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1999 Fiscal Year Final Research Report Summary

Molecular cloning and functional expression of kidney-specific organic anionic drug transporters

Research Project

Project/Area Number 09470025
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field General pharmacology
Research InstitutionKyorin University School of Medicine

Principal Investigator

ENDOU Hitoshi  Kyorin University School of Medicine, Department of Pharmacology & Toxicology, Professor, 医学部, 教授 (20101115)

Co-Investigator(Kenkyū-buntansha) SEKINE Takashi  Kyorin University School of Medicine, Department of Pharmacology & Toxicology, Assistant, 医学部, 助手 (50255402)
TAKEDA Michio  Kyorin University School of Medicine, Department of Pharmacology & Toxicology, Lecturer, 医学部, 講師 (40255401)
KANAI Yoshikatsu  Kyorin University School of Medicine, Department of Pharmacology & Toxicology, Lecturer, 医学部, 助教授 (60204533)
CHA Seok ho  Kyorin University School of Medicine, Department of Pharmacology & Toxicology, Assistant, 医学部, 助手 (50276200)
HOSOYAMADA Makoto  Kyorin University School of Medicine, Department of Pharmacology & Toxicology, Assistant, 医学部, 助手 (00291659)
INATOMI Jun  Kyorin University School of Medicine, Department of Pharmacology & Toxicology, Assistant (00311960)
Project Period (FY) 1997 – 1999
Keywordsorganic anion / organic anion transporter / para-amino hippurate / estron sulfate / ochratoxin A / organic cation transporter / carnitine transporter / multispecific substrate recognition
Research Abstract

Most drugs ingested into the body are metabolized by drug-metabolizing enzymes in the liver, and converted to more polarized hydrophilic compounds. Thus formed drug metabolites contain either negative or positive charge, and more anionic compounds are produced. To eliminate these drug metabolites out of the body, specific membrane proteins named transporters are required.
There are two major pathways for drug elimination, one of which is hepatic one through bile and another is renal one to urine. In this investigation, we tried to clone kidney-specific organic anion transporters, and to characterize several isoforms.
In 1997, we could succeed to isolate a novel organic anion transporter from rat kidneys and named it OAT (organic anion transporter) 1. Thereafter, three members of OAT family have been identified. OAT2 is liver-specific having different spectrum of transport substrates from OAT1. OAT3 having 536 amino acid residue is expressed in the liver, kidney and brain showing 49% and 39% identities with OAT1 and OAT2, respectively. OAT3 mediates high affinity transport of PAH, ochratoxin A, and estron sulfate. Human OAT4 is expressed in the kidney and placenta and consists of 550 amino acids having identity at 38%〜44% with OAT1〜3. The OAT4 is also multispecific in substrate recognition, like estron sulfate, dehydroepiandrosterone sulfate, and ochratoxin A.
Although we could chine 4 isoforms of OAT family, OAT1〜4, molecular mechanisms on substrate recognition remain to be carried out by further investigation. Since OATs reveal weak but significant similarity in their structure with organic cation transporters and carnitine transporters, possible molecular evolution should be clarified among these families. The multi specificity seen in OATs may be originated from relatively simple substrate binding to the transporters and the hypothesis of two important biding sites like hydrophobic moiety and ionic charge needs to be elucidated.

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Published: 2001-10-23  

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