What are the plasma targets of the oxidant hypochlorous acid? A kinetic modeling approach

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

SN - 0893-228X

VL - 22

SP - 807

EP - 817

JO - Chemical Research in Toxicology

JF - Chemical Research in Toxicology

IS - 5

ER -