Mechanism of expression and function of drug transporters in endotoxemia

2010 Fiscal Year Final Research Report

• Project/Area Number: 20590587
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Laboratory medicine
• Research Institution: Aichi Medical University
• Principal Investigator: HASEGAWA Takaaki Aichi Medical University, 医学部, 教授 (80198720)
• Co-Investigator(Kenkyū-buntansha): FENG GuoーGang 愛知医科大学, 医学部, 講師 (70351111)
• Project Period (FY): 2008 – 2010
• Keywords: エンドトキシン / トランスポーター / サイトカイン / 生体膜輸送

Research Abstract

Firstly, the effect of endotoxin (ET) on the function and expression of hepatic breast cancer resistance protein (Bcrp) was investigated in mice. In vivo clearance experiments showed that the biliary clearance (CL_<BILE>) of mitoxantrone was significantly decreased 24 h after ET injection. Both Western blot and immunofluorescence analyses also revealed that the protein levels of hepatic Bcrp were decreased 24 h after injection of ET. ET significantly induced the overproduction of the cytokines IL-6 and IL-1β. Pretreatment with IL-6 significantly decreased the CL_<BILE> of mitoxantrone. Hepatic Bcrp was significantly down-regulated by injection of IL-6 (50,000U/mouse). These findings suggest that ET reduces Bcrp-mediated hepatobiliary excretion of mitoxantrone by decreasing the expression of hepatic Bcrp, which is likely due to increased IL-6 levels. Secondly, to clarify ET-induced changes in organic anion transport ability, GFR and renal tubular secretion clearance of PAH which is a substrate for renal organic anion transporter 1 (Oat1) and Oat3 were investigated in endotoxemic rats. The expression of Oat1 and Oat3 mRNA was decreased, and the expression returned to control levels after 72 h after injection of ET. These findings suggest that the decreased mRNA levels of renal Oat1 and Oat3 are involved in the decreased renal tubular secretion clearance of PAH in endotoxemic rats and that these changes are transient and recovered time-dependently.

