The roles of bilirubin and ascorbic acid as physiological antioxidant against oxidative stress.

胆红素（BR）是由血红素合成的，具有清除自由基如活性氧（ROS）的活性。近年来，从人尿中分离到BR氧化代谢物（BOM），其中两种被命名为biotripyrrin-a和-b。在这项研究中，(1)我们研究了BR作为抗氧化应激的抗氧化剂的生理作用，(2)我们研究了尿液中的BOM可能是一种代谢标志物，用于预测由ROS产生引起的疾病的发生。(1)将具有抗坏血酸（AsA）合成遗传缺陷的ODS大鼠腹腔注射脂多糖（LPS），其处理引起氧化应激。LPS处理显著增加了尿液中的BOM，而饲喂抗坏血酸显著抑制了这种增加。肝血红素加氧酶-1是胆红素合成的限速酶，被称为氧化应激诱导的蛋白质，LPS处理显著诱导。这种诱导也被喂食抗坏血酸所抑制。这些结果表明BR作为一种生理性抗氧化剂与抗坏血酸协同抗氧化应激。（II）胰岛素依赖型糖尿病（IDDM）是一种自身免疫性疾病，似乎是由于细胞内ROS的产生引起胰岛的破坏而发展起来的。非肥胖型糖尿病小鼠（NOD）是IDDM的小鼠模型。在高血糖发生之前，每只NOD小鼠在9周龄至16周龄之间尿BOM均有所增加。这一结果提示，尿液中BOM的增加可能是预测IDDM发病的代谢标志物。

Bilirubin (BR) is synthesized from heme, and has an activity to scavenge free radicals such as reactive oxygen species (ROS). Recently, BR oxidative metabolites (BOM) were isolated from human urine, and two of them were named as biotripyrrin-a and -b. In this study, (I) we investigated the physiological role of BR as an antioxidant against oxidative stress, and (II) we examined the possibility that BOM in urine could be a metabolic marker to prodict the onset of disease that is caused by the production of ROS.(I) The ODS rat that is a rat mutant with a hereditary defect in ascorbic acid (AsA) synthesis was intraperitoneally injected with lipopolysaccharide (LPS) whose treatment caused an oxidative stress. LPS treatment markedly increased BOM in urine, and this increase was significantly suppressed by feeding ascorbic acid. Hepatic heme oxygenase-1, which is a rate-limiting enzyme in bilirubin synthesis and is known as a protein induced by oxidative stress, was markedly induced by the LPS treatment. This induction was also suppressed by feeding ascorbic acid. These results indicated that BR acts as a physiological antioxidant synergistically with ascorbic acid against oxidative stress.(II) Insulin-dependent diabetes (IDDM) is an autoimmune desease, and seems to be developed by the destruction of pancreatic islets caused by the production of intecellular ROS.Nonobese diabetic (NOD) mouse is an mouse model for IDDM.The increase of urinary BOM was observed in each NOD mouse between 9-week-old and 16-week-old before the development of hyperglycemia. This result suggests the possibility that the increase of BOM in urine is a metabolic marker for predicting the onset of IDDM.