Pauline Nyssen1, Anthony Maho2, Romain Malempré3, André Matagne3, Ange Mouithys-Mickalad4, Maryse Hoebeke5. 1. Biomedical Spectroscopy Laboratory, Department of Physics, CESAM, University of Liège, Building B5a, Quartier Agora, Allée du 6 Août, 19, Sart-Tilman, 4000 Liège, Belgium. Electronic address: pnyssen@uliege.be. 2. Greenmat, Department of Chemistry, CESAM, University of Liège, Building B6c, Quartier Agora, Allée du 6 Août, 19, Sart-Tilman, 4000 Liège, Belgium. 3. Laboratory of Enzymology and Protein folding, Centre for Protein Engineering, InBioS, University of Liège, Building B6a, Quartier Agora, Allée du 6 Août, 19, Sart-Tilman, 4000 Liège, Belgium. 4. Centre for Oxygen R&D (CORD), Department of Chemistry, CIRM, University of Liège, Building B6a, Quartier Agora, Allée du 6 Août, 13, Sart-Tilman, 4000 Liège, Belgium. 5. Biomedical Spectroscopy Laboratory, Department of Physics, CESAM, University of Liège, Building B5a, Quartier Agora, Allée du 6 Août, 19, Sart-Tilman, 4000 Liège, Belgium.
Abstract
BACKGROUND: Propofol (2,6-diisopropylphenol) is frequently used as intravenous anesthetic agent, especially in its injectable form (Diprivan), to initiate and maintain sedative state during surgery or in intensive care units. Numerous studies have reported the antioxidant and anti-inflammatory effect of propofol. The oxidant enzyme myeloperoxidase (MPO), released from activated neutrophils, plays a key role in host defense. An increase of the circulating MPO concentration has been observed in patients admitted in intensive care unit and presenting a systemic inflammatory response related to septic shock or trauma. METHODS: This study investigates the immunomodulatory action of propofol and Diprivan as inhibitor of the oxidant activity of MPO. The understanding of the redox action mechanism of propofol and Diprivan on the myeloperoxidase chlorination and peroxidase activities has been refined using the combination of fluorescence and absorption spectroscopies with docking and cyclic voltammetry. RESULTS: Propofol acts as a reversible MPO inhibitor. The molecule interacts as a reducing substrate in the peroxidase cycle and promotes the accumulation of compound II. At acidic pH (5.5), propofol and Diprivan do not inhibit the chlorination activity, but their action increases at physiological pH (7.4). The main inhibitory action of Diprivan could be attributed to its HOCl scavenging property. GENERAL SIGNIFICANCE: Propofol can act as a reversible MPO inhibitor at clinical concentrations. This property could, in addition to other previously proven anti-inflammatory actions, induce an immunomodulatory action, beneficial during clinical use, particularly in the treatment of systemic inflammation response syndrome.
BACKGROUND: Propofol (2,6-diisopropylphenol) is frequently used as intravenous anesthetic agent, especially in its injectable form (Diprivan), to initiate and maintain sedative state during surgery or in intensive care units. Numerous studies have reported the antioxidant and anti-inflammatory effect of propofol. The oxidant enzyme myeloperoxidase (MPO), released from activated neutrophils, plays a key role in host defense. An increase of the circulating MPO concentration has been observed in patients admitted in intensive care unit and presenting a systemic inflammatory response related to septic shock or trauma. METHODS: This study investigates the immunomodulatory action of propofol and Diprivan as inhibitor of the oxidant activity of MPO. The understanding of the redox action mechanism of propofol and Diprivan on the myeloperoxidase chlorination and peroxidase activities has been refined using the combination of fluorescence and absorption spectroscopies with docking and cyclic voltammetry. RESULTS: Propofol acts as a reversible MPO inhibitor. The molecule interacts as a reducing substrate in the peroxidase cycle and promotes the accumulation of compound II. At acidic pH (5.5), propofol and Diprivan do not inhibit the chlorination activity, but their action increases at physiological pH (7.4). The main inhibitory action of Diprivan could be attributed to its HOCl scavenging property. GENERAL SIGNIFICANCE: Propofol can act as a reversible MPO inhibitor at clinical concentrations. This property could, in addition to other previously proven anti-inflammatory actions, induce an immunomodulatory action, beneficial during clinical use, particularly in the treatment of systemic inflammation response syndrome.