Research Products

• [Journal Article] Involvement of sulfate conjugation and multidrug resistance-associated protein 2 (Mrp2) in sex-related differences in the pharmacokinetics of garenoxacin in rats. (2011)
  • Author(s): Hayashi T, Abe F, Kato M, Saito H, Ueyama J, Kondo Y, Imai Y, Katoh M, Nadai M, Hasegawa T
  • Journal Title: J.Infect. Chemother. 17 Pages: 24-28
  • Peer Reviewed
• [Journal Article] Endotoxin does not alter the pharmacokinetics of micafungin, but it impairs biliary excretion of micafungin via multidrug resistance associated protein 2 (ABCC2/Mrp2) in rats. (2011)
  • Author(s): Noda T, Abe F, Ueyama J, Kato M, Katoh M, Nadai M, Saito H, Hasegawa T
  • Journal Title: J.Infect. Chemother. 17 Pages: 207-213
  • Peer Reviewed
• [Journal Article] β-Glucuronidase activity is a sensitive biomarker to assess low-level organophosphorus insecticide exposure. (2010)
  • Author(s): Ueyama J, Satoh T, Kondo T, Takagi K, Shibata E, Goto M, Kimata A, Saito I, Hasegawa T, Wakusawa S, Kamijima M
  • Journal Title: Toxicol Lett. 133 Pages: 115-119
  • Peer Reviewed
• [Journal Article] a novel WD40-repeat protein, mediates spontaneous and tumor necrosis factor-induced apoptosis. (2010)
  • Author(s): Feng GG, Li C, Huang L, Tsunekawa K, Sato Y, Fujiwara Y, Komatsu T, Honda T, Fan JH, Goto H, Koide T, Hasegawa T, Ishikawa N, Naofen
  • Journal Title: Biochem. Biophys. Res.Commun. 394 Pages: 153-157
  • Peer Reviewed
• [Journal Article] Active ingredients of traditional Japanese (kampo) medicine, inchinkoto, in murine concanavalin A-induced hepatitis. (2010)
  • Author(s): Mase A, Makino B, Tsuchiya N, Yamamoto M, Kase Y, Takeda S, Hasegawa T
  • Journal Title: J.Ethnopharmacol. 127 Pages: 742-749
  • Peer Reviewed
• [Journal Article] Effect of a Kampo preparation, byakkokaninjinto, on pharmacokinetics of ciprofloxacin and tetracycline. (2009)
  • Author(s): Ohnishi M, Hitoshi K, Katoh M, Nadai M, Abe F, Kurono S, Haniuda M, Saito H, Hasegawa T
  • Journal Title: Biol.Pharm.Bull. 32 Pages: 1080-1084
  • Peer Reviewed
• [Journal Article] Urinary excretion of 3-phenoxybenzoic acid in middle-aged and elderly general population of Japan. (2009)
  • Author(s): Ueyama J, Kimata A, Kamijima M, Hamajima N, Ito Y, Suzuki K, Inoue T, Yamamoto K, Takagi K, Saito I, Miyamoto K.-I, Hasegawa T, Kondo T
  • Journal Title: Environ.Res. 109 Pages: 175-180
  • Peer Reviewed
• [Journal Article] Heme oxygenase-1 mediates the anti-allergic actions of quercetin in rodent mast cells. (2009)
  • Author(s): Matsushima, M., Takagi, K., Ogawa M., Hirose E., Ota Y., Abe F., Baba K., Hasegawa T., Hasegawa T, Kawabe T
  • Journal Title: Inflamm.Res. 58 Pages: 705-715
  • Peer Reviewed
• [Journal Article] Association of serum NOx level with clustering of metabolic syndrome components in middle-aged and elderly general populations in Japan. (2008)
  • Author(s): Ueyama J, Kondo T, Imai R, Kimata A, Yamamoto K, Suzuki K, Inoue T, Ito Y, Miyamoto K.-I, Hasegawa T, Hamajima N
  • Journal Title: Environ. Health Preventive Med. 13 Pages: 36-42
  • Peer Reviewed
• [Journal Article] Effect of Thalidomide on Endotoxin-Induced Decreases in Activity and Expression of Hepatic Cytochrome P450 3A2. (2008)
  • Author(s): Ueyama J, Nadai M, Zhao YL, Kanazawa H, Takagi K, Kondo T, Takagi K, Wakusawa S, Abe F, Saito H, Miyamoto K, Hasegawa T
  • Journal Title: Biol.Pharm.Bull. 31 Pages: 1598-1600
  • Peer Reviewed
• [Journal Article] Involvement of multidrug resistance associated protein 2(ABCC2/Mrp2) in biliary excretion of micafungin in rats. (2008)
  • Author(s): Abe F, Ueyama J, Kimata A, Kato M, Hayashi T, Nadai M, Saito H, Takeyama N, Noguchi H, Hasegawa T
  • Journal Title: Life Sci. 83 Pages: 229-235
  • Peer Reviewed
• [Journal Article] Role of plasma proteins in pharmacokinetics of micafungin, an antifungal antibiotic, in analbuminemic rats. (2008)
  • Author(s): Abe F, Ueyama J, Kawasumi N, Nadai M, Hayashi T, Kato M, Ohnishi M, Saito H, Takeyama N, Hasegawa T
  • Journal Title: Antimicrob. Agents Chemother. 52 Pages: 3454-3456
  • Peer Reviewed
• [Journal Article] Cyclooxygenase-2 expression in invasive transitional cell carcinoma of the urinary bladder. (2008)
  • Author(s): Yamada Y, Nakamura K, Inoue Y, Naruse K, Aoki S, Taki T, Tobiume M, Zennami K, Katsuda R, Hara K, Kyoku I, Mitsutake N, Arakawa M, Saito H, Hasegawa T, Noguchi H, Honda N
  • Journal Title: Mol.Med.Reports 1 Pages: 791-795
  • Peer Reviewed
• [Journal Article] Effect of the organophosphoruspesticide diazinon on glucose tolerance in type 2 diabetic rats. (2008)
  • Author(s): Ueyama J, Kamijima M, Asai K, Mochizuki A, Wang D, Kondo T, Suzuki T, Takagi K, Takagi K, Kanazawa H, Miyamoto K, Wakusawa S, Hasegawa T
  • Journal Title: Toxicol. Lett. 182 Pages: 42-47
  • Peer Reviewed
• [Journal Article] Quality of life improvement in patients diagnosed with hormone refractory prostate cancer with bone metastatis as a result of chemotherapy and the administration of zoledronic acid. (2008)
  • Author(s): Arakawa M, Saito H, Hasegawa T, Kato Y, Ishikawa K
  • Journal Title: Palliative Care Res. 3 Pages: 308-315
  • Peer Reviewed
• [Journal Article] Pharmacokinetic-pharmacodynamic study of itraconazole in patientswith fungal infections in intensive care units.
  • Author(s): Hagihara M, Kasai H, Umemura T, Kato T, Hasegawa T, Mikamo H
  • Journal Title: J.Infect. Chemother. 17 Pages: 224-230
  • Peer Reviewed
• [Journal Article] Panipenem does not alter the pharmacokinetics of the active metabolite of irinotecan SN-38 and SN-38 glucuronide (SN-38G) in rats.
  • Author(s): Kato A, Ueyama J, Abe F, Hotta K, Tukiyama I, Ohshima T, Saito H, Hasegawa T
  • Journal Title: Anticancer Res. in press
  • Peer Reviewed
• [Book] 臨床への薬物動態学 (2009)
  • Author(s): 岩川精吾, 他
  • Total Pages: 311
  • Publisher: 廣川書店
• [Book] シンプル薬理学 (2008)
  • Author(s): 石川直久, 他
  • Total Pages: 328
  • Publisher: 南江堂