Introduction

The Chinese herbal medicine Sho-saiko-to, a mixture of seven herbal preparations, is an officially approved prescription drug in Japan and is widely administered in Japan to patients with chronic hepatitis C virus (HCV) infection. The most common cause of hepatic fibrosis is chronic HCV infection, the characteristic feature of which is hepatic steatosis. Hepatic steatosis leads to an increase in lipid peroxidation in hepatocytes, which in turn leads to the activation of hepatic stellate cells (HSCs). HSCs are also thought to be the primary target cells of inflammatory stimuli, and produce collagen. Tests indicate that Sho-saiko-to improves liver function, and a prospective study reported a reduced incidence of hepatocellular carcinoma in patients with HCV-related cirrhosis. However, little information is available concerning the mechanism by which Sho-saiko-to protects against hepatic fibrosis and carcinoma. Several laboratories, including ours, have demonstrated the preventive and therapeutic effects of Sho-saiko-to on experimental hepatic fibrosis, as well as its inhibitory effect on the activation of HSCs. We provided evidence that Sho-saiko-to functions as a potent fibrosuppressant via the inhibition of oxidative stress in hepatocytes and

HSCs, and that its active components are baicalin and baicalein. In addition, Sho-saiko-to has anticarcinogenic properties in that it inhibits chemical hepatocarcinogenesis in animals, inhibits the proliferation of hepatoma cells by inducing apoptosis, and arrests the cell cycle. Among the active components ofSho-saiko-to, baicalin, baicalein, and saikosaponin-a have the ability to inhibit cell proliferation. It should be noted that baicalin and baicalein are flavonoids, the chemical structures of which are very similar to those of silybinin and quercetin, which show antifibrogenic activities. This may provide valuable information on the search for novel antifibrogenic agents.

Herbal medicines have been used in China for thousands of years. Their principles are based on clinical experience and practice, but the effective ingredients in most of these medications have not been identified. Chinese herbal medicines have now attracted the attention of practitioners of Western medicine, and are being manufactured in Japan in uniform quality and in sufficient quantities for use as drugs for hospital use. Among these, the herbal medicine Sho-saiko-to, or Xiao-Chai-Hu-Tang (Chinese name), which has been used in the treatment of pyretic diseases in China, is an officially approved prescription drug in Japan. Sho-saiko-to is the most commonly administered drug in Japan to outpatients with chronic liver diseases, especially those with chronic HCV infection, chronic hepatitis C (1,2), and cirrhosis (3). HCV infections are widespread throughout the world, and are recognized as a major causative factor in chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC) (4 5). In fact, the World Health Organization reported that up to 3% of the world's population is infected with HCV, suggesting that more than 170 million chronic carriers are currently at risk for developing cirrhosis and HCC (6).

The usual daily dose of Sho-saiko-to is 7.5 g, administered orally in three equal doses. Seven and one-half grams of Sho-saiko-to contains 4.5 g of dried Sho-saiko-to extract, which is prepared from boiled water extracts of seven herbs: 7.0 g of Bupleurum root, 5.0 g of Pinellia tuber, 3.0 g of Scutellaria root, 3.0 g of jujube fruit, 3.0 g of ginseng root, 2.0 g of glycyrrhiza root, and 1.0 g of ginger rhizome (Table 1). For the putative major active ingredients, the approximate concentrations of the components in 50 mg/mL of the ethanol extract of Sho-saiko-to have been determined to be baicalin: 1.75 mg/mL (3.5%), glycyrrhizin: 500 Ag/mL (1%), baicalein: 150 Ag/mL (0.3%), each of saikosaponin-a, -c, and -d, and ginsenoside Rb1 and ginsenoside Rg1: 100 Ag/mL (0.2%), wogonin: 20 Ag/mL (0.04%), and viscidulin III: less than 50 Ag/mL (<0.1%) (Table 1) (7).

