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

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.