title: 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.
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.
authors.affiliation: Laboratory of Clinical Pharmaceutics & Therapeutics, Division of Pharmasciences, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12-jo, Nishi-6-chome, Kita-ku, Sapporo 060-0812, Japan.
authors.forename: Jiro
authors.initials: J
authors.lastname: Ogura
authors.affiliation: Laboratory of Clinical Pharmaceutics & Therapeutics, Division of Pharmasciences, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12-jo, Nishi-6-chome, Kita-ku, Sapporo 060-0812, Japan.
authors.forename: Kaori
authors.initials: K
authors.lastname: Kuwayama
authors.affiliation: Laboratory of Clinical Pharmaceutics & Therapeutics, Division of Pharmasciences, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12-jo, Nishi-6-chome, Kita-ku, Sapporo 060-0812, Japan.
authors.forename: Shunichi
authors.initials: S
authors.lastname: Sasaki
authors.affiliation: Laboratory of Clinical Pharmaceutics & Therapeutics, Division of Pharmasciences, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12-jo, Nishi-6-chome, Kita-ku, Sapporo 060-0812, Japan.
authors.forename: Chihiro
authors.initials: C
authors.lastname: Kaneko
authors.affiliation: Laboratory of Clinical Pharmaceutics & Therapeutics, Division of Pharmasciences, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12-jo, Nishi-6-chome, Kita-ku, Sapporo 060-0812, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Koizumi
authors.affiliation: Laboratory of Clinical Pharmaceutics & Therapeutics, Division of Pharmasciences, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12-jo, Nishi-6-chome, Kita-ku, Sapporo 060-0812, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Yabe
authors.affiliation: Laboratory of Clinical Pharmaceutics & Therapeutics, Division of Pharmasciences, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12-jo, Nishi-6-chome, Kita-ku, Sapporo 060-0812, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Tsujimoto
authors.affiliation: Laboratory of Clinical Pharmaceutics & Therapeutics, Division of Pharmasciences, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12-jo, Nishi-6-chome, Kita-ku, Sapporo 060-0812, Japan.
authors.forename: Reiko
authors.initials: R
authors.lastname: Takeno
authors.affiliation: Laboratory of Clinical Pharmaceutics & Therapeutics, Division of Pharmasciences, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12-jo, Nishi-6-chome, Kita-ku, Sapporo 060-0812, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Takaya
authors.affiliation: Laboratory of Clinical Pharmaceutics & Therapeutics, Division of Pharmasciences, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12-jo, Nishi-6-chome, Kita-ku, Sapporo 060-0812, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Kobayashi
authors.affiliation: Laboratory of Clinical Pharmaceutics & Therapeutics, Division of Pharmasciences, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12-jo, Nishi-6-chome, Kita-ku, Sapporo 060-0812, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Yamaguchi
authors.affiliation: Laboratory of Clinical Pharmaceutics & Therapeutics, Division of Pharmasciences, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12-jo, Nishi-6-chome, Kita-ku, Sapporo 060-0812, Japan. Electronic address: ken-i@pharm.hokudai.ac.jp.
authors.forename: Ken
authors.initials: K
authors.lastname: Iseki
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000375:Aging; D000493:Allopurinol / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D018938:Caco-2 Cells / Q000187:drug effects / Q000378:metabolism; D019281:Dimerization; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006074:Gout Suppressants / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D033461:Hyperuricemia / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control; D019271:Hypoxanthine / Q000494:pharmacology; D007082:Ileum / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D007288:Inosine / Q000633:toxicity; D066237:Intestinal Elimination / Q000187:drug effects; D007413:Intestinal Mucosa / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism*; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014527:Uric Acid / Q000378:metabolism*; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C489249:Abcg2 protein, rat; D004791:Enzyme Inhibitors; D006074:Gout Suppressants; D009363:Neoplasm Proteins; D017382:Reactive Oxygen Species; D014527:Uric Acid; D019271:Hypoxanthine; D007288:Inosine; D000493:Allopurinol; D014969:Xanthine Oxidase
keywords: Aging; Breast cancer resistance protein; Hyperuricemia; Reactive oxygen species; Uric acid excretion