Modeling the interaction of peroxynitrite with low-density lipoproteins. I. Plasma levels of peroxynitrite.

Peroxynitrite is a strong candidate for the material responsible for the initiation of peroxidation of low-density lipoproteins (LDLs) which is considered the first step in the formation of atherosclerotic plaque. Recent advances in the understanding of peroxynitrite chemistry allow the construction of a kinetic model that can be used to understand the factors controlling levels in plasma. These results indicate that the carbon dioxide catalysed decomposition of peroxynitrite produces large quantities of reactive species, but the rapid decomposition of this intermediate, ONOOCO(-)(2), may limit its availability to attack LDLs at points distant from the site of production. In this case, peroxynitrite itself may be of greater quantitative importance in LDL peroxidation.

Modeling the interaction of peroxynitrite with low-density lipoproteins. II: reaction/diffusion model of peroxynitrite in low-density lipoprotein particles.

Peroxynitrite is a possible initiator for the free radical chain reaction that results in peroxidation of low-density lipoproteins (LDL) which is the first step in atherogenisis. This paper reports on the use of a diffusion/reaction model to examine the processes involved in peroxynitrite attack on LDL particles. Results indicate that because of the short distance involved, diffusion is much more rapid than chemical decomposition. Because of this decoupling the free radicals generated by peroxynitrite decomposition may be found at any point in the LDL particle. At the concentrations expected in physiological systems only a small proportion of LDL particles may contain peroxynitrite molecules. However, these particles may still be profoundly effected because of the long reaction chain length expected after initiation.

Modeling the interaction of peroxynitrite with low-density lipoproteins. III: the role of antioxidants.

Peroxynitrite is a candidate for the substance responsible for the initiation of peroxidation of low-density lipoproteins (LDL) in blood. This is believed to be the initial step in the formation of atherosclerotic plaque. Using kinetic arguments, this paper examines possible routes in both LDL particles and in the surrounding plasma for antioxidants to block peroxidation. The antioxidants considered include ascorbate ion, glutathione and human serum albumin in plasma as well as alpha -tocopherol, ubiquinone-10 and carotenoids in the LDL particles. The results suggest that in the plasma compartment the most efficacious blocking mechanism is the reaction of ascorbate ion with the peroxynitrite precursor, superoxide ion. The situation in LDL particles is much less clear cut because of the paucity of kinetic data in this medium. However, some constraints are suggested on the requirements for an effective antioxidant.

A kinetic model of the system: tyrosyl radical-nitrogen oxide-superoxide ion.

It is generally recognized that the initial step in the formation of atherosclerotic plaque in humans involves the peroxidation of low density lipoproteins (LDL). However, there is no agreement on the mechanism that initiates peroxidation. Among the candidates are several that involve tyrosyl radical, nitrogen oxide, and superoxide ion or their mutual reaction products. In this paper a kinetic model of this system is constructed that examines the nature of these reactions, and places some constraints on their possible overall contribution to the initiation of peroxidation. The reversible reaction of nitric oxide and tyrosyl radical acts to "buffer" tyrosyl radical concentrations while the reaction of tyrosyl radical with superoxide ion scavenges tyrosyl radical. Quantitatively, the reaction of nitric oxide with superoxide to form peroxynitrite is a more important process, but the physiological significance would appear to be related to details of the decay of peroxynitrite that are still in dispute.

A kinetic model of the myeloperoxidase-hydrogen peroxide-chloride ion system in phagolysosomes.

A kinetic model has been constructed of the myeloperoxidase-hydrogen peroxide-chloride ion system of mammalian neutrophils. The model includes the reactions that form chlorinated species and those compounds formed through the reactions of phenolic compounds. Model calculations show that N-chlorotaurine is the primary long-lived product of this system, but that tyrosine peroxide is a major secondary product produced by the generation of tyrosyl radicals. While N-chlorotaurine is formed in much larger concentration than tyrosine peroxide, its lower toxicity may mean that tyrosine peroxide may be the more important mediator of toxic stress in the host associated with inflammatory processes. Care must be taken in the interpretation of dityrosine levels as indicating neutrophil derived oxidant damage. Tyrosine peroxide competes with the formation of dityrosine. Therefore, a high level of oxidative stress may be present even in the absence of significant levels of dityrosine.

Slowly dechlorinated organic chloramines.

Dechlorination of some organic chloramines with aqueous sulfite solutions does not take place instantaneously as previously assumed. Field dechlorination times on the order of hours for some compounds that are found in chlorinated effluents appear likely on the basis of laboratory studies. These chlorinated compounds are not detected by standard analytical methods in the presence of sulfite ion.