title: Protective effect of Juzen-taiho-to on hepatocarcinogenesis is mediated through the inhibition of Kupffer cell-induced oxidative stress.
abstract: Traditional 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.
authors.affiliation: Department of Environmental Sciences and Engineering, School of Public Health, University of North Carolina at Chapel Hill, USA.
authors.forename: Masato
authors.initials: M
authors.lastname: Tsuchiya
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kono
authors.forename: Masanori
authors.initials: M
authors.lastname: Matsuda
authors.forename: Hideki
authors.initials: H
authors.lastname: Fujii
authors.forename: Ivan
authors.initials: I
authors.lastname: Rusyn
mesh_terms: D000368:Aged; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control* / Q000601:surgery; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D019610:Cytoprotection / Q000187:drug effects; D004048:Diethylamines / Q000494:pharmacology; D004195:Disease Models, Animal; D018572:Disease-Free Survival; D004365:Drugs, Chinese Herbal / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007728:Kupffer Cells / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D051379:Mice; D009364:Neoplasm Recurrence, Local / Q000473:pathology / Q000517:prevention & control; D018384:Oxidative Stress / Q000187:drug effects*
chemical_list: D004048:Diethylamines; D004365:Drugs, Chinese Herbal; C063587:juzentaihoto; C031406:N-nitrodiethylamine
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