title: Contribution of reductase activity to quinone toxicity in three kinds of hepatic cells.
abstract: Two mechanisms have been proposed to explain quinone cytotoxicity: oxidative stress via the redox cycle, and the arylation of intracellular nucleophiles. The redox cycle is catalyzed by intracellular reductases, and therefore the toxicity of redox cycling quinone is considered to be closely associated with the reductase activity. This study examined the relationship between quinone toxicity and the intracellular reductase activity using 3 kinds of hepatic cells; rat primary hepatocytes, HepG2 and H4IIE. The intracellular reductase activity was; primary hepatocyte >>HepG2>H4IIE. The three kinds of cells showed almost the same vulnerability to an arylating quinone, 1,4-naphthoquinone (NQ). However, the susceptibility to a redox cycling quinone, 2,3-dimethoxy-1,4-naphthoquinone (DMNQ) was; primary hepatocyte>HepG2>H4IIE. In addition, the cytotoxicity elicited by DMNQ was significantly attenuated in HepG2 cells and almost completely suppressed in primary hepatocytes by diphenyleneiodonium chloride, a reductase inhibitor. These data suggest that cells with a high reductase activity are susceptible to redox cycling quinones. This study provides essential evidence to assess the toxicity of quinone-based drugs during their developmental processes.
authors.affiliation: Graduate School of Integrated Arts and Sciences, Hiroshima University, Higashi-Hiroshima, Japan. ishiyasu@hiroshima-u.ac.jp
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Ishihara
authors.forename: Kaori
authors.initials: K
authors.lastname: Tsuji
authors.forename: Satomi
authors.initials: S
authors.lastname: Ishii
authors.forename: Kyoko
authors.initials: K
authors.lastname: Kashiwagi
authors.forename: Norio
authors.initials: N
authors.lastname: Shimamoto
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects*; D006801:Humans; D008297:Male; D010084:Oxidation-Reduction; D010088:Oxidoreductases / Q000378:metabolism*; D011809:Quinones / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D011809:Quinones; D010088:Oxidoreductases