Hepatoprotective therapy by slit2

Abstract

The present invention relates to a pharmaceutical composition for preventing or treating drug hepatotoxicity diseases and a health functional food composition for preventing or alleviating drug hepatotoxicity diseases and, more specifically, to a pharmaceutical composition for preventing or treating drug hepatotoxicity diseases and a health functional food composition for preventing or alleviating drug hepatotoxicity diseases, each composition comprising Slit2 protein or a nucleic acid coding therefor as an active ingredient. The present invention relates to a composition of VEGF-GRAB.

Description

Hepatoprotective therapy by SLIT2 The present invention relates to a pharmaceutical composition for preventing or treating drug-induced liver toxicity disease and a health functional food composition for preventing or improving the disease, and more particularly, to a pharmaceutical composition for preventing or treating drug-induced liver toxicity disease comprising a Slit2 protein or a nucleic acid encoding the same as an active ingredient, and a health functional food composition for preventing or improving drug-induced liver toxicity disease comprising the same. The liver is the largest organ in the human body, weighing approximately 1.2 to 1.5 kg in adults. Its vital role is to process and store body substances. Detoxification, which involves breaking down and metabolizing various drugs, alcohol, and other toxic substances into forms that can be excreted, is a particularly important function of the liver. Because the liver breaks down and metabolizes toxic substances, it is also the organ most at risk of damage from them. While the liver possesses remarkable regenerative capacity, excessive or persistent damage can lead to irreversible damage. When liver function declines, it becomes unable to process toxins and waste products, leading to abnormalities in sugar and fat metabolism and difficulties in synthesizing essential proteins. Liver damage can lead to various liver diseases, including hepatitis, cirrhosis, and liver cancer. In particular, drugs used to affect bodily functions must be broken down by the liver, so they can act as toxic substances to the liver and cause liver damage. Acetaminophen is a representative substance that causes liver damage. Acetaminophen is a drug widely used as an antipyretic and analgesic and has fewer side effects compared to other drugs. However, because it is readily available at pharmacies, it is easily abused. Overdose of acetaminophen or its use in combination with other drugs such as alcohol can cause fatal liver damage. Although some herbal medicines and extracts have been confirmed to have some therapeutic effects on acetaminophen-induced liver damage, there is currently no treatment that has been proven to be appropriate for the treatment of acetaminophen-induced liver damage. Meanwhile, Slit proteins are known to play a crucial role in the development and growth of the nervous system and are present in various species, including humans. Slit proteins regulate physiological activity and function as regulators of various intracellular processes in various tissues. In particular, SLIT2 is known to contribute to anti-inflammatory effects (Zhao H, et al., J Immunol. 2014 Jan 1;192(1):385-93), promote cell division, and have been reported to be involved in cell regeneration (Antooxidants, 2021, 10, 86). However, its hepatocellular protective ability has not been reported. Under this technical background, the inventors of the present invention studied the various functions of the Slit 2 protein, confirmed the drug-induced hepatotoxicity treatment effect when administering the Slit2 protein, and completed the present invention. The above information described in this background section is solely intended to enhance understanding of the background of the present invention and may not include information that constitutes prior art already known to a person of ordinary skill in the art to which the present invention pertains. Summary of the invention The purpose of the present invention is to provide a pharmaceutical composition for preventing