBJRGP might affect several key steps
in the process of hepatic fibrosis and possess
Multiple compound of traditional Chinese multi‐drug effects for treatment of liver
medicine fibrosis.

FuFangBieJiaRuanGanPian (復方鱉甲軟肝片) Fuzhenghuayufang (扶正化瘀方):

(FFBJRGP): FuFangBieJiaRuanGanPian is a Fuzhenghuayu decoction, also called as 319
multiple description developed by BeiJing302 decoction, is composed of Radix salviae
Hospital according to the traditional Chinsee miltiorrhizae, Cordyceps sinensis, Semen
theory and a long‐term clinical and persicae, etc. From the study to investigate
experimental experience. It is composed of the effect of Fuzhenghuayu decoction (solution
Carapax Trionycis (Biejia)、Paeonia veitchii of herb extract concentration of 0.04g/ml) on
Lynch (ChiShao), Cordyceps Sinensis autocrine activation of hepatic stellate cell
(Dongchongxiacao)、Radix Isatidis (HSC), the drug‐serum inhibited VEGF
(BanLanGen) and otherwise traditional Chinese secretion from activated HSC and activation of
medicine [29]. To study the effect of the HSC. Fuzhenghuayu decoction acts effectively
FFBJRGP in an experimental model of hepatic against the autocrine activation pathway of
fibrosis and its pharmacodynamics, hepatic HSC. The mechanism may be associated with
fibrosis induced by carbon tetrachloride in rat the inhibition of the secretion of VEGF by
176 大田大學校 韓醫學硏究所 論文集 第15卷 第2號

activated HSC [32]. In experimental study, TaoHongSiWuTang 桃紅四物湯 (TaoRen桃仁,

Fuzhenghuayufang could inhibit tumor growth HongHua紅花, DangGui當歸, ChuanXiong川芎,
in vivo, and resist hepatic fibrosis and striking ShengDi 生地黃, BaiShao白芍藥); Qi‐shu‐ke‐li (氣
increase of TGF‐βⅡR expression [33]. 舒顆粒) (Guang An Men Hospital, BeiJing,China
Academy of Chinese Medical Sciences,
Fufangdanshen (861chongji): Compound 861 developed the compound “Qi‐shu‐ke‐li”, have a
is made of total 10 herbs including clinical treatment history about 20 years).
HuangQi(Root Astragali), DanShen(Salviae Above these compound of traditional Chinese
Miltiorrhizae）, JiXueTeng(Caulis Spatholobi) medicine widely used in therapy of liver
and Salvia miltiorrhiza as its chief component. fibrosis and proved an clinical efficacy in
Compound 861 has been shown experimentally China.
to be effective in suppressing fibrogenesis,
enhancing collagen degradation, and inhibiting
TIMP expression. The antifibrotic mechanism Discussion and conclusion
due to decreases the mRNA level of MMP‐2,
but transiently increases the enzymatic Liver fibrosis, the common and basic
activities of MMP‐2. Compound 861 may be pathological change of all kinds of chronic
mediated by decreasing TIMPs, the inhibitors hepatic disease, is the early stage of hepatic
of MMPs, during resolution stage of fibrosis. cirrhosis. The fibrogenic process is dynamic,
This is probably one of the mechanisms and is a serious but reversible consequence.
where by herbal Cpd 861 exerted its China and Korea has a high incidence of
antifibrotic action in this experiment [34]. hepatic injury and fibrosis, but current
The compound 861 showed the therapeutic therapeutic options remain inadequate. Untill
effect on cell proliferation in human hepatic now, specific, effective, safe and cheap
stellate cells (LX‐2) and human hepatocellular antifibrotic therapies are yet lacking, so to
liver carcinoma cells(HepG2), and expression develop the effective therapies is most urgent.
of alpha‐smooth muscle actin(alpha‐SMA) in LX In near future, targeting of stellate cells, gene
‐2 cells. Since hepatic cell proliferation and therapy, cytokine antagonist, and fibrogenic
high level of alpha‐SMA are associated with mediators will be a mainstay of antifibrotic
liver fibrosis, Cpd 861 may be a useful therapy. The advantage of TCM therapy due
candidate in treatment of liver disease [35]. to traditional herb medicines have effective
multi‐component, so as to widely action with
Other multiple compound of traditional many targets, and have less side effects.
Chinese medicine: Xuefuzhuyutang 血府逐瘀湯 As shown above examples, oriental medicine
(DangGui當歸, ChuanXiong川芎, ChiShao赤勺藥, in China and Korea has a numerous herb‐
TaoRen桃仁and HongHua紅花, etc.); Minor derived heaptotherapeutic medicines based on
bupleurum decoction (also named long historical practical experience and
XiaoChaiHuTang小柴胡湯: ChaiHu柴胡, countless kinds of medical plants. General
HuangQin黃芩, BanXia半夏, ShengJiang生姜, concept of oriental medical pharmacology has
RenShen人蔘, GanCao甘草, DaZao大棗); suggested that the herbs with activities of
 간경화 치료에 대한 중국 한의학의 연구 개요 177

“activating blood circulation to dissipate blood proliferation, morphology and expression of

stasis, and supporting the healthy energy” TGF‐β1. CHINESE JOURNAL OF NEW DRUGS
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