MARKER GENES FOR SCREENING OF DRUG-INDUCED TOXICITY IN HUMAN CELLS AND SCREENING METHOD USING THE SAMEThe present invention relates to a marker gene for screening a drug inducing toxicity in human and a screening method using the same. More precisely, the invention relates to a microarray on which marker genes up-or down-regulated specifically by 16 drugs inducing pulmonary toxicity, teratogenicity, nephrotoxicity, cardiotoxicity or mutation (Methotrexate, Nitrofurantoin, Amiodarone, Carbamazepine, Valproic acid, Thalidomide, Cisplatin, Gentamycin, Amphotericine, Furylfuramide, N-nitroso-N-methylurea, methylmethanesulfonate, 4-nitroquinoline-N-oxide, 2-nitrofluorene, Doxorubicin and Daunorubicin) are integrated, a kit comprising the said microarray, and a screening method of a drug inducing toxicity in human using the same. The DNA microarray containing the marker gene of the present invention facilitates the construction of Toxtarget Array for screening a drug inducing toxicity in human using drug-specific genes, suggesting that this chip can be effectively used for monitoring drugs or chemicals carrying toxicity to human or determining risks thereof and also it can be used as a tool for examining mechanisms of toxicity/side effects caused by the drugs.A DNA microarray for screening a drug inducing toxicity in human, on which oligonucleotides comprising whole nucleic acid sequence or 18-30 nucleic acids of those genes selected among group 1)-group 6) or their complementary sequences are integrated: Group 1) one or more genes selected from the following gene group showing changes in expression specifically by the treatment of a drug causing pulmonary toxicity:GenBank AF289615 (hypothetical protein), GenBank NM—000575 (interleukin 1, alpha), GenBank NM—001001958 (olfactory receptor, family 7, subfamily g, member 3), GenBank NM—001295 [chemokine(c-c motif) receptor 1], GenBank NM—002305 [lectin, galactoside-binding, soluble, (galectin 1)], GenBank NM—004293 (guanine deaminase), GenBank NM—030754 (serum amyloid a2);Group 2) one or more genes selected from the following gene group showing changes in expression specifically by the treatment of a drug causing teratogenicity:GenBank NM—000735 (glycoprotein hormones, alpha polypeptide), GenBank NM—004155 [serpin peptidase inhibitor, clade b (ovalbumin), member 9], GenBank NM—005668 (st8 alpha-n-acetyl-neuraminide alpha-2,8-sialyltransferase 4), GenBank NM—032484 (homolog of mouse lgp1);Group 3) one or more genes selected from the following gene group showing changes in expression specifically by the treatment of a drug causing nephrotoxicity:GenBank NM—000134 (fatty acid binding protein 2, intestinal), GenBank NM—005203 (collagen, type xiii, alpha 1), GenBank NM—015946 (pro1770 protein), GenBank NM—138417 [kti12 homolog, chromatin associated (s. cerevisiae)], GenBank NM—145202 (proline-rich acidic protein 1), GenBank NM—173160 (fxyd domain containing ion transport regulator 4);Group 