Babbs C F, Steiner M G
Biomedical Engineering Center, Purdue University, West Lafayette, IN 47907.
Free Radic Biol Med. 1990;8(5):471-85. doi: 10.1016/0891-5849(90)90060-v.
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 microM/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 (1 to 50 microM) 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.
为了探究导致生物系统中细胞内脂质过氧化的自由基反应机制，我们建立了一个计算模型，该模型可同时模拟多达109个酶促反应和自由基反应，这些反应被认为与膜脂质过氧化的引发、传播和终止有关。各种反应的速率常数均取自已发表的文献。模拟模型包括一个脂质膜隔室和一个水性胞质隔室，各种化学物质在这两个隔室之间进行分配。脂质过氧化由铁催化、超氧化物驱动的芬顿反应引发。一个用“C”语言编写的计算机程序实现了对九种相关自由基浓度的稳态速率方程的数值求解。通过改进的欧拉技术对速率方程进行积分，以描述过氧化氢、三价铁和二价铁、不饱和脂质、脂质氢过氧化物、超氧阴离子以及包括超氧化物歧化酶（SOD）和过氧化氢酶在内的生物抗氧化剂模拟浓度随时间的变化。初步结果为膜脂质过氧化机制带来了重要见解：1. 膜隔室内脂质的分离和浓缩促进了链传播；2. 在没有抗氧化剂的情况下，氧化应激期间脂质氢过氧化物的计算浓度以约40微摩尔/分钟的速度线性增加；3. 脂质过氧化严重依赖于氧浓度，且模拟的依赖性与实验函数相似；4. 脂质过氧化会被维生素E样抗氧化剂、SOD和过氧化氢酶迅速淬灭；5. 引发脂质过氧化仅需要少量（1至50微摩尔）的“游离”铁；6. 只有当细胞防御机制因长期氧化应激而被削弱或克服时，才会发生大量脂质过氧化，因此理解自由基生成与抗氧化防御系统之间的平衡对于理解和控制生物学和医学中的自由基反应至关重要。
