| RRC ID |
65005
|
| 著者 |
Kitagishi H, Minegishi S, Yumura A, Negi S, Taketani S, Amagase Y, Mizukawa Y, Urushidani T, Sugiura Y, Kano K.
|
| タイトル |
Feedback Response to Selective Depletion of Endogenous Carbon Monoxide in the Blood.
|
| ジャーナル |
J Am Chem Soc
|
| 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.
|
| 巻・号 |
138(16)
|
| ページ |
5417-25
|
| 公開日 |
2016-4-27
|
| DOI |
10.1021/jacs.6b02211
|
| PMID |
27057920
|
| MeSH |
Animals
Carbon Monoxide / blood*
Coordination Complexes / pharmacokinetics*
Feedback, Physiological
Gene Expression Regulation, Enzymologic
Heme Oxygenase-1 / genetics
Heme Oxygenase-1 / metabolism*
Hep G2 Cells
Humans
Iron / chemistry*
Male
Membrane Proteins / genetics
Membrane Proteins / metabolism*
Mice, Inbred C57BL
|
| IF |
14.612
|
| リソース情報 |
| ヒト・動物細胞 |
Hep G2(RCB1886) |
