論文 - 詳細
| RRC ID | 37524 |
|---|---|
| 著者 | Ogura J, Kuwayama K, Sasaki S, Kaneko C, Koizumi T, Yabe K, Tsujimoto T, Takeno R, Takaya A, Kobayashi M, Yamaguchi H, Iseki K. |
| タイトル | 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. |
| ジャーナル | Biochem Pharmacol |
| Abstract |
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. |
| 巻・号 | 97(1) |
| ページ | 89-98 |
| 公開日 | 2015-9-1 |
| DOI | 10.1016/j.bcp.2015.06.021 |
| PII | S0006-2952(15)00337-8 |
| PMID | 26119820 |
| MeSH | ATP Binding Cassette Transporter, Subfamily G, Member 2 ATP-Binding Cassette Transporters / antagonists & inhibitors* ATP-Binding Cassette Transporters / chemistry ATP-Binding Cassette Transporters / genetics ATP-Binding Cassette Transporters / metabolism Aging* Allopurinol / pharmacology Allopurinol / therapeutic use Animals Caco-2 Cells / drug effects Caco-2 Cells / metabolism Dimerization Enzyme Induction / drug effects Enzyme Inhibitors / pharmacology Enzyme Inhibitors / therapeutic use Gout Suppressants / pharmacology Gout Suppressants / therapeutic use Humans Hyperuricemia / chemically induced Hyperuricemia / metabolism Hyperuricemia / prevention & control Hypoxanthine / pharmacology Ileum / drug effects Ileum / growth & development Ileum / metabolism Inosine / toxicity Intestinal Elimination / drug effects Intestinal Mucosa / drug effects Intestinal Mucosa / growth & development Intestinal Mucosa / metabolism* Male Mitochondria / drug effects Mitochondria / enzymology Mitochondria / metabolism Neoplasm Proteins / antagonists & inhibitors* Neoplasm Proteins / chemistry Neoplasm Proteins / genetics Neoplasm Proteins / metabolism Rats, Wistar Reactive Oxygen Species / agonists Reactive Oxygen Species / antagonists & inhibitors Reactive Oxygen Species / metabolism* Uric Acid / metabolism* Xanthine Oxidase / antagonists & inhibitors Xanthine Oxidase / chemistry Xanthine Oxidase / metabolism* |
| IF | 4.96 |
| 引用数 | 14 |
| WOS 分野 | PHARMACOLOGY & PHARMACY |
| リソース情報 | |
| ヒト・動物細胞 | CACO-2(RCB0988) |