Oxidative stress plays an important role in hepatocarcinogenesis. Although Sho-saiko-to (TJ-9), a Japanese herbal medicine which has been recently administered to patients with chronic liver disease in Japan, prevents hepatocarcinogenesis, the mechanism by which TJ-9 protects against cancer development is not fully understood. 8-Hydroxy-2-deoxyguanosine (8-OHdG), a DNA adduct by reactive oxygen species, is known as a parameter of genetic risk for hepatocarcinogenesis. To clarify whether the preventive effect on hepatocarcinogenesis by TJ-9 is dependent on 8-OHdG, the effect on 8-OHdG levels by TJ-9 was examined by using high-performance liquid chromatography-mass spectrometry (LC-MS) in a diethylnitrosamine (DEN)-induced hepatocarcinogenesis model of male Fisher rats. TJ-9 reduced the number of preneoplastic cells, detected as the glutathione S transferase P (GST-P)-positive hepatocytes, and inhibited the development of liver tumors. TJ-9 also significantly decreased the formation of 8-OHdG, as indicated by LC-MS and immunohistochemical analysis. In addition, ornithine decarboxylase (ODC) activity and the number of proliferating cell nuclear antigen (PCNA)-positive cells were not altered. An electron paramagnetic resonance spin-trapping technique showed that TJ-9 scavenges hydroxyl radicals in a dose-dependent manner. In conclusion, the results of the present study suggest that TJ-9 prevents hepatocarcinogenesis in association with inhibition of 8-OHdG formation. (HEPATOLOGY 2002;35:
1125-1133.)C hronic infection with hepatitis B and C viruses is the leading cause of hepatocellular carcinoma (HCC), one of the most common cancers in the world. 1 Human hepatocarcinogenesis is a multistep process with the involvement of molecular events accumulating in the cells during the stage of chronic liver disease. The molecular events that occur in cancer arise as a result of genetic changes caused by direct insults to the DNA. 2 Several different types of chemopreventive agents with effective stages of specific treatments have been studied for the management of the disease, and the proper timing of therapeutic intervention may be very important. 3 The Japanese herbal medicine Sho-saiko-to (TJ-9) contains crude extracts of 7 herbs (bupleurum root, pinellia tuber, scutellaria root, jujube fruit, ginseng root, glycyrrhiza root, and ginger rhizome), which is widely administered to patients with chronic liver disease in Japan. 4 TJ-9 is known to protect experimental liver injury caused by D-galactosamine 5 and liver fibrosis by inhibition of lipid peroxide formation in liver cells. 6 In humans, a double-blind, multicenter, clinical trial showed that TJ-9 lowered aspartate aminotransferase, alanine aminotransferase, and ␥-glutamyltransferase in patients with chronic hepatitis. 7 TJ-9 has been also shown to be effective in terms of antitumor activity against HCC development. 8 However, the mechanisms by which TJ-9 and its effective ingredients protect against cancer have not been identified.8-hydroxy-2Ј-deoxyguanosine (8-OHdG)...