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 Yuko, Kajimura Mayumi, Matsumoto Kenji, Suematsu Makoto
Department of Biochemistry and Integrative Medical Biology, Department of Surgery, School of Medicine, Keio University, Tokyo, Japan.
Hepatology. 2009 Jan;49(1):141-50. doi: 10.1002/hep.22604.
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.
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.
一氧化碳（CO）是一种由血红素加氧酶（HO）产生的应激诱导气体，可引发针对毒物的适应性反应；然而，其受体机制尚不清楚。在CO过量产生的肝脏的代谢组分析中的意外观察表明，限速转硫途径和H₂S生成的胱硫醚β-合酶（CBS）在气体反应受体中发挥作用。使用重组CBS的研究表明，CO与辅基血红素结合，稳定六配位的CO-Fe（II）-组氨酸复合物以阻断其活性，而一氧化氮（NO）形成五配位结构而不抑制它。CO过量产生的肝脏下调H₂S以刺激HCO₃⁻依赖性胆汁分泌：这些反应通过阻断HO或通过提供H₂S而减弱。杂合CBS基因敲除小鼠的肝脏在过量产生CO时既不下调H₂S也不表现出胆汁分泌。在雌二醇诱导的胆汁淤积小鼠模型中，通过诱导HO-1过量产生CO通过刺激HCO₃⁻排泄显著改善胆汁输出；这种胆汁分泌反应在基因敲除小鼠中未发生。
从代谢组分析中收集的结果表明，CBS作为H₂S的CO敏感调节剂来支持胆汁排泄，揭示了该酶在应激引发的针对胆汁依赖性解毒过程的适应性反应中的假定作用。
