KR102125828B1 - 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 PDFInfo
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Abstract
Description
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 diagnosis of hepatotoxicity sensitivity induced by drugs and a method for predicting hepatotoxicity sensitivity 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. The liver converts drugs that enter the body into safe substances and removes toxicity, but liver toxicity may occur when these substances are excessively introduced into the body. In addition, in addition to drugs, chemicals used for experimental or industrial purposes, compounds derived from natural products, and extracts derived from medicinal plants may also cause liver toxicity.
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.On the other hand, hepatotoxicity induced by drugs, that is, drug-induced liver injury (DILI) can be said to be a major cause of acute hepatotoxicity. Weak liver damage can range from very mild liver toxicity to acute liver failure, and is largely classified as endogenous hepatotoxicity and specific constitutional hepatotoxicity. Endogenous hepatotoxicity mainly refers to a phenomenon induced through direct drug reactions, reactions to drugs, etc., and specific constitutional hepatotoxicity refers to a phenomenon induced according to concentrations of drugs.
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 스트레스를 유도하며 DNA의 손상을 야기한다. 또한, 간성상 세포의 활성을 유도하는 VEGF, TGF-β1 신호전달 물질에 의해 간섬유증이 유발될 수 있으며, NF-κB 신호전달로 시작해서 IFN-γ, TNF-α, IL-6와 같은 사이토카인을 발현해 세포자살이나, 염증반응을 유도시킨다.Carbon tetrachloride (CCl4), alcohol, and galactosamine (GalN) are representative examples of the substance that induces hepatotoxicity. It reacts with CCl3OO·, and these products induce oxidative stress and damage DNA. In addition, hepatic fibrosis can be induced by VEGF and TGF-β1 signaling substances that induce the activity of hepatic stellate cells, starting with NF-κB signaling and cytokines such as IFN-γ, TNF-α, IL-6 Expression of kine induces apoptosis 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 to acetaldehyde by ADH (alcohol dehydrogenase), an enzyme in the liver, where NAD is reduced to NADH, and high concentrations of NADH accumulate to promote fatty acid production, resulting in fatty liver. In addition, oxidative stress is applied to secrete cytokines such as IL-1, IL-6, and Il-8 to cause inflammatory reactions or apoptosis. In addition, when hepatocytes are attacked by endotoxin emitted by ethanol digested in the intestine, cytokines such as TNF-α are secreted to induce hepatic stellate cell activity and cause liver fibrosis.
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 두 가지 요인으로 인해 급성간부전을 유발시킨다.Galactosamine (GalN) can generate free radicals when oxidized by an enzyme such as cytochrome p450. When subjected to this oxidative stress, it releases factors such as IL-1β, IL-6, and TNF-α, resulting in acute liver It can cause disease, and an increase in NF-κB and MAPK can also lead to an immune response, causing acute liver failure due to these two factors, such as expressing a programmed cell death 4 (PDCD4) protein.
한편, 새로운 간독성 약물로 보고된 시스플라틴(Cisplatin)은 주로 고환암, 방광암, 난소암, 전립선암 등의 치료에 사용되는 1 세대 항암제로써 암세포와 일반세포 모두에 독성을 나타내는 것으로 보고되었다. 이러한 시스플라틴은 간에서 CYP2E1에 의해 대사가 이루어지면서 나오는 superoxide 같은 산화적 스트레스로 인해 DNA를 손상시키고, 미토콘드리아의 전자전달효소 1번 및 4번을 방해하여 ATP 생성을 저해하고, 미토콘드리아 막 전위의 감소로 칼슘이온의 섭취를 감소시키며, 항산화 기능의 이상을 초래해 독성을 유발한다. 직접적으로는 DNA의 intra, inter strand의 Guanine에 붙어서 전사를 방해하여 세포자살을 유도하므로, 시스플라틴 약물 복용 전 약물에 대한 민감성을 나타낼 수 있는지 미리 예측할 수 있는 방법에 대한 연구가 필요하다.On the other hand, cisplatin, a new hepatotoxic drug, has been reported to be toxic to both cancer cells and normal cells as a first-generation anticancer agent mainly used in the treatment of testicular cancer, bladder cancer, ovarian cancer, and prostate cancer. These cisplatins damage DNA due to oxidative stress such as superoxide from metabolism by CYP2E1 in the liver, interfere with mitochondrial electron transfer enzymes 1 and 4, inhibit ATP production, and reduce mitochondrial membrane potential. It reduces the intake of calcium ions and causes abnormalities in antioxidant functions, causing toxicity. As it directly induces apoptosis by preventing transcription by attaching to Guanine of intra and inter strands of DNA, it is necessary to study how to predict in advance whether it can show drug sensitivity before taking cisplatin drugs.
