Hepatology Research 33 (2005) 174–177

Hepatoprotective bile acid ‘ursodeoxycholic acid (UDCA)’

Property and difference as bile acids
Kaoru Ishizaki ∗ , Teruaki Imada, Makoto Tsurufuji
Research Laboratory IV, Pharmaceutical Research Division, Mitsubishi Pharma Corporation,
1000, Kamoshida-cho, Aoba-ku, Yokohama, Kanagawa 227-0033, Japan

Available online 6 October 2005

Abstract

Ursodeoxycholic acid (UDCA) is a bile acid, which is present in human bile at a low concentration of only 3% of total bile acids. It is
a 7␤-hydroxy epimer of the primary bile acid chenodeoxycholic acid (CDCA). UDCA is isolated from the Chinese drug ‘Yutan’ a powder
preparation derived from the dried bile of adult bears. For centuries, Yutan has been used in the treatment of hepatobiliary disorders. In
Japan, it has also been in widespread use as a folk medicine from the mid-Edo period. In Japan, not only basic studies such as isolation,
crystallization, definition of the chemical structure and establishment of the synthesis of UDCA have been conducted but clinical studies have
been conducted. First reports on the effects of UDCA in patients with liver diseases came from Japan as early as 1961. In the 1970s, the first
prospective study of patients with gallbladder stones treated with UDCA demonstrating gallstone dissolution was reported. In late 1980s, a
number of controlled trials on the use of UDCA in primary biliary cirrhosis (PBC) were reported. Since then, a variety of clinical studies have
shown the beneficial effect of UDCA in liver disease worldwide. To date, UDCA is utilized for the treatment of PBC for which it is the only
drug approved by the U.S. Food and Drug Administration (FDA).
In recent years, with the advent of molecular tools, the mechanisms of action of bile acids and UDCA have been investigated, and various
bioactivities and pharmacological effects have been revealed. Based on the results of these studies, the bioactive substances in bile acids that
are involved in digestive absorption may play important roles in signal transduction pathways. Furthermore, the mechanisms of action of
UDCA is evidently involved.
We reveal the physicochemical properties of UDCA as bile acid and overview the established pharmacological effects of UDCA from its
metabolism. Furthermore, we overview the current investigations into the mechanism of action of UDCA in liver disease.
© 2005 Elsevier Ireland Ltd. All rights reserved.

Keywords: Ursodeoxycholic acid (UDCA); Bile acids; Hepatoprotection

1. Introduction 2. Physicochemical properties of bile acids

Ursodeoxycholic acid (UDCA) is a bile acid, which is
present in human bile as a low concentration of only 3%
of total bile acids. A variety of clinical studies have shown
the beneficial effect of UDCA in liver disease worldwide.
We reveal the physicochemical properties of UDCA as bile
acid and overview the established pharmacological effects of
UDCA from its metabolism.
∗ Corresponding author. Tel.: +81 45 963 4737; fax: +81 45 963 4641.
E-mail address: Ishizaki.Kaoru@mh.m-pharma.co.jp (K. Ishizaki).
2.1. Biosynthetic pathways and species of bile acids
In humans, two primary bile acids (cholic acid, CA and
chenodeoxycholic acid, CDCA) are synthesized from choles-
terol in hepatocytes. After biosynthesis, these two primary
bile acids are conjugated with either glycine or taurine and
excreted into the intestine with bile. Some of them are con-
verted to the secondary bile acids by enterobacteria. That is,
CA is converted to deoxycholic acid (DCA). CDCA is con-
verted to lithocholic acid (LCA) and UDCA. In biliary bile
acid composition, the major bile acid is CA, CDCA and there
is a small portion of UDCA.

1386-6346/$ – see front matter © 2005 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.hepres.2005.09.029
 K. Ishizaki et al. / Hepatology Research 33 (2005) 174–177 175

2.2. Enterohepatic circulation of bile acids

One property of bile acids is enterohepatic circulation.

That is, in liver, amidated bile acids are secreted through the
biliary tract to the duodenum. In the intestine, bile acids help
the digestion and absorption of lipid and are mainly actively
absorbed from ileum transporter. They return to the liver via
the portal vein. In the colon, some bile acids are deconjugated
and dehydroxylated by enterobacteria and reabsorbed. So,
they rarely exist in the systemic circulation.

