Urinary excretion of oxidative metabolites of bilirubin in fenofibrate-treated rats.
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.
Kobayashi
Akio
A
Toxicology Research Lab., Central Pharmaceutical Research Institute, Japan Tobacco Inc., 23 Naganuki Hadano, Kanagawa 257-0024, Japan.
Takahashi
Tadakazu
T
Sugai
Shoichiro
S
Miyakawa
Yoshifumi
Y
Iwatsuka
Hisashi
H
Yamaguchi
Tokio
T
D000818:Animals; D001663:Bilirubin / Q000097:blood / Q000652:urine*; D002374:Catalase / Q000097:blood; D004305:Dose-Response Relationship, Drug; D011345:Fenofibrate / Q000633:toxicity*; D000960:Hypolipidemic Agents / Q000633:toxicity*; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D009929:Organ Size / Q000187:drug effects; D010084:Oxidation-Reduction; D020675:Peroxisomes / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D013312:Stress, Physiological / Q000652:urine
D000960:Hypolipidemic Agents; D017382:Reactive Oxygen Species; D002374:Catalase; D001663:Bilirubin; D011345:Fenofibrate