KR102004244B1 - Biomarker composition for diagnosing susceptibility to hepatotoxicity and diagnosing method thereof - Google Patents

Biomarker composition for diagnosing susceptibility to hepatotoxicity and diagnosing method thereof Download PDF

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KR102004244B1
KR102004244B1 KR1020170182412A KR20170182412A KR102004244B1 KR 102004244 B1 KR102004244 B1 KR 102004244B1 KR 1020170182412 A KR1020170182412 A KR 1020170182412A KR 20170182412 A KR20170182412 A KR 20170182412A KR 102004244 B1 KR102004244 B1 KR 102004244B1
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윤준원
황다빈
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가톨릭대학교 산학협력단
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Abstract

본 발명은 테트라스파닌 12(tetraspanin 12)를 유효성분으로 함유하는 간독성 진단용 바이오마커 조성물 및 이를 이용한 간독성 민감성 예측 방법에 관한 것으로, 보다 상세하게는 아세트아미노펜을 투여하기 전 랫트의 혈액과 투여 후 랫트의 혈액 내 유전자 발현 패턴을 확인한 결과, 아세트아미노펜에 의해 간독성이 유발된 개체의 약물 투여 전 혈액에서 테트라스파닌 12 발현 수준이 증가되어 있는 것을 확인함에 따라, 아세트아미노펜 투여 전 혈액에서 개체의 아세트아미노펜 민감성을 미리 예측하기 위한 간독성 진단용 바이오마커로 제공될 수 있으며, 상기 바이오마커는 간독성 진단용 키트 또는 간독성 민감성 예측 방법에 사용될 수 있다.The present invention relates to a biomarker composition for hepatotoxicity diagnosis containing tetraspanin 12 as an active ingredient and a method for predicting the sensitivity of hepatotoxicity using the same. More particularly, , It was confirmed that the level of tetraspanin 12 expression was increased in the blood before the administration of the drug to the subjects suffering from hepatotoxicity caused by acetaminophen. Therefore, it was confirmed that the amount of acetaminophen May be provided as a biomarker for hepatotoxicity diagnosis for predicting sensitivity, and the biomarker may be used for a hepatotoxicity diagnostic kit or a hepatotoxicity sensitivity prediction method.

Description

간독성 민감성 진단용 바이오마커 조성물 및 이를 이용한 예측 방법{Biomarker composition for diagnosing susceptibility to hepatotoxicity and diagnosing method thereof}TECHNICAL FIELD The present invention relates to a biomarker composition for diagnosing hepatotoxicity sensitivity and a method for predicting susceptibility to hepatotoxicity and diagnosing method therefor.

본 발명은 약물로 인해 유도되는 간독성 민감성 진단용 바이오마커 조성물 및 이를 이용한 간독성 민감성 예측 방법에 관한 것이다.The present invention relates to a biomarker composition for diagnosing hepatotoxicity sensitivity induced by a drug and a method for predicting the sensitivity of hepatotoxicity using the same.

간독성, 또는 간세포독성은 약물투여 등으로 인해 간이 손상된 상태를 의미한다. 간은 체내로 들어온 약물을 안전한 물질로 변환시켜 이에 대한 독성을 제거하는 역할을 하지만, 이러한 물질들이 체내로 과량 유입될 경우에는 간 독성이 일어날 수도 있다. 또한, 약물 이외에도 실험용이나 산업용으로 쓰이는 화학물질, 천연물 유래의 화합물, 약용식물 유래의 추출물들도 간독성을 유발할 수 있다. Hepatotoxicity, or hepatocellular toxicity, refers to a condition in which the liver is damaged due to drug administration or the like. The liver converts the drug into a safe substance and removes the toxicity of the drug. However, excessive toxicity of these substances may cause liver toxicity. In addition to drugs, chemical substances used for laboratory and industrial use, compounds derived from natural materials, and extracts derived from medicinal plants may cause hepatotoxicity.

