Gutteridge J M, Halliwell B
Oxygen Chemistry Laboratory, Royal Brompton Hospital, London, UK.
Ann N Y Acad Sci. 2000;899:136-47. doi: 10.1111/j.1749-6632.2000.tb06182.x.
In the late 1950's free radicals and antioxidants were almost unheard of in the clinical and biological sciences but chemists had known about them for years in the context of radiation, polymer and combustion technology. Daniel Gilbert, Rebeca Gerschman and their colleagues related the toxic effects of elevated oxygen levels on aerobes to those of ionizing radiation, and proposed that oxygen toxicity is due to free radical formation, in a pioneering paper in 1956. Biochemistry owes much of its early expansion to the development and application of chromatographic and electrophoretic techniques, especially as applied to the study of proteins. Thus, superoxide dismutase (SOD) enzymes (MnSOD, CuZnSOD, FeSOD) were quickly identified. By the 1980's Molecular Biology had evolved from within biochemistry and microbiology to become a dominant new discipline, with DNA sequencing, recombinant DNA technology, cloning, and the development of PCR representing milestones in its advance. As a biological tool to explore reaction mechanisms, SOD was a unique and valuable asset. Its ability to inhibit radical reactions leading to oxidative damage in vitro often turned out to be due to its ability to prevent reduction of iron ions by superoxide. Nitric oxide (NO.) provided the next clue as to how SOD might be playing a critical biological role. Although NO. is sluggish in its reactions with most biomolecules it is astoundingly reactive with free radicals, including superoxide. Overall, this high reactivity of NO. with radicals may be beneficial in vivo, e.g. by scavenging peroxyl radicals and inhibiting lipid peroxidation. If reactive oxygen species are intimately involved with the redox regulation of cell functions, as seems likely from current evidence, it may be easier to understand why attempts to change antioxidant balance in aging experiments have failed. The cell will adapt to maintain its redox balance. Indeed, transgenic animals over-expressing antioxidants show some abnormalities of function. There must therefore be a highly complex interrelationship between dietary, constitutive, and inducible antioxidants with the body, under genetic control. The challenge for the new century is to be able to understand these relationships, and how to manipulate them to our advantage to prevent and treat disease.
在20世纪50年代后期，自由基和抗氧化剂在临床和生物科学领域几乎无人知晓，但化学家们在辐射、聚合物和燃烧技术领域已经对它们有所了解多年。1956年，丹尼尔·吉尔伯特、丽贝卡·格施曼及其同事在一篇开创性的论文中，将高氧水平对需氧生物的毒性作用与电离辐射的毒性作用联系起来，并提出氧毒性是由于自由基的形成。生物化学早期的许多发展都归功于色谱和电泳技术的发展与应用，尤其是应用于蛋白质研究时。因此，超氧化物歧化酶（SOD）（锰超氧化物歧化酶、铜锌超氧化物歧化酶、铁超氧化物歧化酶）很快被识别出来。到了20世纪80年代，分子生物学从生物化学和微生物学中发展起来，成为一门占主导地位的新学科，DNA测序、重组DNA技术、克隆以及聚合酶链反应的发展是其发展过程中的里程碑。作为探索反应机制的生物学工具，超氧化物歧化酶是一种独特而有价值的资产。它在体外抑制导致氧化损伤的自由基反应的能力，往往被证明是由于它能够防止超氧化物还原铁离子。一氧化氮（NO·）为超氧化物歧化酶如何发挥关键生物学作用提供了下一条线索。尽管一氧化氮与大多数生物分子的反应较为迟缓，但它与自由基，包括超氧化物，反应却极为迅速。总体而言，一氧化氮与自由基的这种高反应性在体内可能是有益的，例如通过清除过氧自由基和抑制脂质过氧化。如果活性氧物种确实如目前证据所显示的那样，与细胞功能的氧化还原调节密切相关，那么就更容易理解为什么在衰老实验中试图改变抗氧化剂平衡的尝试会失败。细胞会进行适应以维持其氧化还原平衡。事实上，过度表达抗氧化剂的转基因动物表现出一些功能异常。因此，在基因控制下，饮食中的、组成性的和诱导性的抗氧化剂与身体之间必然存在高度复杂的相互关系。新世纪面临的挑战是能够理解这些关系，以及如何利用它们来预防和治疗疾病。