4) one or more genes selected from the following gene group showing changes in expression specifically by the treatment of a drug causing mutation:GenBank NM—000715 (complement component 4 binding protein, alpha), GenBank NM—001141 (arachidonate 15-lipoxygenase, type b), GenBank NM—001711 (biglycan), GenBank NM—001974 (egf-like module containing, mucin-like, hormone receptor-like 1), GenBank NM—003722 (tumor protein p73-like), GenBank NM—005510 [dom-3 homolog z (c. elegans)], GenBank NM—007267 (transmembrane channel-like 6);Group 5) one or more genes selected from the following gene group showing changes in expression specifically by the treatment of a drug causing cardiotoxicity:GenBank NM—012415 (fibrinogen silencer binding protein), GenBank NM—021101 (claudin 1); andGroup 6) one or more genes selected from the following gene group showing changes in expression specifically by the treatment of a drug causing general toxicity:GenBank NM—000051 [ataxia telangiectasia mutated (includes complementation groups a, c and d)], GenBank NM—000104 (cytochrome p450, family 1, subfamily b, polypeptide 1), GenBank NM—000120 [epoxide hydrolase 1, microsomal (xenobiotic)], GenBank NM—000240 (monoamine oxidase a), GenBank NM—000546 [tumor protein p53 (li-fraumeni syndrome)], GenBank NM—000639 [fas ligand (tnf superfamily, member 6)], GenBank NM—000762 (cytochrome p450, family 2, subfamily a, polypeptide 6), GenBank NM—000771 (cytochrome p450, family 2, subfamily c, polypeptide 9), GenBank NM—000773 (cytochrome p450, family 2, subfamily e, polypeptide 1), GenBank NM—000780 (cytochrome p450, family 7, subfamily a, polypeptide 1), GenBank NM—000847 (glutathione s-transferase a3), GenBank NM—000851 (glutathione s-transferase m5), GenBank NM—000927 [atp-binding cassette, sub-family b (mdr/tap), member 1], GenBank NM—000940 (paraoxonase 3), GenBank NM—000962 [prostaglandin-endoperoxide synthase 1 (prostaglandin g/h synthase and cyclooxygenase)], GenBank NM—001540 (heat shock 27 kda protein 1), GenBank NM—001565 [chemokine (c-x-c motif) ligand 10], GenBank NM—001746 (calnexin), GenBank NM—001752 (catalase), GenBank NM—001885 (crystallin, alpha b), GenBank NM—001979 (epoxide hydrolase 2, cytoplasmic), GenBank NM—002021 (flavin containing monooxygenase 1), GenBank NM—002083 [glutathione peroxidase 2 (gastrointestinal)], GenBank NM—002155 [heat shock 70 kda protein 6 (hsp70b′)], GenBank NM—003167 [sulfotransferase family, cytosolic, 2a, dehydroepiandrosterone(dhea)-preferring, member 1], GenBank NM—003786 [atp-binding cassette, sub-family c (cftr/mrp), member 3], GenBank NM—003932 [suppression of tumorigenicity 13 (colon carcinoma) (hsp70 interacting protein)], GenBank NM—004050 (bcl2-like 2), GenBank NM—004083 (dna-damage-inducible transcript 3), GenBank NM—004323 (bcl2-associated athanogene), GenBank NM—004343 (calreticulin), GenBank NM—004605 (sulfotransferase family, cytosolic, 2b, member 1), GenBank NM—004820 (cytochrome p450, family 7, subfamily b, polypeptide 1), GenBank NM—004832 (glutathione s-transferase omega 1), GenBank NM—005420 (sulfotransferase family le, estrogen-preferring, member 1), GenBank NM—005431 (x-ray repair complementing defective repair in Chinese hamster cells 2), GenBank NM—005953 (metallothionein 2a), GenBank NM—006308 (heat sh...
