Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues
Reexamination Certificate
2001-06-07
2004-01-06
Spector, Lorraine (Department: 1647)
Chemistry: natural resins or derivatives; peptides or proteins;
Proteins, i.e., more than 100 amino acid residues
C435S183000
Reexamination Certificate
active
06673898
ABSTRACT:
TECHNICAL FIELD
The present invention relates to gene participating in an organic anion (organic negatively-charged ion) transport and to a polypeptide for which the gene codes. More particularly, the present invention relates to an organic anion transporter OAT4 of a placenta type, to gene coding therefor, to a probe for detecting the gene and to an antibody which is able to recognize the protein.
BACKGROUND OF THE INVENTION
Kidney and liver play an important role in metabolism and excretion of xenobiotics and pharmaceuticals. Urinary tubule cells of kidney are epithelial cells having a polarity and contact the blood via a basolateral membrane to carry out transfer of various substances. It has been predicted from the physiological studies up to now that a part of the organic ion is incorporated into kidney by a transport carrier (transporter) via a basolateral membrane and also that an organic anion produced by metabolism in cells is excreted by the transporter.
Since organic anion contains pharmaceuticals and environmental toxins or many of metabolites thereof, an organic anion transport system has been widely known as a xenobiotics excretion system or a pharmaceuticals transport system as well.
Incorporation of an organic anion by urinary tubule cells has been studied by an experimental system using an isolated organ perfusion method, an isolated cell membrane vesicle system, etc. However, according to the conventional means, it is difficult to analyze the organic anion transport system via basolateral membrane in detail and there has been a demand that the transporter per se is isolated and analyzed.
Organic anion transport is also carried out in the tissues other than kidney and liver. Placenta is a tissue where material exchange is actively carried out between fetus and the mother's body and the substances necessary for living organism including saccharides and amino acids are efficiently transported to fetus from the mother's body via a transporter.
On the other hand, placenta also plays a role as a tissue barrier for fetus against the external environment. Placenta shows a certain type of limitation to a free transfer of the xenobiotics ingested by mother's body to the fetus and a part of such a function is thought to be by a removal of the xenobiotics from a fetus circulation by a xenobiotic excretion transporter.
In addition, various metabolic reactions also take place even in the body of the fetus and, as a result, an organic anion is generated. Due to an anatomical specificity of the fetus, most of excretion of such metabolites is done via placenta. It is rational to conclude that an organic anion transporter is present in placenta and plays such a role.
As such, it is believed that the transport of xenobiotics (particularly, transport of organic anion) in placenta plays an important role for the growth and the genetic toxicity of fetus. However, details of the transfer therein have been unknown than that in kidney and liver.
The present inventors have isolated and reported on an organic anion transporter OAT1 (
J. Biol. Chem
., volume 272, pages 18526-18529, 1997), OAT2 (
FEBS Letter
, 429, pages 179-182, 1998) and OAT 3 (
J. Biol. Chem
., volume 274, pages 13675-13680, 1999) which play a central role in kidney, liver, brain, etc. Patent applications for them have been also filed already. OAT1, OAT2 and OAT3 are the transporters which are able to transport many organic anions having different chemical structures and they carry out the transport of various anionic pharmaceuticals as well.
Isolation and identification of OAT1, OAT2 and OAT3 show that organic anion transporters form a family. Members of this family have been known to be expressed not only in organs such as kidney and liver which play a central role in external excretion of xenobiotics but also in brain which forms a tissue barrier.
From those facts, the present inventors have predicted the presence of an organic anion transporter in placenta as a functional unit of the tissue barrier and as a route for excretion of metabolites of fetus and have isolated a novel organic anion transporter existing in placenta.
DISCLOSURE OF THE INVENTION
An object of the present invention is to identify and to provide a novel organic anion transporter gene participating in an organic anion transport in placenta and also an organic anion transporter which is a polypeptide for which the gene codes. Other objects are obvious from the following descriptions.
REFERENCES:
patent: WO98/53064 (1998-11-01), None
patent: WO99/13072 (1999-03-01), None
patent: WO 01/49728 (2001-07-01), None
patent: WO 01/62923 (2001-08-01), None
Bisson, et al, 1993, Crit Rev Biochem Mol Biol, 28:259-308.*
Liang, H., et al, 1998, Mol. Cell. Biol. 18(2):926-935.*
Race, et al, 1999, Biochem. Biophys. Res. Comm., 255: 508-514.*
M. Hosoyhamada et al.,American Journal of Physiology, vol. 276, No. 1, Part 2, pp. F122-F128 (1999).
J. Race et al.,Biochemical and Biophysical Research Communications, 255(2):508-514 (1999).
Database EMBL Online, AC H12876, XP002188136 (1995).
Database EMBL Online, AC N54154, XP002188137 (1996).
Van Der et al.,Placenta, 15(3):279-289 (1994).
H. Cha Seok et al.,Journal of Biological Chemistry, 275(6):4507-4512 (2000).
Sekine T., et al. “Molecular cloning and characterization of multispecific organic anion transporter 4 expressed in the placenta”Japanese Journal of Pharmacology (Mar. 2000), vol. 82, suppl. 1, p. 114P.
Sekine T., et al. “Molecular identification of an organic anion transporter (OAT) family and its role in the transmemberane trasnport of anionic drugs”, Japanese Journal of Pharmacology (Mar. 2000), vol. 82, suppl. 1, p. 5P.
Sekine T., et al., “Expression cloning and characterization of a novel multispecific organic anion transporter”, Journal of Biological Chemistry (1997), vol. 272, No. 30, p. 18526-18529.
Sekine T., et al. “Identification of multispecific organic anion transporter 2 expressed predominantly in the liver”, FEBS Letters (1998), vol. 429, p. 179-182.
Kusuhara H., et al., “Molecular cloning and characterization of a new multispecific organic anion transporter from rat brain”, Journal of Biological Chemistry (May 1999), vol. 274, No. 19, p. 13675-13680.
Endou H., et al. “Recent advances in molecular mechanisms of nephrotoxicity”, Toxicology Letters (1998), vol. 102-103, p. 29-33.
Hillier L., et al. “Generation and analysis of 280,000 human expressed sequence tags”, Genome Research (1996), vol. 6, No. 9, p. 807-828.
Cha Seok Ho
Endou Hitoshi
Sekine Takashi
Corless Peter F.
Edwards & Angell LLP
Japan Science and Technology Corporation
O'Day Christine C.
Spector Lorraine
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