TY - JOUR
T1 - Cystathionine β-synthase as a carbon monoxide-sensitive regulator of bile excretion
AU - Shintani, Tsunehiro
AU - Iwabuchi, Takuya
AU - Soga, Tomoyoshi
AU - Kato, Yuichiro
AU - Yamamoto, Takehiro
AU - Takano, Naoharu
AU - Hishiki, Takako
AU - Ueno, Yuki
AU - Ikeda, Satsuki
AU - Sakuragawa, Tadayuki
AU - Ishikawa, Kazuo
AU - Goda, Nobuhito
AU - Kitagawa, Yuko
AU - Kajimura, Mayumi
AU - Matsumoto, Kenji
AU - Suematsu, Makoto
N1 - Copyright:
Copyright 2009 Elsevier B.V., All rights reserved.
PY - 2009
Y1 - 2009
N2 - 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 β-synthase (CBS) that rate-limits transsulfuration pathway and H2S 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-over-producing livers down-regulated H2S to stimulate HCO3- -dependent choleresis: these responses were attenuated by blocking HO or by donating H2S. Livers of heterozygous CBS knockout mice neither down-regulated H2S 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 HCO3- excretion; such a choleretic response did not occur in the knockout mice. Conclusion: Results collected from metabolome analyses suggested that CBS serves as a CO-sensitive modulator of H2S to support biliary excretion, shedding light on a putative role of the enzyme for stress-elicited adaptive response against bile-dependent detoxification processes.
AB - 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 β-synthase (CBS) that rate-limits transsulfuration pathway and H2S 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-over-producing livers down-regulated H2S to stimulate HCO3- -dependent choleresis: these responses were attenuated by blocking HO or by donating H2S. Livers of heterozygous CBS knockout mice neither down-regulated H2S 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 HCO3- excretion; such a choleretic response did not occur in the knockout mice. Conclusion: Results collected from metabolome analyses suggested that CBS serves as a CO-sensitive modulator of H2S to support biliary excretion, shedding light on a putative role of the enzyme for stress-elicited adaptive response against bile-dependent detoxification processes.
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U2 - 10.1002/hep.22604
DO - 10.1002/hep.22604
M3 - Article
C2 - 19085910
AN - SCOPUS:58949089444
VL - 49
SP - 141
EP - 150
JO - Hepatology
JF - Hepatology
SN - 0270-9139
IS - 1
ER -