or treating drug hepatotoxicity disease, which comprises a Slit2 protein or a nucleic acid encoding the same as an active ingredient. Another object of the present invention is to provide a method for preventing or treating drug-induced liver toxicity, comprising administering a Slit2 protein or a nucleic acid encoding the same. Another object of the present invention is to provide a use of the Slit2 protein or a nucleic acid encoding the same for preventing or treating drug-induced liver toxicity. Another object of the present invention is to provide the use of a Slit2 protein or a nucleic acid encoding the same for the manufacture of a medicament for the prevention or treatment of drug-induced liver toxicity. Another object of the present invention is to provide a health functional food composition for preventing or improving drug hepatotoxicity disease, which contains Slit2 protein as an active ingredient. In order to achieve the above purpose, the present invention provides a pharmaceutical composition for preventing or treating drug hepatotoxicity disease, which comprises Slit2 protein or a nucleic acid encoding the same as an active ingredient. The present invention also provides a method for preventing or treating drug-induced liver toxicity, comprising administering the Slit2 protein or a nucleic acid encoding the same. The present invention also provides a use of the Slit2 protein or a nucleic acid encoding the same for the prevention or treatment of drug-induced liver toxicity. The present invention also provides the use of the Slit2 protein or a nucleic acid encoding the same for the manufacture of a medicament for the prevention or treatment of drug-induced liver toxicity diseases. The present invention provides a health functional food composition for preventing or improving drug hepatotoxicity disease, which contains Slit2 protein as an active ingredient. Figure 1 is a schematic diagram showing the timing and dose of administration of Slit2 protein and APAP in an animal model of hepatotoxicity. Figure 2 is a photograph showing histological confirmation of the degree of liver tissue damage in a group administered acetaminophen and / or SLIT2 protein in an animal model of hepatotoxicity. Figure 3 is a photograph showing histological confirmation of the degree of liver tissue damage in a group administered acetaminophen and / or SLIT2 protein in an animal model of hepatotoxicity-induced aging. Figure 4 is a graph showing the expression levels of AST and ALT, which are markers of hepatocellular damage, for groups administered acetaminophen and / or SLIT2 protein in an animal model of hepatotoxicity. Figure 5 is a graph showing the expression levels of AST and ALT, which are markers of hepatocellular damage, for groups administered acetaminophen and / or SLIT2 protein in an aging animal model induced by hepatotoxicity. Figure 6 shows the results of an analysis confirming the expression level of CYP2E1 for a group administered acetaminophen and / or SLIT2 protein in an animal model of hepatotoxicity. Figure 7 shows microscopic images of human hepatocyte cell lines (HH) treated with acetaminophen and / or SLIT2 protein. Arrows indicate damaged cells (spreading and enlarging). Figure 8 is a graph showing the level of expression of inflammatory factors in groups administered acetaminophen and / or SLIT2 protein to human hepatocyte cell lines (HH). Figure 9 is a graph showing the level of expression of inflammatory factors in groups administered acetaminophen and / or SLIT2 protein to Chang liver cell lines. Figure 10 shows the amount of reactive oxygen species generated in groups administered acetaminophen and / or SLIT2 protein to human hepatocyte cell lines (HepG2). Figure 11 shows histological photographs obtained using immunoprecipitation in a group administered acetaminophen and / or SLIT2 protein in an animal model of hepatotoxicity. CD11b (an immune cell marker) was used in immunoprecipitation to observe immune cell activity. Figure 12 is a graph showing the level of expression of inflammatory factors for groups administered acetaminophen and / or SLIT2 protein in an animal model of hepatotoxicity. Figure 