Sho-saiko-to has been shown to improve liver function (1,2), as well as to alleviate the subjective symptoms associated with chronic liver diseases, such as digestive discomfort. In a double-blind, multicenter clinical trial, Sho-saiko-to was shown to lower the serum levels of aspartate aminotransferase

TABLE 1 Main Active Ingredients of 7.5 g Sho-saiko-to

Herbal

Amount

Main active

Approximate

components

(g)

ingredients

concentration (%)

Bupleurum root

7.0

Saikosaponin-a

0.2

Saikosaponin-b1, -b2

Saikosaponi-c

0.2

Saikosaponi-d

0.2

Pinellia tuber

5.0

Ephedrine

Scutellaria root

3.0

Baicalin

3.5

Baicalein

0.3

Wogonin

0.04

Viscidulin III

<0.1

Jujube fruit

3.0

Cyclic AMP

Ginseng root

3.0

Ginsenoside Rb1

0.2

Ginsenosid g1

0.2

Glycyrrhiza root

2.0

Glycyrrhizin

1

Liquiritin

Ginger rhizome

1.0

6-Gingerol

6-Shogaol

Zingerone

(AST), alanine aminotransferase (ALT), and gamma-glutamyl transpeptidase (gamma-GTP) (1), in patients with chronic hepatitis. As shown in Figure 1, in addition to serum ALT levels, serum concentrations of hepatic fibro-genesis markers of the 7S domain of type IV collagen (7S-IV) and the amino terminal propeptide of type III procollagen (P-III-P) were significantly attenuated by Sho-saiko-to in chronic hepatitis C patients with fibrosis of Stages 0-3. Hepatic fibrosis, or the deposition of extracellular matrix (ECM), is classified on a scale of 0-4: 0, no fibrosis; 1, portal fibrosis without septa; 2, few septa; 3, numerous septa without cirrhosis; 4, cirrhosis. Hepatic fibrosis is often associated with inflammation and cell death, which accompanies the repair processes, and is a consequence of severe liver damage that occurs in many patients with chronic liver diseases, including chronic HCV infection. The main origin of the abnormal ECM proteins is a cell known as the hepatic stellate cell (HSC) (also known as the fat-storing cell, lipocyte, or the Ito cell). HSCs are located in the space of Disse in close contact with hepatocytes and sinusoidal endothelial cells. Their three-dimensional structure consists of the cell body and several long and branching cytoplasmic processes (8). It is now evident that HSCs undergo proliferation and transformation under inflammatory stimuli into a-smooth muscle actin (alpha-SMA)-positive myofibro-blast-like cells, which are referred to as activated cells, and serve as the origin

Figure 1 Changes in individual percentages of the initial values for serum levels of ALT and hepatofibrogenesis markers of 7S domain of type IV collagen (7S-IV) and amino-terminal propeptide of type II procollagen (P-III-P) after administration of Sho-saiko-to to chronic hepatitis C patients with fibrosis of stages 0-1 (O, n = 10), 2 (A, n = 8), and 3, (•, n = 8). Values are expressed as mean percentages (± SD) of each initial value before treatment. *p < 0.05.

Figure 1 Changes in individual percentages of the initial values for serum levels of ALT and hepatofibrogenesis markers of 7S domain of type IV collagen (7S-IV) and amino-terminal propeptide of type II procollagen (P-III-P) after administration of Sho-saiko-to to chronic hepatitis C patients with fibrosis of stages 0-1 (O, n = 10), 2 (A, n = 8), and 3, (•, n = 8). Values are expressed as mean percentages (± SD) of each initial value before treatment. *p < 0.05.

of much of the collagen hypersecretion and nodule formation that occurs during hepatic fibrosis and cirrhosis (9,10).

Furthermore, in a prospective study, Sho-saiko-to inhibited the development of HCC in patients with cirrhosis (3). Although Sho-saiko-to is widely used in the treatment of chronic hepatitis C and cirrhosis, little is known about the mechanism by which it protects against hepatic fibrosis and carcinoma. This chapter summarizes our current knowledge of the biological functions of Sho-saiko-to as it relates to fibrogenesis and carcinogenesis in the liver.

Herbal Healing For Everyone

Herbal Healing For Everyone

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