본 발명은 개체의 약물에 대한 민감도를 예측할 수 있는 혈액 내 바이오마커 조성물을 제공함으로써, 시스플라틴 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 sensitivity of an individual to a drug, thereby predicting hepatotoxicity that may be induced due to cisplatin administration before drug administration, thereby preventing hepatotoxicity according to drug administration in advance. Want to provide
본 발명은 Nfatc4 (Nuclear factor of activated T-cells 4; cytoplasmic 4)를 유효성분으로 함유하는 간독성 민감성 진단용 바이오마커 조성물을 제공한다.The present invention provides a biomarker composition for diagnosing hepatotoxicity sensitivity containing Nfatc4 (Nuclear factor of activated T-cells 4; cytoplasmic 4) as an active ingredient.
본 발명은 Nfatc4의 발현수준을 측정할 수 있는 제제를 유효성분으로 포함하는 간독성 민감성 진단용 키트를 제공한다.The present invention provides a kit for diagnosing hepatotoxicity sensitivity comprising an agent capable of measuring the expression level of Nfatc4 as an active ingredient.
본 발명은 약물 투여 전 개체로부터 분리된 생물학적 시료를 수집하는 단계; 상기 수집된 시료 내 Nfatc4의 발현 수준을 확인하는 단계; 및 상기 Nfatc4 발현 수준을 대조군과 비교하여 감소 수준을 확인하는 단계를 포함하는 약물에 의해 유도되는 간독성 민감성 예측 방법을 제공한다.The present invention comprises the steps of collecting a biological sample isolated from the individual before drug administration; Confirming the expression level of Nfatc4 in the collected sample; And it provides a method for predicting hepatotoxicity sensitivity induced by drugs comprising the step of confirming the reduction level by comparing the Nfatc4 expression level with the control.
본 발명에 따르면, 시스플라틴에 의해 간독성이 유발된 개체의 약물 투여 전 간 조직에서 Nfatc4의 발현 수준이 감소되어 있는 것을 확인함에 따라, 상기 Nfatc4를 시스플라틴 투여 전 간 조직에서 개체의 시스플라틴 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, as it is confirmed that the expression level of Nfatc4 in the liver tissue is reduced before administration of the drug to the liver induced by cisplatin, pre-predicting the cisplatin sensitivity of the individual in the liver tissue before administration of the Nfatc4 to cisplatin It can be provided as a biomarker for liver toxicity diagnosis, the biomarker can be used in a liver toxicity diagnostic kit or a method for predicting liver toxicity sensitivity.
도 1은 민감군(Susceptible group) 및 둔감군(Resistant group)의 약물 투여 전 간 조직 내 Nfatc4 mRNA 발현량을 비교한 결과이다.1 is a result of comparing the expression level of Nfatc4 mRNA in liver tissue before drug administration of the susceptible group and the susceptible 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, 시스플라틴 투여 후 간독성이 나타난 실험동물과 시스플라틴 투여 후에도 간독성이 둔감하게 나타난 실험동물의 약물 투여 전 간 조직에서 유전자 발현 패턴을 확인한 결과, 간독성이 나타난 개체의 시스플라틴 투여 전 간 조직에서 Nfatc4의 발현 수준이 증가된 것을 확인함에 따라, 본 발명을 완성하였다.The inventors of the present invention predict that there will be genes associated with sensitivity to hepatotoxicity caused by drugs among genes in the blood that innately express differences in expression for each individual, and hepatotoxicity after administration of cisplatin and experimental animals showing hepatotoxicity after cisplatin administration. As a result of confirming the gene expression pattern in liver tissue prior to drug administration of the dullly shown experimental animals, the present invention was completed by confirming that the expression level of Nfatc4 was increased in liver tissue before administration of cisplatin in an individual with liver toxicity.