13 shows the results of an analysis confirming the expression level of CYP2E1 for a group administered acetaminophen and / or SLIT2 protein to an aging animal model and hepatic cell line (HepG2) induced by hepatotoxicity. Detailed description of the invention and preferred embodiments Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Generally, the nomenclature used herein is well known and commonly used in the art. Acetaminophen, primarily used as an antipyretic and analgesic, is a widely used drug worldwide and is known to have few side effects, but taking high doses of acetaminophen can cause liver toxicity (Antioxidants, 2021, 10, 86). In one embodiment of the present invention, when Slit2 protein is administered to an animal model and a cell model in which drug hepatotoxicity is induced by administration of acetaminophen, it was confirmed that the destruction of liver cells caused by high doses of acetaminophen is suppressed, the expression of AST and ALT, which are markers of drug hepatotoxicity, is reduced, the activity of immune cells is reduced, and the expression of inflammatory factors is reduced, so that it can be usefully used as a pharmaceutical composition for preventing or treating drug hepatotoxicity and / or a health functional food composition for preventing or improving drug hepatotoxicity. Therefore, in one aspect, the present invention relates to a pharmaceutical composition for preventing or treating drug hepatotoxicity disease, comprising a Slit2 protein or a nucleic acid encoding the same as an active ingredient. In another aspect, the present invention relates to a method for preventing or treating drug-induced liver toxicity, comprising administering a Slit2 protein or a nucleic acid encoding the same. In another aspect, the present invention relates to the use of Slit2 protein or a nucleic acid encoding the same for the prevention or treatment of drug-induced liver toxicity diseases. In another aspect, the present invention relates to the use of a Slit2 protein or a nucleic acid encoding the same for the manufacture of a medicament for the prevention or treatment of drug-induced liver disease. The term "Slit2 protein (Slit homolog 2 protein)" used in the present invention is a protein discovered in Drosophila, which has homologous proteins in various biological species, and which is encoded by the SLIT2 gene in humans (Chedotal A (February 2008). Adv Exp Med Biol. Advances in Experimental Medicine and Biology. 621: 65-80). Slit2 protein is a secreted axon guidance molecule that binds to ROBO-1, -2, -3, and -4, Laminin-1, DAN, Gremlin, and Glypican-1. Slit2 protein binds to ROBO receptors and initiates axon repulsion, thereby regulating axon guidance. Slit2 protein has also been shown to induce growth cone collapse, inhibit oligodendrocyte precursor cell migration, and promote axon elongation, branch formation, and fasciculation. Outside the nervous system, Slit2 protein plays a role in a wide range of biological processes, including cell adhesion and migration, tumor progression and metastasis, angiogenesis, lymphangiogenesis, HIV-1 replication, platelet function and thrombus formation, and stem cell aging. It is also known as an anti-inflammatory protein (Zhao H, et al., J Immunol. 2014 Jan 1;192(1):385-93. doi: 10.4049 / jimmunol.1302021. Epub 2013 Nov 22. PMID: 24272999; PMCID: PMC3908786.). In the present invention, the Slit2 protein may be characterized as being recombinant human Slit2. In the present invention, the Slit2 protein is used to mean not only a natural protein but also a recombinant protein and a fragment thereof, as long as its activity is maintained. In the present invention, the Slit2 protein may be characterized by including a sequence selected from the group consisting of NCBI reference sequences NP_004778.1, NP_001276064.1, NP_001276065.1, XP_005248268.1, XP_006714049.1, XP_011512211.1, XP_016864334.1, and XP_011512212.2. In the present invention, the Slit2 protein may be characterized by having an amino acid sequence represented by sequence number 1, but is not limited thereto as long as it has the same function. The Slit2 protein of the present invention is a