title: Aryl hydrocarbon receptor-mediated induction of microsomal drug-metabolizing enzyme activity by indirubin and indigo.
abstract: Indirubin and indigo, which are thought to be natural ligands for aryl hydrocarbon receptor (AhR), showed marked AhR ligand activities in a reporter gene assay using recombinant yeast. Their activities were comparable with or more potent than that of 2,3,7,8-tetrachlorodibenzo-p-dioxin. When indirubin and indigo were administered to mice, ethoxyresorufin-O-dealkylase and methoxyresorufin-O-dealkylase activities in the liver were increased, but subsequently decreased within 2 days. Indirubin was more potent than indigo. Levels of cytochrome P450 1A1/2 proteins and mRNAs in the liver of mice dosed with indirubin were also enhanced. These enhancing effects of indirubin and indigo were not observed in AhR knock-out mice. Ethoxyresorufin-O-dealkylase and methoxyresorufin-O-dealkylase activities in rat hepatocytes and HepG2 cells were enhanced by the addition of indirubin or indigo, but less potently than by 2,3,7,8-tetrachlorodibenzo-p-dioxin. Indigocarmine, a sulfate derivative of indigo, which is used as food additive, did not show these inducing effects on drug-metabolizing enzymes. Our results suggest that indirubin and indigo act as inducers for cytochrome P450 1A1/2 mediated by AhR in mammals in vivo.
authors.affiliation: Graduate School of Biomedical Sciences, Hiroshima University, Japan.
authors.forename: Kazumi
authors.initials: K
authors.lastname: Sugihara
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Kitamura
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Yamada
authors.forename: Takashige
authors.initials: T
authors.lastname: Okayama
authors.forename: Shigeru
authors.initials: S
authors.lastname: Ohta
authors.forename: Keisuke
authors.initials: K
authors.lastname: Yamashita
authors.forename: Mineo
authors.initials: M
authors.lastname: Yasuda
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Fujii-Kuriyama
authors.forename: Ken'ich
authors.initials: K
authors.lastname: Saeki
authors.forename: Saburo
authors.initials: S
authors.lastname: Matsui
authors.forename: Tomonari
authors.initials: T
authors.lastname: Matsuda
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis / Q000235:genetics; D019388:Cytochrome P-450 CYP1A2 / Q000096:biosynthesis / Q000235:genetics; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D007203:Indigo Carmine; D007211:Indoles / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000378:metabolism*; D015003:Yeasts / Q000235:genetics / Q000378:metabolism
chemical_list: D007211:Indoles; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D003577:Cytochrome P-450 Enzyme System; D007203:Indigo Carmine; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; C027185:indirubin