Dinkova-Kostova Albena T, Talalay Paul
Division of Clinical Pharmacology, Department of Medicine, The Johns Hopkins University School ofMedicine, Baltimore, MD, USA.
Mol Nutr Food Res. 2008 Jun;52 Suppl 1:S128-38. doi: 10.1002/mnfr.200700195.
Cellular protection against oxidative and electrophile toxicities is provided by two types of small-molecule antioxidants: (i) direct antioxidants, which are redox active, short-lived, are sacrificed in the process of their antioxidant actions and need to be replenished or regenerated, and may evoke pro-oxidant effects; and (ii) indirect antioxidants, that may or may not be redox active. Indirect antioxidants activate the Keap1/Nrf2/ARE pathway resulting in transcriptional induction of a battery of cytoprotective proteins (also known as phase 2 enzymes) that act catalytically, are not consumed, have long half-lives, and are unlikely to evoke pro-oxidant effects. These protective systems are involved in a complex functional interplay, such that many cytoprotective proteins participate in the synthesis and/or regeneration of direct antioxidants, whereas some direct antioxidants are required for the catalytic functions of cytoprotective proteins. Importantly, many inducers of cytoprotective proteins have been isolated from edible plants, e. g., sulforaphane from broccoli and curcumin from turmeric. Both are pleiotropic agents with multiple biological activities that could collectively contribute to their protective effects in various animal studies, including models of carcinogenesis, hypertension, neuronal and retinal damage. In addition to inducing cytoprotective proteins, molecules like curcumin which contain Michael acceptor functionalities (olefins or acetylenes conjugated to electron withdrawing groups) and phenolic hydroxyl groups can scavenge directly and potently oxygen- and nitrogen-centered reactive intermediates. Such bifunctional antioxidants can play a dual protective role by: (i) scavenging hazardous oxidants directly and instantaneously, and (ii) inducing cytoprotective enzymes that in turn function to resolve the consequences of hazardous processes that are already in progress, and to ensure long-term protection against subsequent challenges.
（i）直接抗氧化剂，它们具有氧化还原活性，寿命短，在抗氧化作用过程中会被消耗，需要补充或再生，并且可能引发促氧化作用；（ii）间接抗氧化剂，它们可能具有或不具有氧化还原活性。间接抗氧化剂激活Keap1/Nrf2/ARE途径，导致一系列具有催化作用、不被消耗、半衰期长且不太可能引发促氧化作用的细胞保护蛋白（也称为II相酶）的转录诱导。这些保护系统参与复杂的功能相互作用，使得许多细胞保护蛋白参与直接抗氧化剂的合成和/或再生，而一些直接抗氧化剂是细胞保护蛋白催化功能所必需的。重要的是，许多细胞保护蛋白的诱导剂已从可食用植物中分离出来，例如西兰花中的萝卜硫素和姜黄中的姜黄素。两者都是具有多种生物活性的多效性药物，在各种动物研究中，包括癌症发生、高血压、神经元和视网膜损伤模型中，它们的综合作用可能有助于其保护作用。除了诱导细胞保护蛋白外，像姜黄素这样含有迈克尔受体功能基团（与吸电子基团共轭的烯烃或乙炔）和酚羟基的分子可以直接且有效地清除以氧和氮为中心的反应性中间体。这种双功能抗氧化剂可以通过以下方式发挥双重保护作用：（i）直接且即时地清除有害氧化剂，（ii）诱导细胞保护酶，这些酶反过来作用于解决已经发生的有害过程的后果，并确保对后续挑战的长期保护。
