tailieunhanh - Báo cáo khoa học: Simulation study of methemoglobin reduction in erythrocytes Differential contributions of two pathways to tolerance to oxidative stress

Methemoglobin (metHb), an oxidized form of hemoglobin, is unable to bind and carry oxygen. Erythrocytes are continuously subjected to oxida-tive stress and nitrite exposure, which results in the spontaneous formation of metHb. To avoid the accumulation of metHb, reductive pathways medi-ated by cytochrome b5 or flavin, | ỊFEBS Journal Simulation study of methemoglobin reduction in erythrocytes Differential contributions of two pathways to tolerance to oxidative stress Ayako Kinoshita1 Yoichi Nakayama1 2 Tomoya Kitayama1 and Masaru Tomita1 1 Institute for Advanced Biosciences Keio University Kanagawa Japan 2 Network Biology Research Centre ArticellSystems Corporation Keio Fujisawa Innovation Village Fujisawa Japan Keywords erythrocyte mathematical modeling metabolism methemoglobin oxidative stress Correspondence Y. Nakayama Institute for Advanced Biosciences Keio University Fujisawa Kanagawa 252-8520 Japan Fax Tel 81 466 57 5099 E-mail ynakayam@ Note The mathematical model described here has been submitted to JWS Online database and can be accessed free of charge at http database Received 25 August 2006 revised 30 November 2006 accepted 10 January 2007 doi 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