인체 독성 유발 약물 탐색용 마커유전자 및 이를 이용한 탐색 방법본 발명은 인체 의약품 독성 유발 약물 탐색용 마커유전자 및 이를 이용한 탐색 방법에 관한 것으로, 더욱 상세하게는 폐독성, 최기형성, 신장독성, 심혈관독성 또는 돌연변이성를 유발하는 총 16종의 약물(메토트렉세이트, 니트로푸란토인, 아미오다론, 카르바마제핀, 발프론산, 탈리도마이드, 시스플란틴, 겐타마이신, 암포테리신, 푸리푸라아마이드, N-니트로-N-메틸우레아, 메틸메탄슬폰산, 4-니트로퀴놀린-N-옥사이드, 2-니트로플루오렌, 독소루비신 및 다우노루비신)에 의해 특이적으로 유전자 발현이 증가 또는 감소하는 마커유전자를 하나의 칩에 집적한 마이크로어레이칩, 상기 마이크로어레이칩을 포함하는 키트, 및 이를 이용한 인체 의약품 독성 유발 약물의 탐색 방법에 관한 것이다. 본 발명의 마커유전자를 포함하는 DNA 마이크로어레이 칩은 특정 약물에 특이적으로 반응하는 유전자들을 이용하여 인체 독성 유발 약물 탐색용 독소표적 어레이(Toxtarget Array)를 제작하여 인체 의약품 독성의 위험성을 지닌 약물 또는 화학물질을 모니터링 및 판정하는데 유용하게 사용될 수 있으며, 각 약물들의 독성 및 부작용을 일으키는 작용 기작을 규명하는 도구로 이용될 수 있다.하기 1 그룹 ~ 6 그룹의 유전자의 핵산서열의 전부 또는 18 내지 30개의 핵산 서열로 구성되는 상기 유전자의 단편인 올리고뉴클레오티드 또는 그의 상보가닥 분자가 집적된, 인체 독성 유발 약물 탐색용 DNA 마이크로어레이 칩:1그룹) 폐독성 유발 약물의 처리에 의하여 발현이 특이적으로 변화하는 하기의 유전자 군으로부터 선택되는 어느 하나 이상의 유전자:유전자등록번호(GenBank) AF289615(hypothetical protein), 유전자등록번호(GenBank) NM_000575(interleukin 1, alpha), 유전자등록번호(GenBank) NM_001001958(olfactory receptor, family 7, subfamily g, member 3), 유전자등록번호(GenBank) NM_001295[chemokine(c-c motif) receptor 1], 유전자등록번호(GenBank) NM_002305[lectin, galactoside-binding, soluble, 1(galectin 1)], 유전자등록번호(GenBank) NM_004293(guanine deaminase), 유전자등록번호(GenBank) NM_030754(serum amyloid a2); 2그룹) 최기형성 유발 약물의 처리에 의하여 발현이 특이적으로 변화하는 하기의 유전자 군으로부터 선택되는 어느 하나 이상의 유전자:유전자등록번호(GenBank) NM_000735(glycoprotein hormones, alpha polypeptide), 유전자등록번호(GenBank) NM_004155[serpin peptidase inhibitor, clade b(ovalbumin), member 9], 유전자등록번호(GenBank) NM_005668(st8 alpha-n-acetyl-neuraminide alpha-2,8-sialyltransferase 4), 유전자등록번호(GenBank) NM_032484(homolog of mouse lgp1);3그룹) 신장독성 유발 약물의 처리에 의하여 발현이 특이적으로 변화하는 하기의 유전자 군으로부터 선택되는 어느 하나 이상의 유전자:유전자등록번호(GenBank) NM_000134(fatty acid binding protein 2, intestinal), 유전자등록번호(GenBank) NM_005203(collagen, type xiii, alpha 1), 유전자등록번호(GenBank) NM_015946(pro1770 protein), 유전자등록번호(GenBank) NM_138417[kti12 homolog, chromatin associated(s. cerevisiae)], 유전자등록번호(GenBank) NM_145202(proline-rich acidic protein 1), 유전자등록번호(GenBank) NM_173160(fxyd domain containing ion transport regulator 4);4그룹) 돌연변이성 유발 약물의 처리에 의하여 발현이 특이적으로 변화하는 하기의 유전자 군으로부터 선택되는 어느 하나 이상의 유전자:유전자등록번호(GenBank) NM_000715(complement component 4 binding protein, alpha), 유전자등록번호(GenBank) NM_001141(arachidonate 15-lipoxygenase, type b), 유전자등록번호(GenBank) NM_001711(biglycan), 유전자등록번호(GenBank) NM_001974(egf-like module containing, mucin-like, hormone receptor-like 1), 유전자등록번호(GenBank) NM_003722(tumor protein p73-like), 유전자등록번호(GenBank) NM_005510[dom-3 homolog z(c. elegans)], 유전자등록번호(GenBank) NM_007267(transmembrane channel-like 6);5그룹) 심혈관독성 유발 약물의 처리에 의하여 발현이 특이적으로 변화하는 하기의 유전자 군으로부터 선택되는 어느 