concept that includes a fragment of the Slit2 protein that still maintains the activity of the Slit2 protein, in which some amino acids at the N-terminus or C-terminus are truncated from the amino acid sequence of the Slit2 protein of the above-mentioned sequence number 1, and further includes a concept that includes a Slit2 protein that still maintains the activity of the Slit2 protein, including substitutions, preferably conservative substitutions, of some amino acids in the Slit2 protein. As used herein, the term "conservative substitution" refers to a modification of a polypeptide that involves replacing one or more amino acids with amino acids having similar biochemical properties without causing a loss of biological or biochemical function of the polypeptide. A "conservative amino acid substitution" is a substitution that replaces an amino acid residue with an amino acid residue having a similar side chain. Classes of amino acid residues having similar side chains are well known and defined in the art. These classes include amino acids with basic side chains (e.g., lysine, arginine, histidine), amino acids with acidic side chains (e.g., aspartic acid, glutamic acid), amino acids with uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), amino acids with non-polar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), amino acids with beta-branched side chains (e.g., threonine, valine, isoleucine), and amino acids with aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). It is expected that the STC-1 protein of the present invention may have conservative amino acid substitutions and still retain activity, and as long as the characteristics of the Slit2 protein according to the present invention are maintained, a protein in which a mutation due to conservative substitution occurs is also included in the scope of the present invention. In the present invention, the term "nucleic acid" preferably refers to DNA or RNA. In relation to the nucleic acid, the terms "polynucleotide," "nucleotide," "nucleotide sequence," and "oligonucleotide" are used interchangeably. Polynucleotides of any length may comprise polymeric forms of nucleotides, deoxyribonucleotides or ribonucleotides, or analogs thereof. Polynucleotides may have any three-dimensional structure and may perform any function, known or unknown. Polynucleotides may comprise one or more modified nucleotides, such as methylated nucleotides and nucleotide analogs. Modifications to the nucleotide structure may occur before or after polymer assembly. The nucleic acid encoding the Slit2 protein of the present invention may be a nucleic acid encoding the SLIT2 gene, and preferably, may be a nucleic acid including a base sequence encoding the amino acid sequence of SEQ ID NO: 1. The nucleic acid may be a polymer comprising or consisting of nucleotide monomers covalently linked to each other by phosphodiester bonds of a sugar / phosphate backbone. The “nucleic acid” may be DNA or RNA, preferably mRNA, and includes modified nucleic acids, such as base-modified, sugar-modified, or backbone-modified DNA or RNA molecules. The nucleic acid may be injected in the form of ribonucleic acid, for example, messenger ribonucleic acid (mRNA). The nucleic acid according to the present invention may be in the form of mRNA, through which transient protein expression can be achieved. The composition may further comprise a delivery means for delivering the nucleic acid. The delivery means may include a viral or non-viral delivery means. The nucleic acid may be delivered into a living body via a vector to achieve the desired therapeutic effect. The vector may be used to produce an expression product, such as mRNA, or a peptide, polypeptide, or protein. The vector may include a sequence necessary for transcription of a sequence stretch of the vector, such as a promoter sequence, for example, an RNA promoter sequence. The vector may be, for example, an RNA vector or a DNA vector. The vector may be a viral vector or a plasmid vector. The vector may be a circular molecule, and may comprise a double-stranded molecule. Circular, double-stranded DNA molecules can be readily used as storage forms for novel artificial nucleic acid molecules. They can be used for transformation of cells, such as cultured cells. They can be used for in vitro transcription to obtain artificial RNA molecules. The circular vector can be linearized, for example, by restriction enzyme digestion. Adeno-associated virus (AVV), adenovirus, retrovirus, vaccinia virus, lentivirus, and poxvirus can be used as the viral delivery vehicle. The nucleic acid may be delivered via nanoparticles, for example via gold nanoparticles. The above gold nanoparticles can have their surfaces modified. Specific examples of modifications are described in Acc Chem Res. June 18, 2019; 52(6): 1496-1506 and Pharmaceutics 2021, 13, 900, which may be incorporated herein by reference. The mRNA can be delivered to cells by linking gold nanoparticles to the mRNA and forming a complex with a cationic endosomal disruptive polymer (Nature Biomedical Engineering volume 1, pages 889-901 (2017)). The cationic endosomal disruptive polymer can be, for example, polyethylene imine, poly(arginine), poly(lysine), poly(histidine), poly-[2-{(2-aminoethyl)amino}-ethyl-aspartamide] (pAsp(DET)), a block copolymer of poly(ethylene glycol) (PEG) and poly(arginine), a block copolymer of PEG and poly(lysine), or a block copolymer of PEG and poly{N-[N-(2-aminoethyl)-2-aminoethyl]aspartamide} (PEG-pAsp(DET)). In some cases, the surface may use gold particles modified with arginine. Gold particles modified with arginine can be assembled with a nuclease or a polynucleotide encoding the same and / or a cleavage factor or a polynucleotide encoding the same, thereby fusing with the membrane of the target cell and translocating into the cytoplasm (ACS Nano. 2017, 11:2452-2458). The expressed mRNA can be delivered via liposomes, LNPs (lipid nano-particles), or various nanoparticles. Liposomes or LNPs contain cationic lipids, non-cationic lipids, or neutral lipids, and may additionally contain other lipids such as PEG (polyethylene glycol) or cholesterol. Such mRNA delivery systems are specifically described in U.S. Patent Publication Nos. 2018 / 0311176, 2019 / 0032051, and 2021 / 0046192, and International Patent Publication Nos. WO2018 / 081480, WO2020 / 097540, WO2020 / 097548, and WO2021 / 007278, which are incorporated herein by reference. 상기 양이온성 지질은 미국특허공개 제2018 / 0311176호, 제2019 / 0032051호 등을 통해 구체적으로 예시되어 있으며, 예를 들어 N,N-dioleyl-N,N-dimethylammonium chloride (DODAC), N,N-distearyl-N,N-dimethylammonium bromide (DDAB), N-(I-(2,3-dioleyloxy)propyl)-N,N,N-trimethylammonium chloride (DOTAP), N-(I-(2,3-dioleyloxy)propyl)-N,N,N-trimethylammonium chloride (DOTMA), N,N-dimethyl-2,3-dioleyloxy)propylamine (DODMA), 1,2-DiLinoleyloxy-N,N-dimethylaminopropane (DLinDMA), 1,2-Dilinolenyloxy-N,N-dimethylaminopropane (DLenDMA), 1,2-Dilinoleylcarbamoyloxy-3-dimethylaminopropane (DLin-C-DAP), 1,2-Dilinoleyoxy-3-(dimethylamino)acetoxypropane (DLin-DAC), 1,2-Dilinoleyoxy-3-morpholinopropane (DLin-MA), 1,2-Dilinoleoyl-3-dimethylaminopropane (DLinDAP), 1,2-Dilinoleylthio-3-dimethylaminopropane (DLin-S-DMA), 1-Linoleoyl-2-linoleyloxy-3-dimethylaminopropane (DLin-2-DMAP), 1,2-Dilinoleyloxy-3-trimethylaminopropane chloride salt (DLin-TMA.Cl), 1,2-Dilinoleoyl-3-trimethylaminopropane chloride salt (DLin-TAP.Cl), 1,2-Dilinoleyloxy-3-(N-methylpiperazino)propane (DLin-MPZ), or 3-(N,N-Dilinoleylamino)-1,2-propanediol (DLinAP), 3-(N,N-Dioleylamino)-1,2-propanedio (DOAP), 1,2-Dilinoleyloxo-3-(2-N,N-dimethylamino)ethoxypropane (DLin-EG-DMA), 1,2-Dilinolenyloxy-N,N-dimethylaminopropane (DLinDMA), 2,2-Dilinoleyl-4-dimethylaminomethyl-[1,3]-dioxolane (DLin-K-DMA) or analogs thereof, (3aR,5s,6aS)-N,N-dimethyl-2,2-di((9Z,12Z)-octadeca-9, 12-dienyl)tetrahydro-3aH-cyclopenta[d][1,3]dioxol-5-amine (ALN100), (6Z,9Z,28Z,31Z)-heptatriaconta-6,9,28,31-tetraen-19-yl 4-(dimethylamino)butanoate (MC3), 1, 1′-(2-(4-(2-((2-(bis(2-hydroxydodecyl)amino)ethyl)(2-hydroxydodecyl)amino)ethyl)piperazin-1-yl)ethylazanediyl)didodecan-2-ol (Tech G1), 2,2-Dilinoleyl-4-dimethylaminoethyl-[1,3]-dioxolane, β-L-arginyl-2, 3-L-diaminopropionic acid-N-palmityl-N-oleylamide trihydrochloride, N′,N′-dioctadecyl-N-4, 8-diaza-10-aminodecanoylglycine amide.

