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 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.
| Original language | English |
|---|---|
| Pages (from-to) | 141-150 |
| Number of pages | 10 |
| Journal | Hepatology |
| Volume | 49 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - 2009 |
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ASJC Scopus subject areas
- Hepatology
- Medicine(all)
Cite this
Cystathionine β-synthase as a carbon monoxide-sensitive regulator of bile excretion. / Shintani, Tsunehiro; Iwabuchi, Takuya; Soga, Tomoyoshi; Kato, Yuichiro; Yamamoto, Takehiro; Takano, Naoharu; Hishiki, Takako; Ueno, Yuki; Ikeda, Satsuki; Sakuragawa, Tadayuki; Ishikawa, Kazuo; Goda, Nobuhito; Kitagawa, Yuukou; Kajimura, Mayumi; Matsumoto, Kenji; Suematsu, Makoto.
In: Hepatology, Vol. 49, No. 1, 2009, p. 141-150.Research output: Contribution to journal › Article
}
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, Yuukou
AU - Kajimura, Mayumi
AU - Matsumoto, Kenji
AU - Suematsu, Makoto
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.
UR - http://www.scopus.com/inward/record.url?scp=58949089444&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=58949089444&partnerID=8YFLogxK
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 -