본 발명은 Nfatc4 (Nuclear factor of activated T-cells 4; RAT(Nfatc4) NM_001107264)를 유효성분으로 함유하는 간독성 진단용 바이오마커 조성물을 제공할 수 있다.The present invention can provide a biomarker composition for diagnosing liver toxicity containing Nfatc4 (Nuclear factor of activated T-cells 4; RAT(Nfatc4) NM_001107264) as an active ingredient.
보다 상세하게는 상기 간독성은 약물에 의해 유도되는 것일 수 있으며, 보다 바람직하게 상기 약물은 시스플라틴(Cisplatin)일 수 있다.In more detail, the liver toxicity may be induced by a drug, and more preferably, the drug may be cisplatin.
상기 Nfatc4는 약물 투여 전 간 조직에서 발현 수준을 확인하는 것일 수 있다.The Nfatc4 may be to check the expression level in liver tissue before drug administration.
본 발명의 실시예에 따르면, 랫드에 시스플라틴 투여 전 간 조직을 수집하고, 시스플라틴을 25mg/kg 농도로 생리식염수에 녹여서 복강투여한 후, 혈청분석을 통하여 38마리 중 가장 간독성이 심한 민감군 5마리와 간독성이 가장 약한 둔감군 5마리로 분리하고, 각 그룹의 랫드의 혈액을 수집하여 시스플라틴 투여 전 간 조직에서 유전자 변화를 비교한 결과, 도 1과 같이 둔감군(Resistant group)의 약물 투여 전 간 조직에서 Nfatc4 mRNA의 발현량이 민감군(Susceptible group)의 발현량에 비해 약 3.77 배 높은 것이 확인됨에 따라, 간 조직 내 Nfatc4의 발현이 선천적으로 낮을 경우 시스플라틴 과량 노출에 따른 간독성에 민감한 것이 확인되었다.According to an embodiment of the present invention, liver tissue is collected before administration of cisplatin to rats, and cisplatin is dissolved in physiological saline at a concentration of 25 mg/kg, and then administered intraperitoneally. And the hepatotoxicity group was separated into 5 groups with the weakest hepatotoxicity, and blood from each group of rats was collected and compared with genetic changes in liver tissue before cisplatin administration. As shown in FIG. 1, liver before drug administration of the resensitized group was administered. As it was confirmed that the expression level of Nfatc4 mRNA in the tissue was about 3.77 times higher than the expression level of the susceptible group, it was confirmed that when the expression of Nfatc4 in the liver tissue was innately low, it was sensitive to hepatotoxicity due to excessive exposure to cisplatin.
또한, 본 발명은 Nfatc4의 발현수준을 측정할 수 있는 제제를 유효성분으로 포함하는 간독성 진단용 키트를 제공할 수 있다.In addition, the present invention can provide a kit for diagnosing hepatotoxicity comprising an agent capable of measuring the expression level of Nfatc4 as an active ingredient.
상기 Nfatc4의 발현수준을 측정할 수 있는 제제는 상기 Nfatc4의 유전자에 특이적으로 결합하는 프라이머 또는 프로브, 상기 Nfatc4의 단백질에 특이적으로 결합하는 항체, 펩타이드, 앱타머 또는 화합물일 수 있다.The agent capable of measuring the expression level of Nfatc4 may be a primer or probe specifically binding to the gene of Nfatc4, an antibody, peptide, aptamer or compound specifically binding to the protein of Nfatc4.
보다 바람직하게는 약물 투여 전 개체의 간 조직에서 발현이 증가된 Nfatc4 유전자 서열의 전부, 이의 일부를 포함하는 올리고뉴클레오타이드 또는 그의 상보 가닥 분자가 집적된, 시스플라틴으로 인해 유도되는 간독성 예측용 마이크로어레이 칩이 제공될 수 있다. 상기 마이크로어레이 칩은 약물 투여 전 간 조직에서 Nfatc4 유전자의 발현을 비교함으로써, 시스플라틴 투여로 인해 유도될 수 있는 간독성을 보다 유의성 있고 정확하게 비교분석할 수 있다.More preferably, a microarray chip for predicting liver toxicity induced by cisplatin, in which an oligonucleotide comprising all or part of the Nfatc4 gene sequence whose expression is increased in the liver tissue of an individual before drug administration, or a complementary strand molecule thereof is integrated, is integrated. Can be provided. The microarray chip compares the expression of the Nfatc4 gene in liver tissue before drug administration, thereby making it possible to more significantly and accurately compare and analyze hepatotoxicity induced by cisplatin administration.
