title: Cytotoxic effects of benzbromarone and its 1'-hydroxy metabolite in human hepatocarcinoma FLC4 cells cultured on micro-space cell culture plates.
abstract: Treatment with benzbromarone (BBR), a potent uricosuric drug, can be associated with liver injury. Recently, we reported that culture of human hepatocellular carcinoma FLC-4 cells on micro-space cell culture plates could increase the functional expression of drug-metabolizing enzymes including CYP3A4 and CYP2C9, which are involved in 1'-hydroxylation and 6-hydroxylation of BBR, respectively. Therefore, we examined whether BBR and its two metabolites (1'-hydroxy BBR and 6-hydroxy BBR) have cytotoxic effects in FLC4 cells cultured on micro-space cell culture plates. The present study showed that BBR and 1'-hydroxy BBR, but not 6-hydroxy BBR, have cytotoxic effects in cells cultured on micro-space cell culture plates. BBR-induced cytotoxicity was decreased by CYP3A inhibitors (itraconazole and ketoconazole), an Nrf2 activator (tert-butylhydroquinone) and a GSH precursor (N-acetyl-L-cystein). In contrast, BBR-induced cytotoxicity was increased by a GSH biosynthesis inhibitor (buthionine sulfoximine) and an inhibitor of NAD(P)H quinone oxidoreductase 1 (dicoumarol). These results suggested that metabolic activation of 1'-hydroxy BBR via CYP3A, formation of quinone metabolites and the decrease in GSH levels were involved in the BBR-induced cytotoxicity observed in FLC4 cells cultured on micro-space cell culture plates.
authors.affiliation: Laboratory of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan. kaoruk@faculty.chiba-u.jp
authors.forename: Kaoru
authors.initials: K
authors.lastname: Kobayashi
authors.forename: Eri
authors.initials: E
authors.lastname: Kajiwara
authors.forename: Masayuki
authors.initials: M
authors.lastname: Ishikawa
authors.forename: Hanaka
authors.initials: H
authors.lastname: Mimura
authors.forename: Hidenobu
authors.initials: H
authors.lastname: Oka
authors.forename: Yoko
authors.initials: Y
authors.lastname: Ejiri
authors.forename: Masaya
authors.initials: M
authors.lastname: Hosoda
authors.forename: Kan
authors.initials: K
authors.lastname: Chiba
mesh_terms: D001553:Benzbromarone / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000378:metabolism; D003603:Cytotoxins / Q000494:pharmacology*; D006801:Humans; D006900:Hydroxylation; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism
chemical_list: D003603:Cytotoxins; C085922:1'-hydroxybenzbromarone; D001553:Benzbromarone