Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or...
Reexamination Certificate
1999-06-10
2002-08-13
Clark, Deborah J. R. (Department: 1633)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
C435S455000, C435S325000, C424S093200, C530S350000
Reexamination Certificate
active
06432631
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to the processing of anions by the human kidney. In particular, it relates to nucleic acids and polypeptides transcribed and expressed in the kidneys that are responsible for the removal of toxic anions from the circulation.
Sweet et al. have described a rat gene (ROAT1) encoding an organic anion transport protein expressed in the rat kidney (
Journal of Biological Chemistry
272:30088-30095 [11997]). Sekine et al. also appear to have disclosed essentially the same gene, denominated OAT1 (
Journal of Biological Chemistry
272:18526-18529 [1997]). Its apparent murine counterpart has been described in Lopez-Nieto et al.
Journal of Biological Chem.
272:6471-6478 (1997).
It is an object of this invention to isolate nucleic acid encoding a human organic anion transporter (hOAT).
It is another object of this invention to recombinantly express nucleic acid encoding hOAT.
Another object is to obtain hOAT expressed in elevated yields in recombinant cell culture.
An object is to prepare isolated polypeptide encoding hOAT.
An additional object of this invention is to provide novel hOAT polypeptides.
A further object of this invention is an assay for evaluation of potential drug-drug interactions due to interference of one drug or group of drugs with hOAT-mediated active kidney excretion of another drug.
A further object of this invention is an assay system for screening candidate compounds that agonize or antagonize the expression of hOAT and/or the biological activity of hOAT polypeptide, especially its anion transport activity.
Another object is to provide an hOAT screening assay system to identify molecular variants of nephrotoxic compounds that will be taken up and transported by hOAT to a lesser degree than is the case with the parental compound.
A further object is to identify alleles or isoforms of hOAT that are associated with sensitivity to nephrotoxic compounds, particularly nephrotoxic drugs.
These and other objects of the invention will be apparent from consideration of this specification as a whole.
SUMMARY OF THE INVENTION
In accordance with the objects, applicants provide isolated nucleic acid encoding hOAT and isolated hOAT polypeptide. hOAT is expressed in recombinant cells, where it finds use in evaluating compounds for nephrotoxicity or for identifying compounds having the ability to prevent nephrotoxicity. Since hOAT is expressed in human brain, it also finds use in characterizing compounds known or suspected to influence brain function. hOAT also is useful in a method for identifying any hOAT alleles and isoforms which are correlated with patient sensitivity to nephrotoxic agents.
REFERENCES:
patent: WO 97/31111 (1997-08-01), None
patent: WO 97/42321 (1997-11-01), None
patent: WO 98/53064 (1998-11-01), None
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Apiwattanakul et al., “Transport Properties of Nonsteroidal Anti-Inflammatory Drugs by Organic Anion Transporter 1 Expressed in Xenopus laevis Oocytes”, 55:847-854, Mol Pharm, 1999.
Cihlar et al., “The Antiviral Nucleotide Analogs Cidofovir and Adefovir Are Novel Substrates for Human and Rat Renal Organic Anion Transporter 1”, 56:570-580, Molecular Pharmacology, 1999.
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Lopez-Nieto et al., “Molecular Cloning and Characterization of NKT, a Gene Product Related to the Organic Cation Transporter Family that is Almost Exclusively Expressed in the Kidney”, 272(10):6471-6478, J Biol Chem, Mar. 7, 1997.
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Saito et al., “Cloning and Functional Characterization of a Novel Rat Organic Anion Transporter Mediating Basolateral Uptake of Methotrexate in the Kidney”, 271(34):20719-20725, J Biol Chem, Aug. 23, 1996.
Sekine et al., “Expression Cloning and Characterization of a Novel Multispecific Organic Anion Transporter”, 272(30):18526-18529, J Biol Chem, Jul. 25, 1997.
Sweet et al., “Expression Cloning and Characterization of ROAT1”, 272(48):30088-30095, J Biol Chem, Nov. 28, 1997.
Tune, B.M., “Nephrotoxicity of beta-lactam antibiotics: mechanisms and strategies for prevention”, 11:768-772, Pediatr. Nephrol., 1997.
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Mulato et al., “Nonsteroidal Anti-Inflammatory Drugs Efficiently Reduce the Transport and Cytotoxicity of Adefovir Mediated by the Human Renal Organic Anion Transporter 1”, 295(1):10-15, The Journal of Pharmacology and Experimental Therapeutics, Mar. 14, 2000.
Chen Shin-Lin
Clark Deborah J. R.
Gilead Sciences, Inc.
Hensley Max D.
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