[0071] , 1,2-dilinoleyloxy-3-dimethylaminopropane, DLin-KC2-DMA, amino lipid 2,2-dilinoleyl-4-dimethylaminoethyl-[1,3]-dioxolane (DLin-KC2-DMA, 1), 1,2-distearloxy- / V,N-dimethylaminopropane (DSDMA), dilinoleylmethyl-4-dimethylaminobutyrate (DLin-MC3-DMA), DLin-D-DMA, C12-200, 98N12-5, (20Z,23Z)-N,N-dimethylnonacosa-20,23-dien-10-amine, (17Z,20Z)-N,N-dimemylhexacosa-17,20-dien-9-amine, (1Z,19Z)-N5N-dimethylpentacosa-16,19-dien-8-amine, (13Z,16Z)-N,N-dimethyldocosa-13,16-dien-5-amine, (12Z,15Z)-N,N-dimethylhenicosa-12,15-dien-4-amine, (14Z,17Z)-N,N-dimethyltricosa-14,17-dien-6-amine, (15Z,18Z)-N,N-dimethyltetracosa-15,18-dien-7-amine, (18Z,21Z)-N,N-dimethylheptacosa-18,21-dien-10-amine, (15Z,18Z)-N,N-dimethyltetracosa-15,18-dien-5-amine, (14Z,17Z)-N,N-dimethyltricosa-14,17-dien-4-amine, (19Z,22Z)-N,N-dimethyloctacosa-19,22-dien-9-amine, (18Z,21Z)-N,N-dimethylheptacosa-18,21-dien-8-amine, (17Z,20Z)-N,N-dimethylhexacosa-17,20-dien-7-amine, (16Z,19Z)-N,N-dimethylpentacosa-16,19-dien-6-amine, (22Z,25Z)-N,N-dimethylhentriaconta-22,25-dien-10-amine, (21Z,24Z)-N,N-dimethyltriaconta-21,24-dien-9-amine, (18Z)-N,N-dimethylheptacos-18-en-10-amine, (17Z)-N,N-dimethylhexacos-17-en-9-amine, (19Z,22Z)-N,N-dimethyloctacosa-19,22-dien-7-amine, N,N-dimethylheptacosan-10-amine, (20Z,23Z)-N-ethyl-N-methylnonacosa-20,23-dien-10-amine, 1-[(11Z,14Z)-1-nonylicosa-11,14-dien-1-yl]pyrrolidine, (20Z)-N,N-dimethylheptacos-20-en-10-amine, (15Z)-N,N-dimethyleptacos-15-en-10-amine, (14Z)-N,N-dimethylnonacos-14-en-10-amine, (17Z)-N,N-dimethylnonacos-17-en-10-amine, (24Z)-N,N-dimethyltritriacont-24-en-10-amine, (20Z)-N,N-dimethylnonacos-20-en-10-amine, (22Z)-N,N-dimethylhentriacont-22-en-10-amine, (16Z)-N,N-dimethylpentacos-16-en-8-amine, (12Z,15Z)-N,N-dimethyl-2-nonylhenicosa-12,15-dien-1-amine, (13Z,16Z)-N,N-dimethyl-3-nonyldocosa-13,16-dien-1-amine, N,N-dimethyl-1-[(1S,2R)-2-octylcyclopropyl]eptadecan-8-amine, 1-[(1S,2R)-2-hexylcyclopropyl]-N,N-dimethylnonadecan-10-amine, N,N-dimethyl-1-[(1S,2R)-2-octylcyclopropyl]nonadecan-10-amine, N,N-dimethyl-21-[(1S,2R)-2-octylcyclopropyl]henicosan-10-amine,N,N-dimeth-yl-1-[(1S,2S)-2-{[(1R,2R)-2-pentylcyclopropyl]methyl}cyclopropyl]nonadecan-10-amine,N,N-dimethyl-1-[(1S,2R)-2-octylcyclopropyl]hexadecan-8-amine, N,N-dimethyl-[(1R,2S)-2-undecylcyclopropyl]tetradecan-5-amine, N,N-dimethyl-3-{7-[(1 S,2R)-2-octylcyclopropyl]heptyl}dodecan-1-amine, 1-[(1R,2S)-2-heptylcyclopropyl]-N,N-dimethyloctadecan-9-amine, 