Progress in studies of tetrandrine against hepatofibrosis

Abstract

Subject headings liver cirrhosis/therapy; liver cirrhosis/pathology; liver cirrhosis, expremental/therapy; tetrandrine/therapeutic use Tetrandrine (Tet) is the main alkaloid isolated from the lumpy root of Stephania tetrandra s. Moore. Its molecular formula is C 33 H 42 N 2 O 6 and its chemical structure belongs to a dibenzy-isoquindine. Modern pharmacological studies have proved that Tet is a Ca 2+ antagonist, which acts mainly on the calcium channel of cell to block the cross-membrane transportation of calcium ions as well as their intracellular distribution and utilization. In recent years, the actions of Tet in preventing and treating hepatofibrosis have gradually attracted attention of more investigators. With the establishment of the technique of liver cell isolation and culture and advance in technology of molecular biology, studies of the antihepafibrotic effects of Tet have probed into the cellular, subcellular and molecular levels. This article is to give a brief review of such researches over the past few years. EFFECT OF TETRANDRINE ON EXPERIMENTAL HEPATOFIBROSIS IN RATSThe effects of Tet on CC l4 induced rat hepatofibrosis model showed that the serum contents of hyaluronic acid (HA) and serum ALT activities among the Tet treated groups in different stages were all lower than those in the untreated control model (P < 0.01). At the end of the 3rd week, the degrees of liver cell degeneration and necroses and inflammatory cell unvasion in the treated group were all lower than those of the control model. At the end of the 12th week, the control model rats showed an increase in fibroblast proliferation to grade 2.8 with pseudolobule formation on HE and VG staining; however in the corresponding treatment group, the lobular structure was still fairly well preserved, although there were some proliferation of fibroblasts and increase in collagen. These indicate that Tet may improve liver function, reduce liver damage and inhibit the extracellular matrix ( ECM ) formation [1] . Tet could suppress the proliferation and transformation of fat storing cells (FSC or Ito cells), reduce the deposition of type IV collagen and remarkably decrease the number of FSCs in rat with hepatofibrosis, as compared with the saline treated controls (P < 0.01). Moreover, the area of rough endoplasmic neticulum of FSCs in the treated group was less than that of the control group (P < 0.05) [2,3] . In rats with liver cirrhosis and portal hypertension, Tet could reduce liver cell damage and fibroses, and lower the serum ALT, alkaline phosphatase (ALP) and total bilirubin (STB) to normal [4] . Tet could also lower the portal pressure and systemic arterial pressure in portal hypertensive rats [5] . In comparison with the traditional antifibrotic drug colohicine, Tet had more or less similar effects in reducing serum procollagen III peptide (P III P), HA and intrahepatic inflammation and had better effect than colohicine and less toxic side-effects [6] in suppression of proliferation and transformation of FSCs as well as the degree of c...

Tetrandrine inhibits activation of rat hepatic stellate cells stimulated by transforming growth factor-β in vitro via up-regulation of Smad 7

“…Tetrandrine also possess a potently protective effect against liver fibrosis (Li et al, 1998). It has been known to have anti-fibrogenic action on the liver, such as inhibition of inflammatory reaction of an injured liver, attenuation of ECM deposition, decrement in serum collagen levels, and inhibition of proliferation and collagen synthesis induced by the platelet-derived growth factor in fibroblasts or HSCs (Li et al, 1998). More recently, Park et al (2000) revealed that ␣-SMA, the marker of activated HSCs, was significantly reduced in primary-cultured HSCs treated with tetrandrine, but only a relatively high dosage of tetrandrine of up to 5 mg/L was examined and they failed to show how tetrandrine worked.…”

“…PCR reactions were analyzed in a 2% agarose gel with a 100 bp marker ( cardiac and vascular remodeling, inhibition of pulmonary vessel and airway smooth muscle contraction, suppression of tumor cell proliferation and multi-drug resistance, and so on (Lai, 2002;Rao, 2002;Xie et al, 2003;Wang et al, 2004). Tetrandrine also possess a potently protective effect against liver fibrosis (Li et al, 1998). It has been known to have anti-fibrogenic action on the liver, such as inhibition of inflammatory reaction of an injured liver, attenuation of ECM deposition, decrement in serum collagen levels, and inhibition of proliferation and collagen synthesis induced by the platelet-derived growth factor in fibroblasts or HSCs (Li et al, 1998).…”

“…Tetrandrine, a bisbenzylisoquinoline alkaloid isolated from the root of Stephania tetrandra, is the major pharmacologically active component of Stephania tetrandra. It has been shown to possess a potently protective effect against the development of liver fibrosis (Li et al, 1998). Recently, Park et al (2000) revealed that tetrandrine at least partially exerted its anti-hepatofibrogenic effects by a direct inhibiting effect on HSCs, but only a single dosage up to 5 mg/L has been evaluated.…”

Influence of BOL on hyaluronic acid, laminin and hyperplasia in hepatofibrotic rats

“…Recently, studies on the prevention and treatment of liver fibrosis are very popular in China. Besides western medicine [7][8][9][10][11] , single Chinese drug and its effective ingredients [12][13][14][15][16][17][18][19] , anti-hepatofibrotic effect of Chinese complex formula [20][21][22][23][24][25][26][27] are also the main project in researches. These studies illustrate the mechanism and clinical effectiviness [28][29][30][31][32] in anti-hepatofibrosis from different point of view.…”

“…RESULTS: HA was reduced in both the groups with low and high dosage of BOL, which showed a remarkable difference as compared with that of the model group ( low dosage group: 376. 15 Examined by Ridit, BOL could reduce the degeneration and necrosis of liver cells (χ χ χ χ χ 2 = 11. 99 P<0.05), the degree of fibre hyperplasia (χ χ χ χ χ 2 = 13.24 P<0.05) and the pathological change of ultra micro-structure as well.…”