title: Cystathionine beta-synthase as a carbon monoxide-sensitive regulator of bile excretion.
abstract: Carbon monoxide (CO) is a stress-inducible gas generated by heme oxygenase (HO) eliciting adaptive responses against toxicants; however, mechanisms for its reception remain unknown. Serendipitous observation in metabolome analysis in CO-overproducing livers suggested roles of cystathionine beta-synthase (CBS) that rate-limits transsulfuration pathway and H(2)S generation, for the gas-responsive receptor. Studies using recombinant CBS indicated that CO binds to the prosthetic heme, stabilizing 6-coordinated CO-Fe(II)-histidine complex to block the activity, whereas nitric oxide (NO) forms 5-coordinated structure without inhibiting it. The CO-overproducing livers down-regulated H(2)S to stimulate HCO(3) (-)-dependent choleresis: these responses were attenuated by blocking HO or by donating H(2)S. Livers of heterozygous CBS knockout mice neither down-regulated H(2)S nor exhibited the choleresis while overproducing CO. In the mouse model of estradiol-induced cholestasis, CO overproduction by inducing HO-1 significantly improved the bile output through stimulating HCO(3) (-) excretion; such a choleretic response did not occur in the knockout mice.
  
  
  CONCLUSIONS
  Results collected from metabolome analyses suggested that CBS serves as a CO-sensitive modulator of H(2)S to support biliary excretion, shedding light on a putative role of the enzyme for stress-elicited adaptive response against bile-dependent detoxification processes.
authors.affiliation: Department of Biochemistry and Integrative Medical Biology, Department of Surgery, School of Medicine, Keio University, Tokyo, Japan.
authors.forename: Tsunehiro
authors.initials: T
authors.lastname: Shintani
authors.forename: Takuya
authors.initials: T
authors.lastname: Iwabuchi
authors.forename: Tomoyoshi
authors.initials: T
authors.lastname: Soga
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Kato
authors.forename: Takehiro
authors.initials: T
authors.lastname: Yamamoto
authors.forename: Naoharu
authors.initials: N
authors.lastname: Takano
authors.forename: Takako
authors.initials: T
authors.lastname: Hishiki
authors.forename: Yuki
authors.initials: Y
authors.lastname: Ueno
authors.forename: Satsuki
authors.initials: S
authors.lastname: Ikeda
authors.forename: Tadayuki
authors.initials: T
authors.lastname: Sakuragawa
authors.forename: Kazuo
authors.initials: K
authors.lastname: Ishikawa
authors.forename: Nobuhito
authors.initials: N
authors.lastname: Goda
authors.forename: Yuko
authors.initials: Y
authors.lastname: Kitagawa
authors.forename: Mayumi
authors.initials: M
authors.lastname: Kajimura
authors.forename: Kenji
authors.initials: K
authors.lastname: Matsumoto
authors.forename: Makoto
authors.initials: M
authors.lastname: Suematsu
mesh_terms: D000818:Animals; D001646:Bile / Q000378:metabolism*; D002248:Carbon Monoxide / Q000502:physiology*; D003541:Cystathionine beta-Synthase / Q000378:metabolism*; D008297:Male; D055442:Metabolome / Q000502:physiology; D051379:Mice
chemical_list: D002248:Carbon Monoxide; D003541:Cystathionine beta-Synthase