또한, 본 발명은 약물 투여 전 개체로부터 분리된 생물학적 시료를 수집하는 단계; 상기 수집된 시료 내 Nfatc4의 발현 수준을 확인하는 단계; 및 상기 Nfatc4 발현 수준을 대조군과 비교하여 감소 수준을 확인하는 단계를 포함하는 약물에 의해 유도되는 간독성 민감성 예측 방법을 제공할 수 있다.In addition, the present invention comprises the steps of collecting a biological sample isolated from the individual before drug administration; Confirming the expression level of Nfatc4 in the collected sample; And it can provide a method for predicting hepatotoxicity sensitivity induced by drugs comprising the step of confirming the reduction level by comparing the Nfatc4 expression level with the control.
상기 간독성은 약물에 의해 유도될 수 있으며, 상기 약물은 시스플라틴(Cisplatin)일 수 있다.The hepatotoxicity may be induced by a drug, and the drug may be cisplatin.
상기 생물학적 시료는 시스플라틴 투여 전 개체 또는 대조군으로부터 분리된 뇨, 혈액, 조직 및 세포로 이루어진 군에서 선택될 수 있으며, 보다 바람직하게는 간 조직일 수 있으나, 이에 한정되지 않는다.The biological sample may be selected from the group consisting of urine, blood, tissue, and cells isolated from an individual or a control group before administration of cisplatin, and more preferably liver tissue, but is not limited thereto.
상기 개체는 시스플라틴 투여 전 사람 또는 동물일 수 있다.The subject may be a human or animal prior to cisplatin administration.
본 발명의 Nfatc4 (Nuclear factor of activated T-cells 4; cytoplasmic 4; NM_001107264)는 Nfat protein family 중 하나로 Nfat protein family는 다양한 반응을 이끌어내 세포 내부의 칼슘양을 증가시키고, 장기의 발달과 세포의 증식에 매우 중요한 역할을 한다. 또한, 다른 유전자와 연관해 세포주기를 조절하며, 세포의 분화, 자살 등 세포의 기본적인 생활사에 관여한다. 특히, Nfatc4의 경우 간의 부분절제 시술을 진행하였을 때 간의 재생에 관여하는 것으로 알려졌다. 상기 Nfatc4 유전자가 없을 경우 흉선에서 세포자살을 막는 단백질인 Bcl-2 단백질의 발현에 문제가 생겨 흉선세포가 자살하게 되어 T 세포의 발달에 영향을 미치는 것으로 알려졌다.The Nfatc4 (Nuclear factor of activated T-cells 4; cytoplasmic 4; NM_001107264) of the present invention is one of the Nfat protein family, and the Nfat protein family elicits various reactions to increase the amount of calcium inside the cell, develop organs and proliferate cells Plays a very important role in In addition, it regulates the cell cycle in connection with other genes, and is involved in the basic life cycle of cells, such as cell differentiation and suicide. In particular, Nfatc4 is known to be involved in liver regeneration when a partial resection of the liver is performed. It is known that in the absence of the Nfatc4 gene, a problem occurs in the expression of Bcl-2 protein, a protein that blocks apoptosis in the thymus, and the thymus cells are suicidal, which is known to affect the development of T cells.
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.Hereinafter, examples will be described in detail to help understanding of the present invention. However, the following examples are merely illustrative of the contents of the present invention, and the scope of the present invention is not limited to the following examples. The embodiments of the present invention are provided to more fully describe the present invention to those skilled in the art.