한편, 약물로 인해 유도된 간독성, 즉, 약인성 간손상(DILI, drug-induced liver injury)은 급성 간독성의 주요 원인이라고 할 수 있다. 약인성 간손상은 정도가 아주 약한 간독성에서부터 급성간부전증(acute liver failure)까지를 모두 말할 수 있으며, 크게 내인성 간독성 및 특이체질성 간독성 현상으로 분류된다. 내인성 간독성은 주로 직접적인 약물 반응, 약물의 대사물에 대한 반응 등을 통해 유도되는 현상을 말하며, 특이체질성 간독성은 약물의 농도에 따라 유도되는 현상을 말한다.Drug-induced hepatotoxicity, or drug-induced liver injury (DILI), is a major cause of acute hepatotoxicity. Mild to moderate hepatic injury can range from very low to acute liver failure and is largely classified as endogenous hepatotoxicity and idiopathic hepatotoxicity. Endogenous hepatotoxicity refers to a phenomenon that is induced mainly through direct drug reactions, reactions to metabolites of drugs, and specific constitutional hepatotoxicity is induced by the concentration of the drug.

이러한 간독성을 유발시키는 물질로 사염화탄소(Carbon tetrachloride; CCl4), 알콜 및 갈락토사민(Galactosamine; GalN) 등이 대표적으로, 사염화탄소(CCl4)는 간에서 CYP2E1이라는 효소에 의해 자유 라디칼을 지닌 CCl3·와 산소와 반응한 CCl3OO·의 형태가 되며, 이 산물들은 산화적 스트레스로 인해 DNA에 손상이 올 수 있다. 또한, 간성상 세포의 활성을 유도하는 VEGF, TGF-β1 신호전달 물질에 의해 간섬유증이 유발시킬 수 있으며, NF-κB 신호전달로 시작해서 IFN-γ, TNF-α, IL-6와 같은 사이토카인을 발현해 세포작살이나, 염증반응을 유도시킨다.Carbon tetrachloride (CCl4), alcohol and galactosamine (GalN) are typical examples of such hepatotoxicity, and carbon tetrachloride (CCl4) is a substance which causes free radicals in the liver by an enzyme called CYP2E1, , And these products are susceptible to DNA damage due to oxidative stress. In addition, hepatic fibrosis can be induced by VEGF and TGF-β1 signaling substances, which induce the hepatic stellate cell activity, and can be induced by NF-κB signal transduction and secreted by cytokines such as IFN-γ, TNF-α and IL- Cain is expressed to induce cell killing or inflammatory reaction.

알코올은 간에 있는 효소인 ADH(alcohol dehydrogenase)에 의해 아세트알데하이드(acetaldehyde)로 분해되며 이때 NAD가 NADH로 환원되며, 높은 농도의 NADH는 지방산생산을 촉진하게 축적되어 지방간을 유래시킨다. 또한, 산화적 스트레스를 주어 IL-1, IL-6, Il-8등의 사이토카인을 분비해 염증 반응이나 세포사멸(apoptosis)이 일어나게 한다. 또한, 장에서 소화된 에탄올이 뿜는 내독소에 의해 간세포가 공격받으면 TNF-α같은 사이토카인을 분비해 간성상세포의 활성을 유도하고 간의 섬유화를 일으킨다.Alcohol is degraded into acetaldehyde by the liver's alcohol dehydrogenase (ADH), where NAD is reduced to NADH and high concentrations of NADH accumulate to promote fatty acid production, resulting in fatty liver. In addition, they induce oxidative stress and secrete cytokines such as IL-1, IL-6, and IL-8 to induce inflammation and apoptosis. In addition, when hepatocytes are attacked by endotoxin that is excreted in ethanol by the digested ethanol, secretion of a cytokine such as TNF-α is induced to induce hepatic astrocyte activity and fibrosis of the liver.

갈락토사민(GalN)은 사이토크롬 p450과 같은 효소에 의해 산화되면 활성산소를 발생시킬 수 있는데 이러한 산화적 스트레스를 받게 될 경우 IL-1β, IL-6, TNF-α와 같은 인자를 내보내 급성간질환을 유발시킬 수 있으며, NF-κB, MAPK의 증가 또한 면역 반응으로 이어질 수 있어 PDCD4(programmed cell death 4)단백질을 발현시키는 등 상기 두가지 요인으로 인해 급성간부전을 유발시킨다.When galactosamine (GalN) is oxidized by an enzyme such as cytochrome p450, it can produce active oxygen. When it is exposed to oxidative stress, it releases factors such as IL-1β, IL-6 and TNF- And NF-κB and MAPK may also lead to an immune response. These two factors induce acute hepatic failure due to the expression of PDCD4 (programmed cell death 4) protein.

