title: Feedback Response to Selective Depletion of Endogenous Carbon Monoxide in the Blood.
abstract: The physiological roles of endogenous carbon monoxide (CO) have not been fully understood because of the difficulty in preparing a loss-of-function phenotype of this molecule. Here, we have utilized in vivo CO receptors, hemoCDs, which are the supramolecular 1:1 inclusion complexes of meso-tetrakis(4-sulfonatophenyl)porphinatoiron(II) with per-O-methylated β-cyclodextrin dimers. Three types of hemoCDs (hemoCD1, hemoCD2, and hemoCD3) that exhibit different CO-affinities have been tested as CO-depleting agents in vivo. Intraperitoneally administered hemoCD bound endogenous CO within the murine circulation, and was excreted in the urine along with CO in an affinity-dependent manner. The sufficient administration of hemoCD that has higher CO-affinity than hemoglobin (Hb) produced a pseudoknockdown state of CO in the mouse in which heme oxygenase-1 (HO-1) was markedly induced in the liver, causing the acceleration of endogenous CO production to maintain constant CO-Hb levels in the blood. The contents of free hemin and bilirubin in the blood plasma of the treated mice significantly increased upon removal of endogenous CO by hemoCD. Thus, a homeostatic feedback model for the CO/HO-1 system was proposed as follows: HemoCD primarily removes CO from cell-free CO-Hb. The resulting oxy-Hb is quickly oxidized to met-Hb by oxidant(s) such as hydrogen peroxide in the blood plasma. The met-Hb readily releases free hemin that directly induces HO-1 in the liver, which metabolizes the hemin into iron, biliverdin, and CO. The newly produced CO binds to ferrous Hb to form CO-Hb as an oxidation-resistant state. Overall, the present system revealed the regulatory role of CO for maintaining the ferrous/ferric balance of Hb in the blood.
authors.affiliation: Department of Molecular Chemistry and Biochemistry, Faculty of Science and Engineering, Doshisha University , Kyotanabe, Kyoto 610-0321, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Kitagishi
authors.affiliation: Department of Molecular Chemistry and Biochemistry, Faculty of Science and Engineering, Doshisha University , Kyotanabe, Kyoto 610-0321, Japan.
authors.forename: Saika
authors.initials: S
authors.lastname: Minegishi
authors.affiliation: Department of Molecular Chemistry and Biochemistry, Faculty of Science and Engineering, Doshisha University , Kyotanabe, Kyoto 610-0321, Japan.
authors.forename: Aki
authors.initials: A
authors.lastname: Yumura
authors.affiliation: Faculty of Pharmaceutical Sciences, Doshisha Women's College of Liberal Arts , Kyotanabe, Kyoto 610-0395, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Negi
authors.affiliation: Department of Microbiology, Kansai Medical University , Hirakata, Osaka 573-1010, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Taketani
authors.affiliation: Faculty of Pharmaceutical Sciences, Doshisha Women's College of Liberal Arts , Kyotanabe, Kyoto 610-0395, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Amagase
authors.affiliation: Faculty of Pharmaceutical Sciences, Doshisha Women's College of Liberal Arts , Kyotanabe, Kyoto 610-0395, Japan.
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Mizukawa
authors.affiliation: Faculty of Pharmaceutical Sciences, Doshisha Women's College of Liberal Arts , Kyotanabe, Kyoto 610-0395, Japan.
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Urushidani
authors.affiliation: Faculty of Pharmaceutical Sciences, Doshisha Women's College of Liberal Arts , Kyotanabe, Kyoto 610-0395, Japan.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Sugiura
authors.affiliation: Department of Molecular Chemistry and Biochemistry, Faculty of Science and Engineering, Doshisha University , Kyotanabe, Kyoto 610-0321, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Kano
mesh_terms: D000818:Animals; D002248:Carbon Monoxide / Q000097:blood*; D056831:Coordination Complexes / Q000493:pharmacokinetics*; D025461:Feedback, Physiological; D015971:Gene Expression Regulation, Enzymologic; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D056945:Hep G2 Cells; D006801:Humans; D007501:Iron / Q000737:chemistry*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008810:Mice, Inbred C57BL
chemical_list: D056831:Coordination Complexes; D008565:Membrane Proteins; D002248:Carbon Monoxide; D007501:Iron; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse