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

Authors

  • Tsunehiro Shintani,

    1. Department of Biochemistry and Integrative Medical Biology, Department of Surgery, School of Medicine, Keio University, Tokyo, Japan
    2. Institute for Advanced Biosciences, Keio University, Tsuruoka City, Japan
    3. First Department of Surgery, College of Medicine, Nagoya University, Nagoya, Japan
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    • These authors contributed equally to this work.

  • Takuya Iwabuchi,

    1. Department of Biochemistry and Integrative Medical Biology, Department of Surgery, School of Medicine, Keio University, Tokyo, Japan
    2. Institute for Advanced Biosciences, Keio University, Tsuruoka City, Japan
    3. First Department of Surgery, College of Medicine, Nagoya University, Nagoya, Japan
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    • These authors contributed equally to this work.

    • T.I. and T.Y. are research associates of Global COE Program for Metabolomic Systems Biology from MEXT.

  • Tomoyoshi Soga,

    1. Department of Biochemistry and Integrative Medical Biology, Department of Surgery, School of Medicine, Keio University, Tokyo, Japan
    2. Institute for Advanced Biosciences, Keio University, Tsuruoka City, Japan
    3. First Department of Surgery, College of Medicine, Nagoya University, Nagoya, Japan
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  • Yuichiro Kato,

    1. Department of Biochemistry and Integrative Medical Biology, Department of Surgery, School of Medicine, Keio University, Tokyo, Japan
    2. Institute for Advanced Biosciences, Keio University, Tsuruoka City, Japan
    3. First Department of Surgery, College of Medicine, Nagoya University, Nagoya, Japan
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  • Takehiro Yamamoto,

    1. Department of Biochemistry and Integrative Medical Biology, Department of Surgery, School of Medicine, Keio University, Tokyo, Japan
    2. Institute for Advanced Biosciences, Keio University, Tsuruoka City, Japan
    3. First Department of Surgery, College of Medicine, Nagoya University, Nagoya, Japan
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    • T.I. and T.Y. are research associates of Global COE Program for Metabolomic Systems Biology from MEXT.

  • Naoharu Takano,

    1. Department of Biochemistry and Integrative Medical Biology, Department of Surgery, School of Medicine, Keio University, Tokyo, Japan
    2. Institute for Advanced Biosciences, Keio University, Tsuruoka City, Japan
    3. First Department of Surgery, College of Medicine, Nagoya University, Nagoya, Japan
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  • Takako Hishiki,

    1. Department of Biochemistry and Integrative Medical Biology, Department of Surgery, School of Medicine, Keio University, Tokyo, Japan
    2. Institute for Advanced Biosciences, Keio University, Tsuruoka City, Japan
    3. First Department of Surgery, College of Medicine, Nagoya University, Nagoya, Japan
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  • Yuki Ueno,

    1. Department of Biochemistry and Integrative Medical Biology, Department of Surgery, School of Medicine, Keio University, Tokyo, Japan
    2. Institute for Advanced Biosciences, Keio University, Tsuruoka City, Japan
    3. First Department of Surgery, College of Medicine, Nagoya University, Nagoya, Japan
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  • Satsuki Ikeda,

    1. Department of Biochemistry and Integrative Medical Biology, Department of Surgery, School of Medicine, Keio University, Tokyo, Japan
    2. Institute for Advanced Biosciences, Keio University, Tsuruoka City, Japan
    3. First Department of Surgery, College of Medicine, Nagoya University, Nagoya, Japan
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  • Tadayuki Sakuragawa,

    1. Department of Biochemistry and Integrative Medical Biology, Department of Surgery, School of Medicine, Keio University, Tokyo, Japan
    2. Institute for Advanced Biosciences, Keio University, Tsuruoka City, Japan
    3. First Department of Surgery, College of Medicine, Nagoya University, Nagoya, Japan
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  • Kazuo Ishikawa,

    1. Department of Biochemistry and Integrative Medical Biology, Department of Surgery, School of Medicine, Keio University, Tokyo, Japan
    2. Institute for Advanced Biosciences, Keio University, Tsuruoka City, Japan
    3. First Department of Surgery, College of Medicine, Nagoya University, Nagoya, Japan
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  • Nobuhito Goda,

    1. Department of Biochemistry and Integrative Medical Biology, Department of Surgery, School of Medicine, Keio University, Tokyo, Japan
    2. Institute for Advanced Biosciences, Keio University, Tsuruoka City, Japan
    3. First Department of Surgery, College of Medicine, Nagoya University, Nagoya, Japan
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  • Yuko Kitagawa,

    1. Department of Biochemistry and Integrative Medical Biology, Department of Surgery, School of Medicine, Keio University, Tokyo, Japan
    2. Institute for Advanced Biosciences, Keio University, Tsuruoka City, Japan
    3. First Department of Surgery, College of Medicine, Nagoya University, Nagoya, Japan
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  • Mayumi Kajimura,

    1. Department of Biochemistry and Integrative Medical Biology, Department of Surgery, School of Medicine, Keio University, Tokyo, Japan
    2. Institute for Advanced Biosciences, Keio University, Tsuruoka City, Japan
    3. First Department of Surgery, College of Medicine, Nagoya University, Nagoya, Japan
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  • Kenji Matsumoto,

    1. Department of Biochemistry and Integrative Medical Biology, Department of Surgery, School of Medicine, Keio University, Tokyo, Japan
    2. Institute for Advanced Biosciences, Keio University, Tsuruoka City, Japan
    3. First Department of Surgery, College of Medicine, Nagoya University, Nagoya, Japan
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  • Makoto Suematsu

    Corresponding author
    1. Department of Biochemistry and Integrative Medical Biology, Department of Surgery, School of Medicine, Keio University, Tokyo, Japan
    2. Institute for Advanced Biosciences, Keio University, Tsuruoka City, Japan
    3. First Department of Surgery, College of Medicine, Nagoya University, Nagoya, Japan
    • Department of Biochemistry and Integrative Medical Biology, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
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    • fax: (81)-3-5363-3466


  • Potential conflict of interest: Nothing to report.

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-overproducing 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. (HEPATOLOGY 2009;49:141-150.)

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