한편, 새로운 간독성 약물로 보고된 아세트아미노펜은 투여 시, 간의 사이토크롬 P450 효소에 의해 N-아세틸-p-벤조퀴논 이민(N-acetyl-p-benzoquinone imine)이 되고, 상기 물질은 미토콘드리아의 투과성을 변화시킴으로 인해 활성산소인 과산화수소가 생겨 간에 산화적 스트레스를 주고 단백질의 질산화를 일으켜 간독성을 유발시킨다. 또한, 미토콘드리아의 세포막전위가 바뀌면서 역기능이 일어나 칼슘의 흡수가 갑자기 높아지고 ATP의 생성량은 감소하게 된다. 이로 인하여 이온의 흡수가 제대로 일어나지 않아 중간대사물질들이 방출되거나 흡입되면서 간조직의 괴사 또는 간병변 증상이 나타난다.On the other hand, acetaminophen, which is reported as a new hepatotoxic drug, becomes N-acetyl-p-benzoquinone imine by the liver cytochrome P450 enzyme upon administration and the substance has a permeability of mitochondria As a result of the change, hydrogen peroxide, which is active oxygen, is produced, which causes oxidative stress and causes nitrification of proteins, thereby causing hepatotoxicity. In addition, the mitochondrial membrane potential shifts, resulting in dysfunction, resulting in a sudden increase in calcium absorption and a decrease in ATP production. Because of this, the absorption of ions does not occur properly, so that the intermediate metabolites are released or inhaled, resulting in necrosis or hepatic symptoms of liver tissue.

이러한 아세트아미노펜으로 인해 유도되는 급성 간독성은 기존의 간독성을 유발시키는 약물들과 다른 방식으로 간독성을 유발시키며, 민감한 사람의 경우 사망에 이를 정도로 치명적일 수 있다. 이는 개개인의 선천적인 유전자 발현 차이가 주요 원인이 될 수 있으므로, 아세트아미노펜 약물 복용 전 약물에 대한 민감성을 나타낼 수 있는지 미리 예측할 수 있는 방법에 대한 연구가 필요하다.These acute hepatotoxicity induced by acetaminophen can lead to hepatotoxicity in a manner different from conventional hepatotoxic drugs, which can be fatal to susceptible individuals. This may be due to individual differences in gene expression, so it is necessary to study how to predict the sensitivity of drugs to acetaminophen before taking the drug.

대한민국공개특허 제10-2013-0053349호 (2013.05.23 공개)Korean Patent Publication No. 10-2013-0053349 (published on May 23, 2013)

본 발명은 개체의 약물에 대한 민감도를 예측할 수 있는 혈액 내 바이오마커 조성물을 제공함으로써, 아세트아미노펜 투여로 인해 유도될 수 있는 간독성을 약물 투여 전 미리 예측하여 약물 투여에 따른 간독성을 사전에 예방하기 위한 방법을 제공하고자 한다.The present invention provides a biomarker composition in blood that can predict the susceptibility of an individual to a drug, thereby providing a method of predicting hepatotoxicity, which can be induced by acetaminophen administration, before administration of the drug, Method.

본 발명은 테트라스파닌 12(tetraspanin 12)를 유효성분으로 함유하는 간독성 진단용 바이오마커 조성물을 제공한다.The present invention provides a biomarker composition for hepatotoxicity diagnosis comprising tetraspanin 12 as an active ingredient.

