Cystathionine β-synthase as a carbon monoxide-sensitive regulator of bile excretion

Tsunehiro Shintani, Takuya Iwabuchi, Tomoyoshi Soga, Yuichiro Kato, Takehiro Yamamoto, Naoharu Takano, Takako Hishiki, Yuki Ueno, Satsuki Ikeda, Tadayuki Sakuragawa, Kazuo Ishikawa, Nobuhito Goda, Yuko Kitagawa, Mayumi Kajimura, Kenji Matsumoto, Makoto Suematsu

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82 Citations (Scopus)

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 languageEnglish
Pages (from-to)141-150
Number of pages10
JournalHepatology
Volume49
Issue number1
DOIs
Publication statusPublished - 2009

ASJC Scopus subject areas

  • Hepatology

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    Shintani, T., Iwabuchi, T., Soga, T., Kato, Y., Yamamoto, T., Takano, N., Hishiki, T., Ueno, Y., Ikeda, S., Sakuragawa, T., Ishikawa, K., Goda, N., Kitagawa, Y., Kajimura, M., Matsumoto, K., & Suematsu, M. (2009). Cystathionine β-synthase as a carbon monoxide-sensitive regulator of bile excretion. Hepatology, 49(1), 141-150. https://doi.org/10.1002/hep.22604