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

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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.