본 발명은 테트라스파닌 12의 발현수준을 측정할 수 있는 제제를 유효성분으로 포함하는 간독성 진단용 키트를 제공한다.The present invention provides a hepatotoxicity diagnostic kit comprising as an active ingredient a preparation capable of measuring the level of expression of tetraspanin 12. [

또한, 본 발명은 약물 투여 전 사람을 제외한 포유류로부터 혈액을 수집하는 단계; 상기 수집된 혈액 내 테트라스파닌 12의 발현 수준을 확인하는 단계; 및 상기 테트라스파닌 12 발현 수준을 대조군과 비교하여 증가 여부를 확인하는 단계를 포함하는 약물에 의해 유도되는 간독성 민감성 예측 방법을 제공한다.The present invention also relates to a method for the treatment of cancer, comprising the steps of: collecting blood from a mammal, Confirming the level of expression of tetraspanin 12 in the collected blood; And comparing the level of expression of tetraspanin 12 with that of the control group to determine whether the increase is greater than the control group.

본 발명에 따르면, 아세트아미노펜을 투여하기 전 랫트의 혈액과 투여 후 랫트의 혈액 내 유전자 발현 패턴을 확인한 결과, 아세트아미노펜에 의해 간독성이 유발된 개체의 약물 투여 전 혈액에서 테트라스파닌 12 발현 수준이 증가되어 있는 것을 확인함에 따라, 아세트아미노펜 투여 전 혈액에서 개체의 아세트아미노펜 민감성을 미리 예측하기 위한 간독성 진단용 바이오마커로 제공될 수 있으며, 상기 바이오마커는 간독성 진단용 키트 또는 간독성 민감성 예측 방법에 사용될 수 있다.According to the present invention, the gene expression pattern in the blood of the rat after administration of the blood of the rat before the administration of acetaminophen was confirmed, and as a result, the level of expression of tetraspanin 12 in the blood before administration of the drug to which hepatotoxicity was induced by acetaminophen It can be provided as a biomarker for hepatotoxicity diagnosis for predicting acetaminophen sensitivity of an individual in blood before administration of acetaminophen and the biomarker can be used in a hepatotoxicity diagnostic kit or a method for predicting the sensitivity of hepatotoxicity .

도 1은 민감군(Susceptible group) 및 둔감군(Resistant group)의 약물 투여 전 혈액 내 테트라스파닌 12 mRNA 발현량을 비교한 결과이다.FIG. 1 shows the results of comparing the amount of tetraspanin 12 mRNA expression in the blood before administration of the susceptible group and the resistant group.

이하, 본 발명을 보다 상세하게 설명한다.Hereinafter, the present invention will be described in more detail.

본 발명의 발명자들은 개체마다 선천적으로 발현차이를 나타내는 혈액 내 유전자 중 약물에 의해 유발되는 간독성의 민감도와 관련이 높은 유전자가 있을 것으로 예상하고, 아세트아미노펜을 투여하기 전 혈액과 아세트아미노펜 투여 후 혈액 내 유전자 발현 패턴을 확인한 결과, 간독성이 나타난 개체의 아세트아미노펜 투여 전 혈액 내에서 테트라스파닌 12 발현 수준이 증가된 것을 확인함에 따라, 본 발명을 완성하였다.The inventors of the present invention expect that there will be a gene that is highly related to the sensitivity of drug-induced hepatotoxicity among the genes in the blood that express innate differences in the expression of each individual, As a result of confirming the gene expression patterns, the present inventors completed the present invention by confirming that the level of tetraspanin 12 expression in the blood of the individuals exhibiting hepatotoxicity was increased before the administration of acetaminophen.

본 발명은 테트라스파닌 12(tetraspanin 12)를 유효성분으로 함유하는 간독성 진단용 바이오마커 조성물을 제공할 수 있다.The present invention can provide a biomarker composition for hepatotoxicity diagnosis containing tetraspanin 12 as an active ingredient.

보다 상세하게는 상기 간독성은 약물에 의해 유도되는 것일 수 있으며, 보다 바람직하게 상기 약물은 아세트아미노펜(acetaminophen)일 수 있다.More specifically, the hepatotoxicity may be induced by a drug, and more preferably, the drug may be acetaminophen.

상기 테트라스파닌 12은 약물 투여 전 혈액 내 발현 수준을 확인하는 것일 수 있다.The tetraspanin 12 may be one that confirms the level of expression in blood before administration of the drug.

본 발명의 실시예에 따르면, 랫츠에 아세트아미노펜 투여 전 혈액을 수집하고, 아세트아미노펜을 1g/kg 농도로 증류수에 녹여서 경구투여한 후, 조직병리학적 분석을 통하여 간세포 염증침윤 및 세포괴사를 확인하여 34마리 중 가장 간독성이 심한 민감군 5마리와 간독성이 가장 약한 둔감군 5마리로 분리하고, 각 그룹의 랫츠의 혈액을 수집하여 아세트아미노펜 투여 전 혈액과 유전자 변화를 비교한 결과, 도 1과 같이 민감군(Susceptible group)에서 약물 투여 전 혈액 테트라스파닌(tetraspanin) 12 mRNA의 발현량이 둔감군(Resistant group)의 발현량에 비해 약 2배 높은 것이 확인됨에 따라, 혈액 중 테트라스파닌 12의 발현이 선천적으로 높을 경우 아세트아미노펜 과량 노출에 따른 간독성에 민감한 것이 확인되었다.According to an embodiment of the present invention, blood is collected in rats before administration of acetaminophen, and acetaminophen dissolved in distilled water at a concentration of 1 g / kg is orally administered. Thereafter, hepatocyte inflammatory infiltration and cell necrosis are confirmed by histopathological analysis Five of the 34 most sensitive group with hepatotoxicity and 5 of the weakest group with hepatotoxicity were separated and the blood of each group of rats was collected and compared with blood before the administration of acetaminophen, In the susceptible group, the expression level of tetraspanin 12 mRNA before the administration of the drug was confirmed to be about twice as high as that of the resistant group, and thus the expression of tetraspanin 12 in the blood Was found to be sensitive to hepatotoxicity due to overexposure to acetaminophen.

또한, 본 발명은 테트라스파닌 12의 발현수준을 측정할 수 있는 제제를 유효성분으로 포함하는 간독성 진단용 키트를 제공할 수 있다.In addition, the present invention can provide a hepatotoxicity diagnostic kit comprising as an active ingredient a preparation capable of measuring the level of expression of tetraspanin-12.

상기 테트라스파닌 12의 발현수준을 측정할 수 있는 제제는 상기 테트라스파닌 12 유전자에 특이적으로 결합하는 프라이머 또는 프로브, 상기 테트라스파닌 12 단백질에 특이적으로 결합하는 항체, 펩타이드, 앱타머 또는 화합물일 수 있다.The agent capable of measuring the expression level of the tetraspanin 12 may be a primer or a probe specifically binding to the tetraspanin 12 gene, an antibody specifically binding to the tetraspanin 12 protein, a peptide, Lt; / RTI >

보다 바람직하게는 약물 투여 전 개체의 혈액에서 발현이 증가된 테트라스파닌 12 유전자 서열의 전부, 이의 일부를 포함하는 올리고뉴클레오타이드 또는 그의 상보 가닥 분자가 집적된, 아세트아미노펜으로 인해 유도되는 간독성 예측용 마이크로어레이 칩이 제공될 수 있다. 상기 마이크로어레이 칩은 약물 투여 전 혈액에서 테트라스파닌 12 유전자의 발현을 비교함으로써, 아세트아미노펜 투여로 인해 유도될 수 있는 간독성을 보다 유의성있고 정확하게 비교분석할 수 있다.More preferably, an acetaminophen-induced hepatotoxicity-predisposing microorganism, in which an oligonucleotide or a complementary strand molecule comprising all or a part of the tetraspanin 12 gene sequence whose expression is increased in the blood of an individual before administration of the drug, An array chip can be provided. The microarray chip can compare the expression of the tetraspanin 12 gene in the blood before administration of the drug, so that the hepatotoxicity induced by the administration of acetaminophen can be more significantly and accurately compared and analyzed.

또한, 본 발명은 약물 투여 전 사람을 제외한 포유류로부터 시료를 수집하는 단계; 상기 수집된 시료 내 테트라스파닌 12의 발현 수준을 확인하는 단계; 및 상기 테트라스파닌 12 발현 수준을 대조군과 비교하여 증가 여부를 확인하는 단계를 포함하는 약물에 의해 유도되는 간독성 민감성 예측 방법을 제공할 수 있다.In addition, the present invention relates to a method for preparing a medicament, comprising the steps of: collecting a sample from a mammal, Confirming the expression level of tetraspanin 12 in the collected sample; And comparing the level of expression of tetraspanin 12 with that of the control group to determine whether or not the expression level of the tetraspanin 12 is increased, thereby providing a method for predicting drug-induced hepatotoxicity sensitivity.

