Confirmation of superoxide generation via xanthine oxidase in streptozotocin-induced diabetic mice.
Reactive oxygen species (ROS) may play key roles in vascular inflammation and atherogenesis in patients with diabetes. In this study, xanthine oxidase (XO) system was examined as a potential source of superoxide in mice with streptozotocin (STZ)-induced experimental diabetes. Plasma XO activity increased 3-fold in diabetic mice (50 +/- 33 microU/ml) 2 weeks after the onset of diabetes, as compared with non-diabetic control mice (15 +/- 6 microU/ml). In vivo superoxide generation in diabetic mice was evaluated by an in vivo electron spin resonance (ESR)/spin probe method. Superoxide generation was significantly enhanced in diabetic mice, and the enhancement was restored by the administration of superoxide dismutase (SOD) and 4,5-dihydroxy-1,3-benzene disulfonic acid (Tiron), which was reported to scavenge superoxide. Pretreatment of diabetic mice with XO inhibitors, allopurinol and its active metabolite oxipurinol, normalized the increased superoxide generation. In addition, there was a correlation (r = 0.78) between the level of plasma XO activity and the relative degree of superoxide generation in diabetic and non-diabetic mice. Hence, the results of this study strongly suggest that superoxide should be generated through the increased XO seen in the diabetic model mice, which may be involved in the pathogenesis of diabetic vascular complications.
Matsumoto
Shingo
S
Laboratory of Bio-function Sciences, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
Koshiishi
Ichiro
I
Inoguchi
Toyoshi
T
Nawata
Hajime
H
Utsumi
Hideo
H
D014013:1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt / Q000378:metabolism; D000493:Allopurinol / Q000494:pharmacology; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004578:Electron Spin Resonance Spectroscopy / Q000379:methods; D005260:Female; D051379:Mice; D008813:Mice, Inbred ICR; D010117:Oxypurinol / Q000494:pharmacology; D017382:Reactive Oxygen Species; D013311:Streptozocin / Q000494:pharmacology*; D013481:Superoxides / Q000378:metabolism*; D013997:Time Factors; D014527:Uric Acid / Q000097:blood; D014969:Xanthine Oxidase / Q000097:blood*
D001786:Blood Glucose; D017382:Reactive Oxygen Species; D013481:Superoxides; D014527:Uric Acid; D014013:1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt; D013311:Streptozocin; D000493:Allopurinol; D014969:Xanthine Oxidase; D010117:Oxypurinol