Simulation study of methemoglobin reduction in erythrocytes: Differential contributions of two pathways to tolerance to oxidative stress

Ayako Kinoshita, Yoichi Nakayama, Tomoya Kitayama, Masaru Tomita

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

Methemoglobin (metHb), an oxidized form of hemoglobin, is unable to bind and carry oxygen. Erythrocytes are continuously subjected to oxidative stress and nitrite exposure, which results in the spontaneous formation of metHb. To avoid the accumulation of metHb, reductive pathways mediated by cytochrome b5 or flavin, coupled with NADH-dependent or NADPH-dependent metHb reductases, respectively, keep the level of metHb in erythrocytes at less than 1% of the total hemoglobin under normal conditions. In this work, a mathematical model has been developed to quantitatively assess the relative contributions of the two major metHb-reducing pathways, taking into consideration the supply of NADH and NADPH from central energy metabolism. The results of the simulation experiments suggest that these pathways have different roles in the reduction of metHb; one has a high response rate to hemoglobin oxidation with a limited reducing flux, and the other has a low response rate with a high capacity flux. On the basis of the results of our model, under normal oxidative conditions, the NADPH-dependent system, the physiological role of which to date has been unclear, is predicted to be responsible for most of the reduction of metHb. In contrast, the cytochrome b5-NADH pathway becomes dominant under conditions of excess metHb accumulation, only after the capacity of the flavin-NADPH pathway has reached its limit. We discuss the potential implications of a system designed with two metHb-reducing pathways in human erythrocytes.

Original languageEnglish
Pages (from-to)1449-1458
Number of pages10
JournalFEBS Journal
Volume274
Issue number6
DOIs
Publication statusPublished - 2007 Mar

Fingerprint

Methemoglobin
Oxidative stress
Oxidative Stress
Erythrocytes
NADP
NAD
Cytochromes b5
Hemoglobins
Cytochrome-B(5) Reductase
Fluxes
Nitrites
Energy Metabolism
Theoretical Models
Mathematical models
Oxygen
Oxidation

Keywords

  • Erythrocyte
  • Mathematical modeling
  • Metabolism
  • Methemoglobin
  • Oxidative stress

ASJC Scopus subject areas

  • Biochemistry

Cite this

Simulation study of methemoglobin reduction in erythrocytes : Differential contributions of two pathways to tolerance to oxidative stress. / Kinoshita, Ayako; Nakayama, Yoichi; Kitayama, Tomoya; Tomita, Masaru.

In: FEBS Journal, Vol. 274, No. 6, 03.2007, p. 1449-1458.

Research output: Contribution to journalArticle

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