<< 실시예Example 1> 1> 간독성Liver toxicity 민감도 예측을 위한 For predicting sensitivity 바이오마커Biomarker 확인 Confirm
SD 랫드 (6주령, 수컷) 38마리를 시스플라틴 투여 전 RNA를 추출하기 위해 마취한 뒤 간의 한 엽을 선택하여 조직을 미리 채취해 놓았다. 3주간의 회복기간을 가진 후 시스플라틴 25mg/kg 농도로 생리식염수에 녹여서 복강투여하였다. Thirty-eight SD rats (6 weeks old, male) were anesthetized to extract RNA prior to cisplatin administration, and then one lobe of the liver was selected and tissue was previously collected. After a three-week recovery period, cisplatin was dissolved in physiological saline at a concentration of 25 mg/kg and administered intraperitoneally.
투여 48시간 후에 부검하여 혈청분석 (ALT, AST)을 수행하였으며(Che et al., 2015, Regul Toxicol Pharmacol. 71(3):379-87), 그 결과를 토대로 38마리 중 가장 간독성이 심하게 나타난 민감군 5마리와 간독성이 가장 약하게 나타난 둔감군 5마리로 그룹핑하였다. 그 후 민감군과 둔감군에서 미리 채취해둔 조직을 이용하여 RNA를 추출하여 RNA seq (Illumina Novaseq6000)를 수행하고 두 군간 본래의 유전자 발현 패턴을 비교 분석하였다 (Fold change 2 이상, p value 0.05 이하).Autopsy was performed by autopsy 48 hours after administration (ALT, AST) (Che et al., 2015, Regul Toxicol Pharmacol. 71(3):379-87). The group was grouped into 5 sensitive groups and 5 insensitive groups with the lowest hepatotoxicity. Thereafter, RNA was extracted using tissues previously collected from the sensitive and insensitive groups to perform RNA seq (Illumina Novaseq6000), and the original gene expression pattern between the two groups was compared and analyzed (
그 결과, 도 1과 같이 둔감군(Resistant group)에서 약물 투여 전 간 Nfatc4 mRNA의 발현량이 민감군(Susceptible group)의 발현량에 비해 3.77배 높은 것이 확인되었다.As a result, as shown in FIG. 1, it was confirmed that the expression level of liver Nfatc4 mRNA was 3.77 times higher than the expression level of the susceptible group in the insensitivity group before drug administration.
상기 결과로부터 간에서 Nfatc4의 발현이 선천적으로 낮을 경우 시스플라틴 과량 노출에 따른 간독성에 민감한 것이 확인되었다.From the above results, it was confirmed that when the expression of Nfatc4 in the liver is low, it is sensitive to hepatotoxicity due to excessive exposure to cisplatin.
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.Since the specific parts of the present invention have been described in detail above, for those skilled in the art, it is obvious that this specific technique is only a preferred embodiment, and the scope of the present invention is not limited thereby. something to do. Therefore, the substantial scope of the present invention will be defined by the appended claims and their equivalents.
Claims (9)
상기 수집된 시료 내 Nfatc4의 발현 수준을 확인하는 단계; 및
상기 Nfatc4 발현 수준을 대조군과 비교하여 감소 수준을 확인하는 단계를 포함하는 시스플라틴에 의해 유도되는 간독성 민감성 예측 방법. Collecting a biological sample isolated from the individual prior to drug administration;
Confirming the expression level of Nfatc4 in the collected sample; And
A method for predicting hepatotoxicity sensitivity induced by cisplatin, comprising comparing the level of Nfatc4 expression with a control to confirm a reduction level.
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| KR20150081633A (en) * | 2014-01-06 | 2015-07-15 | 가톨릭대학교 산학협력단 | Biomarker for predicting and diagnosing drug-induced liver injury |
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| KR20190080149A (en) * | 2017-12-28 | 2019-07-08 | 가톨릭대학교 산학협력단 | Biomarker composition for diagnosing susceptibility to hepatotoxicity and diagnosing method thereof |
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| KR20150081633A (en) * | 2014-01-06 | 2015-07-15 | 가톨릭대학교 산학협력단 | Biomarker for predicting and diagnosing drug-induced liver injury |
| KR20150081631A (en) * | 2014-01-06 | 2015-07-15 | 가톨릭대학교 산학협력단 | Biomarker for predicting and diagnosing drug-induced liver injury using transcriptomics and proteomics |
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