van Acker S A, van den Berg D J, Tromp M N, Griffioen D H, van Bennekom W P, van der Vijgh W J, Bast A
Department of Pharmacochemistry, Vrije Universiteit, Netherlands.
Free Radic Biol Med. 1996;20(3):331-42. doi: 10.1016/0891-5849(95)02047-0.
Flavonoids, a group of naturally occurring antioxidants and iron chelators, might be used as cardioprotective agents in doxorubicin-induced cardiotoxicity, which is believed to be caused by the formation of oxygen free radicals. To investigate the underlying molecular mechanism, we tested a large group of flavonoids from all major structural subclasses on their ability to inhibit doxorubicin (enzymatically)-induced and Fe2+/ascorbate (nonenzymatically)-induced microsomal lipid peroxidation (LPO) and to chelate Fe2+. In addition, we measured half peak oxidation potentials (Ep/2). LPO inhibition data gave a good qualitative correlation with the oxidation potentials. Most flavonoids tested chelated Fe2+, but there were large differences in the chelating capacity. For good scavenging activity, a catechol moiety on ring B is required. The 3-OH moiety can function as a chelation site and can also be oxidized. The 3-OH group in combination with a C2 C3 double bond, increases the scavenging activity. Fe2+ chelation only plays a role in the LPO inhibition by less active scavengers. Chelation can then raise the activity to the level of the most active scavengers, possibly by site-specific scavenging. It can be concluded that Ep/2 values and iron chelating activity can almost completely describe the LPO inhibiting behaviour of the flavonoids.
黄酮类化合物是一类天然存在的抗氧化剂和铁螯合剂，可能用作多柔比星诱导的心脏毒性的心脏保护剂，这种心脏毒性被认为是由氧自由基的形成引起的。为了研究潜在的分子机制，我们测试了一大组来自所有主要结构亚类的黄酮类化合物抑制多柔比星（酶促）诱导的和Fe2+/抗坏血酸（非酶促）诱导的微粒体脂质过氧化（LPO）以及螯合Fe2+的能力。此外，我们测量了半峰氧化电位（Ep/2）。LPO抑制数据与氧化电位具有良好的定性相关性。大多数测试的黄酮类化合物螯合Fe2+，但螯合能力存在很大差异。为了具有良好的清除活性，B环上需要有一个儿茶酚部分。3-OH部分可以作为螯合位点，也可以被氧化。3-OH基团与C2 C3双键结合，可提高清除活性。Fe2+螯合仅在活性较低的清除剂对LPO的抑制中起作用。螯合然后可以将活性提高到最活跃的清除剂的水平，可能是通过位点特异性清除。可以得出结论，Ep/2值和铁螯合活性几乎可以完全描述黄酮类化合物的LPO抑制行为。