하나 이상의 유전자:유전자등록번호(GenBank) NM_012415(fibrinogen silencer binding protein), 유전자등록번호(GenBank) NM_021101(claudin 1); 및6그룹) 일반독성 유발 약물의 처리에 의하여 발현이 특이적으로 변화하는 하기의 유전자 군으로부터 선택되는 어느 하나 이상의 유전자:유전자등록번호(GenBank) NM_000051[ataxia telangiectasia mutated(includes complementation groups a, c and d)], 유전자등록번호(GenBank) NM_000104(cytochrome p450, family 1, subfamily b, polypeptide 1), 유전자등록번호(GenBank) NM_000120[epoxide hydrolase 1, microsomal(xenobiotic)], 유전자등록번호(GenBank) NM_000240(monoamine oxidase a), 유전자등록번호(GenBank) NM_000546[tumor protein p53(li-fraumeni syndrome)], 유전자등록번호(GenBank) NM_000639[fas ligand(tnf superfamily, member 6)], 유전자등록번호(GenBank) NM_000762(cytochrome p450, family 2, subfamily a, polypeptide 6), 유전자등록번호(GenBank) NM_000771(cytochrome p450, family 2, subfamily c, polypeptide 9), 유전자등록번호(GenBank) NM_000773(cytochrome p450, family 2, subfamily e, polypeptide 1), 유전자등록번호(GenBank) NM_000780(cytochrome p450, family 7, subfamily a, polypeptide 1), 유전자등록번호(GenBank) NM_000847(glutathione s-transferase a3), 유전자등록번호(GenBank) NM_000851(glutathione s-transferase m5), 유전자등록번호(GenBank) NM_000927[atp-binding cassette, sub-family b(mdr/tap), member 1], 유전자등록번호(GenBank) NM_000940(paraoxonase 3), 유전자등록번호(GenBank) NM_000962[prostaglandin-endoperoxide synthase 1(prostaglandin g/h synthase and cyclooxygenase)], 유전자등록번호(GenBank) NM_001540(heat shock 27kda protein 1), 유전자등록번호(GenBank) NM_001565[chemokine(c-x-c motif) ligand 10], 유전자등록번호(GenBank) NM_001746(calnexin), 유전자등록번호(GenBank) NM_001752(catalase), 유전자등록번호(GenBank) NM_001885(crystallin, alpha b), 유전자등록번호(GenBank) NM_001979(epoxide hydrolase 2, cytoplasmic), 유전자등록번호(GenBank) NM_002021(flavin containing monooxygenase 1), 유전자등록번호(GenBank) NM_002083[glutathione peroxidase 2(gastrointestinal)], 유전자등록번호(GenBank) NM_002155[heat shock 70kda protein 6(hsp70b')], 유전자등록번호(GenBank) NM_003167[sulfotransferase family, cytosolic, 2a, dehydroepiandrosterone(dhea)-preferring, member 1], 유전자등록번호(GenBank) NM_003786[atp-binding cassette, sub-family c(cftr/mrp), member 3], 유전자등록번호(GenBank) NM_003932[suppression of tumorigenicity 13(colon carcinoma)(hsp70 interacting protein)], 유전자등록번호(GenBank) NM_004050(bcl2-like 2), 유전자등록번호(GenBank) NM_004083(dna-damage-inducible transcript 3), 유전자등록번호(GenBank) NM_004323(bcl2-associated athanogene), 유전자등록번호(GenBank) NM_004343(calreticulin), 유전자등록번호(GenBank) NM_004605(sulfotransferase family, cytosolic, 2b, member 1), 유전자등록번호(GenBank) NM_004820(cytochrome p450, family 7, subfamily b, polypeptide 1), 유전자등록번호(GenBank) NM_004832(glutathione s-transferase omega 1), 유전자등록번호(GenBank) NM_005420(sulfotransferase family 1e, estrogen-preferring, member 1), 유전자등록번호(GenBank) NM_005431(x-ray repair complementing defective repair in chinese hamster cells 2), 유전자등록번호(GenBank) NM_005953(metallothionein 2a), 유전자등록번호(GenBank) NM_006308(heat shock 27kda protein 3), 유전자등록번호(GenBank) NM_006431[chaperonin containing tcp1, subunit 2(beta)], 유전자등록번호(GenBank) NM_006588(sulfotransferase family,..