Kobayashi Akio, Takahashi Tadakazu, Sugai Shoichiro, Miyakawa Yoshifumi, Iwatsuka Hisashi, Yamaguchi Tokio
Toxicology Research Lab., Central Pharmaceutical Research Institute, Japan Tobacco Inc., 23 Naganuki Hadano, Kanagawa 257-0024, Japan.
J Toxicol Sci. 2003 May;28(2):71-5. doi: 10.2131/jts.28.71.
Bilirubin oxidative metabolites (BOM) were shown to be excreted into the urine in rats in which exaggerated oxidative stress was induced. We measured bilirubin (BR) and biopyrrins in the urine of rats treated with fenofibrate, a peroxisome proliferator, which is known to cause oxidative stress. Male Crj:CD(SD)IGS rats aged 6 weeks were treated orally with fenofibrate at 10, 400 and 800 mg/kg for 2 weeks. Urinary excretion of BR and BOM, and the plasma BOM levels were determined after the first dose and after 1-week and 2-week treatment. Urinary excretion of BOM was significantly and dose-dependently increased by fenofibrate treatment at 400 and 800 mg/kg. This became more prominent as the dosing period progressed and reached an 8-fold increase in the 400 mg/kg group and 11-fold increase in the 800 mg/kg group compared with the data before dosing on Day 14. Plasma BOM levels were increased 1.8-fold and 2.7-fold, respectively, at 400 and 800 mg/kg in fenofibrate-treated rats. At 800 mg/kg, there was also increased urinary excretion of BR (2-fold) on Day 14. These changes of BOM in the urine and plasma indicated that BR was oxidized by reactive oxygen species (ROSs), which were produced by treatment with fenofibrate. In conclusion, urinary excretion of BOM, which is a marker for oxidative stress, urinary excretion of BR and the plasma BOM levels were increased in rats treated with fenofibrate. Increased urinary excretions of BR and BOM, and increased plasma BOM levels are likely to be the consequence of physiological protection against the oxidative stress produced by fenofibrate. These findings suggest a possibility that analysis of BOM in the urine and plasma could be helpful in evaluating the degree of oxidative stress in vivo.
在诱导了过度氧化应激的大鼠中，胆红素氧化代谢产物（BOM）被证明会排泄到尿液中。我们测量了用非诺贝特（一种过氧化物酶体增殖剂，已知会引起氧化应激）处理的大鼠尿液中的胆红素（BR）和双吡咯。6周龄的雄性Crj:CD(SD)IGS大鼠口服给予非诺贝特，剂量分别为10、400和800mg/kg，持续2周。在首次给药后以及治疗1周和2周后，测定BR和BOM的尿排泄量以及血浆BOM水平。400和800mg/kg的非诺贝特处理显著且剂量依赖性地增加了BOM的尿排泄量。随着给药期的推进，这种情况变得更加明显，与第14天给药前的数据相比，400mg/kg组增加了8倍，800mg/kg组增加了11倍。非诺贝特处理的大鼠中，400和800mg/kg剂量下血浆BOM水平分别增加了1.8倍和2.7倍。在800mg/kg剂量下，第14天BR的尿排泄量也增加了（2倍）。尿液和血浆中BOM的这些变化表明，BR被非诺贝特处理产生的活性氧（ROS）氧化。总之，在非诺贝特处理的大鼠中，作为氧化应激标志物的BOM尿排泄量、BR尿排泄量以及血浆BOM水平均升高。BR和BOM尿排泄量增加以及血浆BOM水平升高可能是对非诺贝特产生的氧化应激进行生理保护的结果。这些发现表明，分析尿液和血浆中的BOM可能有助于评估体内氧化应激的程度。
