Protective effect of Juzen‐taiho‐to on hepatocarcinogenesis is mediated through the inhibition of Kupffer cell‐induced oxidative stress

AbstractTraditional herbal formulations, such as Juzen‐taiho‐to (TJ‐48), are used extensively in medical practice in Asia even though their mechanism of action remains elusive. This study tested a hypothesis that TJ‐48 is protective against hepatocarcinogenesis by impeding Kupffer cell‐induced oxidative stress. Forty‐eight patients were randomly assigned to receive TJ‐48 (n = 10), or no supplementation (n = 38) for up to 6 years after surgical treatment for hepatocellular carcinoma (HCC). In addition, to investigate the mechanism of protective action of TJ‐48, diethylnitrosamine‐containing water was administered for 22 weeks to male mice that were fed regular chow or TJ‐48‐containing diet. Liver tumor incidence, cell proliferation, number of 8‐hydroxy‐2′‐deoxyguanosine‐ or F4/80‐positive cells, and cytokine expression were evaluated. Although most of the patients experienced recurrence of HCC, a significantly longer intrahepatic recurrence‐free survival was observed in the TJ‐48 group. In mice, TJ‐48 inhibited the development of liver tumors, reduced oxidative DNA damage, inflammatory cell infiltration and cytokine expression. Administration of TJ‐48 improves intrahepatic recurrence‐free survival after surgical treatment of hepatocellular carcinoma. On the basis of animal experiments, we reason that the protective mechanism of TJ‐48 involves inhibition of Kupffer cells. This leads to lower levels of pro‐inflammatory cytokines and oxidants in liver which may slow down the process of hepatocarcinogenesis and improves hepatic recurrence‐free survival in patients with HCC. © 2008 Wiley‐Liss, Inc.