Simulation of free radical reactions in biology and medicine: A new two-compartment kinetic model of intracellular lipid peroxidation☆

Abstract

--To explore mechanisms of free radical reactions leading to intracellular lipid peroxidation in living systems, we developed a computational model of up to 109 simultaneous enzymatic and free radical reactions thought to be involved in the initiation, propagation, and termination of membrane lipid peroxidation. Rate constants for the various reactions were obtained from the published literature. The simulation model included a lipid membrane compartment and an aqueous cytosolic compartment, between which various chemical species were partitioned. Lipid peroxidation was initiated by the iron-catalyzed, superoxide-driven Fenton reaction. A "C"-language computer program implemented numerical solution of the steady-state rate equations for concentrations of nine relevant free radicals. The rate equations were integrated by a modified Euler technique to describe the evolution with time of simulated concentrations of hydrogen peroxide, ferric and ferrous iron, unsaturated lipid, lipid hydroperoxides, superoxide anion, and biological antioxidants, including SOD and catalase. Initial results led to significant insights regarding mechanisms of membrane lipid peroxidation:1.segregation and concentration of lipids within membrane compartments promotes chain propagation; 2.in the absence of antioxidants computed concentrations of lipid hydroperoxides increase linearly about 40 M/min during oxidative stress; 3.lipid peroxidation is critically dependent upon oxygen concentration and the modeled dependence is similar to the experimental function; 4.lipid peroxidation is rapidly quenched by the presence of Vitamin E-like antioxidants, SOD, and catalase; 5.only small (l to 50 M) amounts of "free" iron are required for initiation of lipid peroxidation; 6. substantial lipid peroxidation occurs only when cellular defense mechanisms have been weakened or overcome by prolonged oxidative stress, hence understanding of the balance between free radical generation and antioxidant defense systems is critical to the understanding and control of free radical reactions in biology and medicine.

Impairment of human neutrophil oxidative burst by polychlorinated biphenyls: inhibition of superoxide dismutase activity

“…Superoxide buildup along with significant H 2 O 2 production on exposure to PCBs makes an ideal scenario for these ROS to react with each other to form ·OH. Hydroxyl radicals are known to attack DNA, inducing strand breaks, damaging cellular proteins, and initiating lipid peroxidation either directly or via intermediate radicals of longer half-life [42]. Decreased SOD content and activity have been shown to contribute to apoptotic death in neutrophils [16].…”

Integrative Modeling of Oxidative Stress and C1 Metabolism Reveals Upregulation of Formaldehyde and Downregulation of Glutathione

“…Lipids are the most abundant molecules in the membranes and hence the most probable targets of ROS. Oxidation of lipids occurs at their fatty acids, especially polyunsaturated fatty acids (PUFA) [9]. The oxidation of lipids by ROS produces various oxidized lipids (LOOH) species [12].…”

“…Based on the systematic literature review, three major molecular systems that are involved in the oxidative stress pathway in plants are identified: These included: 1) lipid peroxidation pathway [9], 2) ascorbate-glutathione pathway [10], and 3) ROS production pathway [11].…”

Oxygen radicals in ulcerative colitis

“…In the case of classical chain breaking (Vitamin E-like) antioxidants in particular, high rates of chain propagation occur only when antioxidant has been consumed [29,73]. To the extent that dietary iron and antioxidant consumption vary independently, flares may tend to occur at seemingly unpredictable intervals when dietary iron intake is especially high and dietary antioxidant intake is especially low.…”