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
| Autor: | Takashi Tsujimoto, Ken Iseki, Hiroaki Yamaguchi, Jiro Ogura, Reiko Takeno, Takahiro Koizumi, Atsushi Takaya, Shunichi Sasaki, Keisuke Yabe, Chihiro Kaneko, Masaki Kobayashi, Kaori Kuwayama |
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| Rok vydání: | 2015 |
| Předmět: |
Male
Aging Xanthine Oxidase medicine.medical_specialty Allopurinol Hyperuricemia Biology Biochemistry Gout Suppressants Excretion chemistry.chemical_compound Intestinal mucosa Ileum Internal medicine Intestinal Elimination medicine ATP Binding Cassette Transporter Subfamily G Member 2 Animals Humans Enzyme Inhibitors Intestinal Mucosa Rats Wistar Xanthine oxidase Hypoxanthine Pharmacology chemistry.chemical_classification Reactive oxygen species nutritional and metabolic diseases medicine.disease Inosine Mitochondria Neoplasm Proteins Uric Acid Endocrinology chemistry Enzyme Induction Uric acid ATP-Binding Cassette Transporters Caco-2 Cells Reactive Oxygen Species Dimerization medicine.drug |
| Zdroj: | Biochemical Pharmacology. 97:89-98 |
| ISSN: | 0006-2952 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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