Reactive oxygen species derived from xanthine oxidase interrupt dimerization of breast cancer resistance protein, resulting in suppression of uric acid excretion to the intestinal lumen

被引：27

作者：

Ogura, Jiro ^{[1
]}

Kuwayama, Kaori ^{[1
]}

Sasaki, Shunichi ^{[1
]}

Kaneko, Chihiro ^{[1
]}

Koizumi, Takahiro ^{[1
]}

Yabe, Keisuke ^{[1
]}

Tsujimoto, Takashi ^{[1
]}

Takeno, Reiko ^{[1
]}

Takaya, Atsushi ^{[1
]}

Kobayashi, Masaki ^{[1
]}

Yamaguchi, Hiroaki ^{[1
]}

Iseki, Ken ^{[1
]}

机构：

[1] Hokkaido Univ, Div Pharmasci, Fac Pharmaceut Sci, Lab Clin Pharmaceut &Therapeut,Kita Ku, Sapporo, Hokkaido 0600812, Japan

来源：

BIOCHEMICAL PHARMACOLOGY | 2015年 / 97卷 / 01期

基金：

日本学术振兴会;

关键词：

Hyperuricemia; Aging; Reactive oxygen species; Breast cancer resistance protein; Uric acid excretion; ANION TRANSPORTING POLYPEPTIDES; OXIDATIVE STRESS; TISSUE DISTRIBUTION; URATE; RAT; EFFLUX; IDENTIFICATION; EXPRESSION; BCRP/ABCG2; REDUCTION;

D O I：

10.1016/j.bcp.2015.06.021

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

The prevalence of hyperuricemia/gout increases with aging. However, the effect of aging on function for excretion of uric acid to out of the body has not been clarified. We found that ileal uric acid clearance in middle-aged rats (11-12 months) was decreased compared with that in young rats (2 months). In middle-aged rats, xanthine oxidase (XO) activity in the ileum was significantly higher than that in young rats. Inosine-induced reactive oxygen species (ROS), which are derived from XO, also decreased ileal uric acid clearance. ROS derived from XO decreased the active homodimer level of breast cancer resistance protein (BCRP), which is a uric acid efflux transporter, in the ileum. Pre-administration of allopurinol recovered the BCRP homodimer level, resulting in the recovering ileal uric acid clearance. Moreover, we investigated the effects of ROS derived from XO on BCRP homodimer level directly in Caco-2 cells using hypoxanthine. Treatment with hypoxanthine decreased BCRP homodimer level. Treatment with hypoxanthine induced mitochondrial dysfunction, suggesting that the decreasing BCRP homodimer level might be caused by mitochondrial dysfunction. In conclusion, ROS derived from XO decrease BCRP homodimer level, resulting in suppression of function for uric acid excretion to the ileal lumen. ROS derived from XO may cause the suppression of function of the ileum for the excretion of uric acid with aging. The results of our study provide a new insight into the causes of increasing hyperuricemia/gout prevalence with aging. (C) 2015 Elsevier Inc. All rights reserved.

引用

页码：89 / 98

页数：10

共 46 条

[1] URIC-ACID PROVIDES AN ANTIOXIDANT DEFENSE IN HUMANS AGAINST OXIDANT-CAUSED AND RADICAL-CAUSED AGING AND CANCER - A HYPOTHESIS [J].