What are the plasma targets of the oxidant hypochlorous acid? A kinetic modeling approach
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What are the plasma targets of the oxidant hypochlorous acid? A kinetic modeling approach. / Pattison, David I; Hawkins, Clare Louise; Davies, Michael Jonathan.
In: Chemical Research in Toxicology, Vol. 22, No. 5, 05.2009, p. 807-17.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - What are the plasma targets of the oxidant hypochlorous acid?
T2 - A kinetic modeling approach
AU - Pattison, David I
AU - Hawkins, Clare Louise
AU - Davies, Michael Jonathan
PY - 2009/5
Y1 - 2009/5
N2 - Myeloperoxidase (MPO) is a heme enzyme, released by activated leukocytes at sites of inflammation, which catalyzes the formation of the potent oxidant, hypochlorous acid (HOCl), from H2O2. HOCl is a key component of the inflammatory response and is bactericidal but has been linked with several human pathologies as a result of damage to host tissue. Elevated plasma MPO levels are a strong independent risk factor, and predictor of outcomes, for cardiovascular disease. Rate constants for reaction of HOCl with individual biological targets and the products of these reactions have been determined, but the targets of HOCl in complex biological fluids such as plasma are incompletely defined. In this study, rate constants (M(-1) s(-1)) for the reactions of ascorbate with HOCl (ca. 6 x 10(6)) and imidazole chloramine (7.7 x 10(4)) have been determined to supplement known kinetic parameters. HOCl-mediated oxidation of the major plasma protein, albumin, was investigated both experimentally and computationally; these approaches provide consistent data. The computational studies were extended to examine the fate of HOCl in plasma. The model predicts that plasma proteins consume the majority of HOCl with limited damage to other materials. Ascorbate or alpha-tocopherol, even at the levels achieved in human supplementation studies, do not attenuate these reactions. In contrast, elevated levels of thiocyanate ions (SCN(-)), as detected in heavy smokers, can modulate HOCl-mediated reactions as a result of the formation of the highly specific oxidant hypothiocyanous acid (HOSCN). These observations support the hypothesis that MPO-generated HOSCN is a key agent in smoking-enhanced atherosclerosis.
AB - Myeloperoxidase (MPO) is a heme enzyme, released by activated leukocytes at sites of inflammation, which catalyzes the formation of the potent oxidant, hypochlorous acid (HOCl), from H2O2. HOCl is a key component of the inflammatory response and is bactericidal but has been linked with several human pathologies as a result of damage to host tissue. Elevated plasma MPO levels are a strong independent risk factor, and predictor of outcomes, for cardiovascular disease. Rate constants for reaction of HOCl with individual biological targets and the products of these reactions have been determined, but the targets of HOCl in complex biological fluids such as plasma are incompletely defined. In this study, rate constants (M(-1) s(-1)) for the reactions of ascorbate with HOCl (ca. 6 x 10(6)) and imidazole chloramine (7.7 x 10(4)) have been determined to supplement known kinetic parameters. HOCl-mediated oxidation of the major plasma protein, albumin, was investigated both experimentally and computationally; these approaches provide consistent data. The computational studies were extended to examine the fate of HOCl in plasma. The model predicts that plasma proteins consume the majority of HOCl with limited damage to other materials. Ascorbate or alpha-tocopherol, even at the levels achieved in human supplementation studies, do not attenuate these reactions. In contrast, elevated levels of thiocyanate ions (SCN(-)), as detected in heavy smokers, can modulate HOCl-mediated reactions as a result of the formation of the highly specific oxidant hypothiocyanous acid (HOSCN). These observations support the hypothesis that MPO-generated HOSCN is a key agent in smoking-enhanced atherosclerosis.
KW - Ascorbic Acid
KW - Humans
KW - Hypochlorous Acid
KW - Kinetics
KW - Models, Theoretical
KW - Oxidants
KW - Oxidation-Reduction
KW - Peroxidase
KW - Serum Albumin
KW - Smoking
KW - Thiocyanates
KW - alpha-Tocopherol
U2 - 10.1021/tx800372d
DO - 10.1021/tx800372d
M3 - Journal article
C2 - 19326902
VL - 22
SP - 807
EP - 817
JO - Chemical Research in Toxicology
JF - Chemical Research in Toxicology
SN - 0893-228X
IS - 5
ER -
ID: 129670463