Waldeck A R, Stocker R
Biochemistry Unit, Heart Research Institute, Sydney, NSW, Australia.
Chem Res Toxicol. 1996 Sep;9(6):954-64. doi: 10.1021/tx960057s.
We present kinetic models of various complexity for radical-initiated lipid peroxidation in low density lipoproteins (LDL). The models, comprised of simultaneous differential equations programmed in Mathematica, were used to evaluate the concentration profiles of the reactants of interest. Single-phase reaction schemes describing lipid peroxidation and antioxidation according to the "conventional" and tocopherol-mediated peroxidation (TMP) model were simulated for conditions of low and high radical fluxes produced by thermolabile azo initiators. The results show that the particular dependencies of the rates of lipid peroxidation (Rp) on the rates of initiation (Ri) for the two reaction schemes were accurately predicted by the simulations. Both models qualitatively predicted inhibition of lipid peroxidation in the presence of alpha-tocopherol (alpha-TOH) under high radical flux conditions, suggesting that both can describe inhibited lipid peroxidation in solution under these conditions. TMP, but not the conventional model, could also predict the experimentally observed complex behavior of LDL lipid peroxidation induced with different concentrations of azo initiators. Specifically, TMP faithfully reproduced the observed kinetic chain length of lipid peroxidation of > > 1 at low and < < 1 at high concentration of the initiator (i.e., 0.2 and 10 mM, respectively for LDL at 1 mumol apoB-100/L) during the alpha-TOH-containing period of oxidation. It also demonstrated the experimentally observed nondependence of RpTMP on Ri. Kinetic analysis of radical generation and initiation of lipid peroxidation in an extended, two-compartment model of TMP showed that phase separation of bimolecular reactions in a suspension of LDL particles can lead to a approximately 400-fold increase in the rate of lipid hydroperoxide formation. The experimentally observed co-antioxidant action of water-soluble ascorbate and lipid-soluble ubiquinol-10 were verified using this model. A simple biophysical model constituting the reactions of TMP and incorporating the compartmental nature of an LDL suspension is proposed. Together, the results demonstrate that TMP is the only model that fits the experimental data describing the early stages of LDL lipid peroxidation under various oxidizing conditions. The implications of our findings are discussed in relation to atherogenesis and a recently proposed alternative model of LDL lipid peroxidation (Abuja and Esterbauer (1995) Chem. Res. Toxicol. 8, 753).
我们提出了低密度脂蛋白（LDL）中自由基引发的脂质过氧化反应的各种复杂程度的动力学模型。这些模型由用Mathematica编写的联立微分方程组成，用于评估感兴趣的反应物的浓度分布。针对热不稳定偶氮引发剂产生的低自由基通量和高自由基通量条件，模拟了根据“传统”模型和生育酚介导的过氧化反应（TMP）模型描述脂质过氧化和抗氧化作用的单相反应方案。结果表明，模拟准确预测了两种反应方案中脂质过氧化速率（Rp）对引发速率（Ri）的特定依赖性。两个模型都定性地预测了在高自由基通量条件下，α-生育酚（α-TOH）存在时脂质过氧化受到抑制，这表明两者都可以描述在这些条件下溶液中受抑制的脂质过氧化。TMP模型而非传统模型，还能够预测实验观察到的不同浓度偶氮引发剂诱导的LDL脂质过氧化的复杂行为。具体而言，TMP模型如实地再现了在含α-TOH的氧化阶段，引发剂浓度低（LDL为1μmol载脂蛋白B-100/L时分别为0.2 mM）和高（10 mM）时观察到的脂质过氧化动力学链长>>1和<<1的情况。它还证明了实验观察到的RpTMP对Ri的非依赖性。在扩展的两室TMP模型中对自由基产生和脂质过氧化引发的动力学分析表明，LDL颗粒悬浮液中双分子反应的相分离可导致脂质氢过氧化物形成速率增加约400倍。使用该模型验证了实验观察到的水溶性抗坏血酸和脂溶性泛醌-10的协同抗氧化作用。提出了一个简单的生物物理模型，该模型构成了TMP反应并纳入了LDL悬浮液的区室性质。总之，结果表明TMP是唯一符合描述各种氧化条件下LDL脂质过氧化早期阶段实验数据的模型。我们结合动脉粥样硬化的发生以及最近提出并替代的LDL脂质过氧化模型（Abuja和Esterbauer（1995年）《化学研究毒理学》8, 753）讨论了我们研究结果的意义。