2.3. Formation of micelle of bile acids

Bile acids are surface-active, amphipatic agents. One side

has hydroxyl groups and a carboxyl group, which is its
hydrophilic face and the opposite side is its hydrophobic face.
As a result of this property, they can form micelles with lipid,
so they are indispensable in the digestion and absorption of
fat and fat-soluble vitamins.
2.4. Hydrophilic–hydrophobic balance of bile acids
Individual bile acids differ in hydrophobicity [1]. LCAs
are the most hydrophobic among the human major bile acids.
In contrast, UDCAs are the most hydrophilic. In general,
unconjugated bile acids are more hydrophobic and conju-
gated bile acids are more hydrophilic.
2.5. Comparison of the cytotoxicity of bile acids
Bile acids have detergent effect, so we compared the cyto-
toxicity of bile acids in primary rat hepatocytes. Cytotoxic
index was released GPT activity. UDCA was less cytotoxic
than the other unconjugated bile acids. In general, conjugated
bile acids were less cytotoxic than unconjugates. In particu-
lar, high concentration of TUDCA did not increase the GPT
activity above a certain level in this study (Fig. 1).
2.6. Cytotoxicity of bile acids
Hepatocytes have repeated the cycle of being killed by
apoptosis and regenerated. It is reported that hydrophobic
Fig. 1. Comparison of the cytotoxicity of bile acids.
bile acids have an apoptotic effect [2]. In the healthy liver,
the balance between the dead cells and regenerated cells is
maintained, so GPT does not leak out above a certain level.
On the other hand, in the diseased liver, such a balance col-
lapses by involvement of inflammation, etc., and regeneration
of cells does not fulfill demand. So, the number of dead cells
is more than that of regenerated cells. And, the liver dys-
function is considered to progress. Additionally, in disease,
especially cholestasis, bile acids increase in hepatocytes. Bile
acids, especially, hydrophobic bile acids, are considered to
damage the plasma membrane, induce the mitochondrial dys-
function or increase the cell apoptosis and worsen the liver
dysfunction.
3. Pharmacological effects of UDCA
3.1. Hepatoprotective effect of UDCA
We investigated the effect of TUDCA on TCDCA-induced
GPT release in primary rat hepatocytes. Consequently,
it became clear that TUDCA dose-dependently protected
TCDCA-induced GPT release in hepatocytes (Fig. 2). So,
it is clear that TUDCA has hepatoprotective effect in vitro.

Fig. 2. Effect of TUDCA on TCDCA-induced GPT release in primary rat hepatocytes.

176 K. Ishizaki et al. / Hepatology Research 33 (2005) 174–177

Fig. 3. Clinical efficacy of UDCA for PBC (phase III trial).

3.2. Clinical efficacy of UDCA for PBC 3.3. Other mechanisms of action of UDCA

Based on these studies, we considered the clinical
efficacy of UDCA. It is PBC that bile acids increase in
the liver and they are considered to be deeply involved
in liver dysfunction, so we tried to treat UDCA in PBC
patients [3]. Consequently, it became clear that serum ALT
and ALP decreased to about 50% of pretreatment and
the liver dysfunction was improved by UDCA treatment
(Fig. 3).
In this study, we investigated the serum bile acid composi-
tion. The rate of UDCA increased from 7.7 to 58.4%, and the
rates of the other bile acids decreased respectively in UDCA
over 1 year treatment (Fig. 4). It became clear that replace-
ment of hydrophobic bile acids to UDCA led to the efficacy
of this therapy, as expected.
In addition to the above thing, UDCA has the outstand-
ing choleretic effect. In the recent study, various trans-
porters involved in the bile acid transport in hepatocytes have
been identified. The down-regulation of these transporters
in cholestasis liver has been reported. And the expression
of tight junction protein involved in bile acid transport has
been reported to decline, too. On the other hand, the down-
regulation of these protein expressions is reported to recover
in UDCA treatment [4–8]. These effects are considered to
have led to the outstanding choleretic effects of UDCA.
Furthermore, it has become clear that UDCA also has an
antioxidative and antiapoptotic effects, and these multiple
effects are considered to have led to improve liver conditions
[9,10].

Fig. 4. Effect of UDCA on serum bile acid composition in PBC patients (phase III trial).
 K. Ishizaki et al. / Hepatology Research 33 (2005) 174–177
4. Conclusion
In conclusion, UDCA has various mechanisms of action
and these multiple actions are considered to have led to
improve liver conditions.
References
[1] Heuman DM. Quantitative estimation of the hydrophilic–hydropho-
bic balance of mixed bile salt solutions. J Lipid Res 1989;30:719–30.
[2] Rodrigues CMP, Fan G, Ma X, Kren BT, Steer CJ. A novel role for
ursodeoxycholic acid in inhibiting apoptosis by modulating mito-
chondrial membrane perturbation. J Clin Invest 1998;101:2790–
9.
[3] Toda G, Tanaka N, Ikeda Y, et al. The long-term trial of ursodeoxy-
cholic acid treatment in patients with primary biliary cirrhosis. Igaku
to yakugaku 1999;41:609–33.
[4] Shoda J, Kano M, Oda K, et al. The expression levels of plasma
membrane transporters in the cholestatic liver of patients undergoing
177
biliary drainage and their association with the impairment of biliary
secretory function. Am J Gastroenterol 2001;96:3368–78.
[5] Rost D, Herrmann T, Sauer P, et al. Regulation of rat organic
anion transporters in bile salt-induced cholestatic hepatitis: effect
of ursodeoxycholate. Hepatology 2003;38:187–95.
[6] Trauner M, Arrese M, Soroka CJ, et al. The rat canalicular con-
jugate export pump (Mrp2) is down-regulated in intrahepatic and
obstructive cholestasis. Gastroenterology 1997;113:255–64.
[7] Fickert P, Zollner G, Fuchsbichler A, et al. Effects of ursodeoxy-
cholic and cholic acid feeding on hepatocellular transporter expres-
sion in mouse liver. Gastroenterology 2001;121:170–83.
[8] Sakisaka S, Kawaguchi T, Taniguchi E, et al. Alterations in tight
junctions differ between primary biliary cirrhosis and primary scle-
rosing cholangitis. Hepatology 2001;33:1460–8.
[9] Crosignani A, Podda M, Battezzati PM, et al. Changes in bile acid
composition in patients with primary biliary cirrhosis induced by
ursodeoxycholic acid administration. Hepatology 1991;14:1000–7.
[10] Poupon RE, Lindor KD, Cauch-Dudek K, Dickson ER, Poupon R,
Heathcote EJ. Combined analysis of randomized controlled trials of
ursodeoxycholic acid in primary biliary cirrhosis. Gastroenterology
1997;113:884–90.