상기 간독성은 약물에 의해 유도될 수 있으며, 상기 약물은 아세트아미노펜(acetaminophen)일 수 있다.The hepatotoxicity may be induced by a drug, and the drug may be acetaminophen.

상기 시료는 아세트아미노펜 투여 전 환자 또는 대조군의 뇨, 혈액, 조직 및 세포로 이루어진 군에서 선택될 수 있으며, 보다 바람직하게는 혈액, 혈장 또는 혈청일 수 있으나, 이에 한정되지 않는다.The sample may be selected from the group consisting of urine, blood, tissue and cells of the patient before the administration of acetaminophen or a control group, more preferably blood, plasma or serum, but is not limited thereto.

이하, 본 발명의 이해를 돕기 위하여 실시예를 들어 상세하게 설명하기로 한다. 다만 하기의 실시예는 본 발명의 내용을 예시하는 것일 뿐 본 발명의 범위가 하기 실시예에 한정되는 것은 아니다. 본 발명의 실시예는 당업계에서 평균적인 지식을 가진 자에게 본 발명을 보다 완전하게 설명하기 위해 제공되는 것이다.BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail with reference to the following examples. However, the following examples are intended to illustrate the contents of the present invention, but the scope of the present invention is not limited to the following examples. Embodiments of the present invention are provided to more fully describe the present invention to those skilled in the art.

<< 실시예Example 1>  1> 간독성Hepatotoxicity 민감도 예측을 위한  For sensitivity estimation 바이오마커Biomarker 확인 Confirm

SD 랫트 (7주령, 수컷) 34마리를 아세트아미노펜 투여 전 RNA를 추출하기 위해 마취한 뒤 안와정맥총에서 혈액을 미리 채취해 놓았다. 1주일의 회복기간을 가진 후 아세트아미노펜 1g/kg 농도로 증류수에 녹여서 경구투여하였다. Twenty-four SD rats (7 weeks old, male) were anesthetized to extract RNA before acetaminophen administration and blood was collected from the orbital vein. After a one week recovery period, acetaminophen was dissolved in distilled water at a concentration of 1 g / kg and then orally administered.

투여 24시간 후에 부검하여 혈청분석 (ALT, AST)을 수행하였으며(Che et al., 2015, Regul Toxicol Pharmacol. 71(3):379-87), 조직병리학적 분석(Yun et al., 2014, Free Radic Biol Med. 77:183-94)을 통하여 간세포 염증침윤 및 세포괴사를 확인하여 34마리 중 가장 간독성이 심한 민감군 5마리와 간독성이 가장 약한 둔감군 5마리로 그룹핑(grouping) 하였다.(Chel et al., 2015, Regul Toxicol Pharmacol. 71 (3): 379-87), histopathological analysis (Yun et al., 2014, Free Radic Biol Med. 77: 183-94), and group 5 was the most sensitive group with the highest hepatotoxicity and the group 5 with the weakest hepatotoxicity.

그 후, 민감군과 둔감군에서 미리 채취해둔 혈액 RNA를 이용해 mRNA 마이크로어레이(affymetrix GeneChip Rat gene 1.0 ST array; Kiba, 2017, Ann Neurosci. 24(1):26-31)를 수행하여 두 군간 본래의 유전자 발현 패턴을 비교 분석하였다 (Fold change 1.5 이상, p value 0.05 이하).After that, mRNA microarrays (affymetrix GeneChip Rat gene 1.0 ST array; Kiba, 2017, Ann Neurosci. 24 (1): 26-31) were performed using the blood RNA preliminarily collected from the sensitive and insensitive groups. (Fold change of 1.5 or more, p value of 0.05 or less).

그 결과, 도 1과 같이 민감군(Susceptible group)에서 약물 투여 전 혈액 테트라스파닌 12 (tetraspanin 12; NM_001015026) mRNA의 발현량이 둔감군(Resistant group)의 발현량에 비해 약 2배 높은 것이 확인되었다.As a result, it was confirmed that the expression level of blood tetraspanin 12 (NM_001015026) mRNA before the drug administration in the susceptible group was about twice as high as that of the resistant group .

상기 결과로부터 혈액 중 테트라스파닌 12의 발현이 선천적으로 높을 경우 아세트아미노펜 과량 노출에 따른 간독성에 민감한 것을 확인할 수 있었다.From the above results, it was confirmed that when the expression of tetraspanin 12 in blood is innately elevated, it is sensitive to hepatotoxicity due to acetaminophen overexposure.

이상으로 본 발명 내용의 특정한 부분을 상세히 기술하였는 바, 당업계의 통상의 지식을 가진 자에게 있어서, 이러한 구체적 기술은 단지 바람직한 실시양태일 뿐이며, 이에 의해 본 발명의 범위가 제한되는 것이 아닌 점은 명백할 것이다. 따라서 본 발명의 실질적인 범위는 첨부된 청구항들과 그것들의 등가물에 의하여 정의된다고 할 것이다.While the present invention has been particularly shown and described with reference to specific embodiments thereof, those skilled in the art will appreciate that such specific embodiments are merely preferred embodiments and that the scope of the present invention is not limited thereby. something to do. It is therefore intended that the scope of the invention be defined by the claims appended hereto and their equivalents.

Claims (9)

테트라스파닌 12(tetraspanin 12)의 발현수준을 측정할 수 있는 제제를 유효성분으로 함유하는 아세트아미노펜(acetaminophen)에 의해 유도되는 간독성 민감성 진단용 조성물.A composition for diagnosing hepatotoxicity sensitivity induced by acetaminophen containing an agent capable of measuring the expression level of tetraspanin 12 as an active ingredient. 삭제delete 삭제delete 청구항 1에 있어서, 상기 조성물은 아세트아미노펜(acetaminophen) 투여 전 혈액 내 테트라스파닌 12의 발현 수준을 확인하기 위한 것을 특징으로 하는 간독성 민감성 진단용 조성물.The composition for diagnosing hepatotoxicity sensitivity according to claim 1, wherein the composition is for confirming the expression level of tetraspanin 12 in blood before administration of acetaminophen. 테트라스파닌 12의 발현수준을 측정할 수 있는 제제를 유효성분으로 포함하는 아세트아미노펜(acetaminophen)에 의해 유도되는 간독성 민감성 진단용 키트.A kit for the diagnosis of hepatotoxicity sensitivity induced by acetaminophen comprising an agent capable of measuring the expression level of tetraspanin-12 as an active ingredient. 청구항 5에 있어서, 상기 테트라스파닌 12의 발현수준을 측정할 수 있는 제제는 상기 테트라스파닌 12 유전자에 특이적으로 결합하는 프라이머 또는 프로브, 상기 테트라스파닌 12 단백질에 특이적으로 결합하는 항체, 펩타이드, 앱타머 또는 화합물인 것을 특징으로 하는 간독성 민감성 진단용 키트.[Claim 6] The method according to claim 5, wherein the agent capable of measuring the level of expression of tetraspanin 12 comprises a primer or a probe specifically binding to the tetraspanin 12 gene, an antibody specifically binding to the tetraspanin 12 protein, A peptide, an aptamer or a compound. 아세트아미노펜(acetaminophen) 투여 전 사람을 제외한 포유류로부터 시료를 수집하는 단계;
상기 수집된 시료 내 테트라스파닌 12의 발현 수준을 확인하는 단계; 및
상기 테트라스파닌 12 발현 수준을 대조군과 비교하여 증가 여부를 확인하는 단계를 포함하는 아세트아미노펜(acetaminophen)에 의해 유도되는 간독성 민감성 예측 방법. Collecting a sample from a mammal other than a human before administration of acetaminophen;
Confirming the expression level of tetraspanin 12 in the collected sample; And
And comparing the level of expression of tetraspanin 12 with that of the control group to determine whether or not the expression level of the tetraspanin 12 is increased. 삭제delete 삭제delete
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