1-[(1S,2R)-2-decylcyclopropyl]-N,N-dimethylpentadecan-6-amine, N,N-dimethyl-1-[(1S,2R)-2-octylcyclopropyl]pentadecan-8-amine, R-N,N-dimethyl-1-[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]-3-(octyloxy)propa-n-2-amine, S-N,N-dimethyl-1-[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]-3-(octy-loxy)propan-2-amine, 1-{2-[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]-1-Roctyloxy)methyl]ethyl}pyrro-lidine, (2S)-N,N-dimethyl-1-[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]-3-[(5Z)-oct-5-en-1-yloxy]propan-2-amine, 1-{2-[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]-1-[(octyloxy)methyl]ethyl}azet-idine, (2S)-1-(hexyloxy)-N,N-dimethyl-3-[(9Z,12Z)-octadeca-9,12-dien-ylo-xy]propan-2-amine, (2S)-1-(heptyloxy)-N,N-dimethyl-3-[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]pr-opan-2-amine, N,N-dimethyl-1-(nonyloxy)-3-[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]propan-2-amine, N,N-dimethyl-1-[(9Z)-octadec-9-en-1-yloxy]-3-(octyloxy)propan-2-am-ine; (2S)-N,N-dimethyl-1-[(6Z,9Z,12Z)-octadeca-6,9,12-trien-1-yloxy]-3-(o-ctyloxy)propan-2-amine, (2 S)-1-[(11Z,14Z)-icosa-11,14-dien-1-yloxy]-N,N-dimethyl-3-(pentyloxy)propa-n-2-amine, (2S)-1-(hexyloxy)-3-[(11Z,14Z)-icosa-11,14-dien-1-yloxy]-N,N-di-methylpropan-2-amine, 1-[(11Z,14Z)-icosa-11,14-dien-1-yloxy]-N,N-dimethyl-3-(octyloxy)propan-2-amine, 1-[(13Z,16Z)-docosa-13,16-dien-1-yloxy]-N,N-dimethyl-3-(octyloxy)pr-opan-2-amine, (2S)-1-[(13Z,16Z)-docosa-13,16-dien-1-yloxy]-3-(hexyloxy)-N,N-dimethylpro-pan-2-amine, (2S)-1-[(13Z)-docos-13-en-1-yloxy]-3-(hexyloxy)-N,N-dimethylpropan-2-amin-e,1-[(13Z)-docos-13-en-1-yloxy]-N,N-dimethyl-3-(octyloxy)propan-2-amine, 1-[(9Z)-hexadec-9-en-1-yloxy]-N,N-dimethyl-3-(octyloxy)propan-2-amine, (2R)-N,N-dimethyl-H(1-metoyloctyl)oxy]-3-[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]propan-2-amine, (2R)-1-[(3,7-dimethyloctyl)oxy]-N,N-dimethyl-3-[(9Z,12Z)-octadeca-9,12-di-en-1-yloxy]propan-2-amine, N,N-dimethyl-1-(octyloxy)-3-({8-[(1S,2S)-2-{[(1R,2R)-2-pentylcyclopropyl]-methyl}cyclopropyl]octyl}oxy)propan-2-amine, N,N-dimethyl-1-{[8-(2-oclylcyclopropyl)octyl]oxy}-3-(octyloxy)propan-2-am-ine and (11E,20Z,23Z)-N,N-dimethylnonacosa-11,20,2-trien-10-amine, 5-carboxyspermylglycine dioctaoleoylamide (“DOGS”), dipalmitoylphosphatidylethanolamine 5-carboxyspermyl-amide (“DPPES”), 1,2-dimyristyloxypropyl-3-dimethyl-hydroxy ethyl ammonium bromide (DMRIE), DMRIE-HP, Lipofectamine (DOSPA), 3b-(N-(N′,N′-dimethylaminoethane)-carbamoyl)cholesterol (“DC-Choi”), N-(1,2-dimyhstyloxyprop-3-yl)-N,N-dimethyl-N-hydroxyethyl ammonium bromide (“DMRIE”), 1,2-Dioleoyl-3-dimethylammonium-propane (“DODAP”), DMDMA, cationic lipid-based transfection reagents TransIT-TKO, LIPOFECTIN, Lipofectamine, OLIGOFECTAMINE or DHARMAFECT, DSDMA, DODMA, DLinDMA, DLenDMA, gamma-DLenDMA, DLin-K-DMA, DLin-K-C2-DMA (also known as DLin-C2K-DMA, XTC2, and C2K), DLin-K-C3-DM A, DLin-K-C4-DMA, DLen-C2K-DMA, y-DLen-C2K-DMA, DLin-M-C2-DMA (also known as MC2), DLin-M-C3-DMA (also known as MC3) or (DLin-MP-DMA)(also known as 1-B11), or mixtures thereof, but are not limited thereto. no., The above non-cationic lipid is specifically exemplified in U.S. Patent Publication Nos. 2018 / 0311176 and 2019 / 0032051, and may be, for example, phosphatidylglycerol, cardiolipin, diacylphosphatidylserine, diacylphosphatidic acid, N-dodecanoyl phosphatidylethanolamine, N-succinyl phosphatidylethanolamine, N-glutaryl phosphatidylethanolamine, or lysylphosphatidylglycerol.경우에 따라서, 상기 비양이온성 지질은 예를 들어, distearoylphosphatidylcholine (DSPC), dioleoylphosphatidylcholine (DOPC), dipalmitoylphosphatidylcholine (DPPC), dioleoylphosphatidylglycerol (DOPG), dipalmitoylphosphatidylglycerol (DPPG), dioleoyl-phosphatidylethanolamine (DOPE), palmitoyloleoylphosphatidylcholine (POPC), palmitoyloleoylphosphatidylethanolamine (POPE), dioleoyl-phosphatidylethanolamine 4-(-maleimidomethyl)-cyclohexane-1-carboxylate (DOPE-mal), dipalmitoyl phosphatidyl ethanolamine (DPPE), dimyristoylphosphoethanolamine (DMPE), distearoyl-phosphatidyl-ethanolamine (DSPE), 16-O-monomethyl PE, 16-O-dimethyl PE, 18-1-trans PE, 1-stearoyl-2-oleoyl-phosphatidyethanolamine (SOPE), cholesterol, phosphatidylglycerols, cardiolipins, diacylphosphatidylserines, diacylphosphatidic acids, N-dodecanoyl phosphatidylethanolamines, N-succinyl phosphatidylethanolamines, N-glutarylphosphatidylethanolamines, lysylphosphatidylglycerols, palmitoyloleyolphosphatidylglycerol (POPG)일 수 있으나, 이에 제한되는 것은 아니다. The above neutral fat is specifically exemplified in U.S. Patent Publication Nos. 2018 / 0311176 and 2019 / 0032051, and may include, but is not limited to, diacylphosphatidylcholine, diacylphosphatidylethanolamine, ceramide, sphingomyelin, dihydrosphingomyelin, cephalin, or cerebrosides. Peptides can be used for the above mRNA delivery. The peptide must have a cationic charge to electrostatically interact with the anionic phosphate group of the nucleic acid, and may include positively charged amino acids to electrostatically interact with the phosphate group. Specific details of peptides usable for mRNA delivery are described in AIMS Biophysics, 7(4): 323-338, which is incorporated herein by reference. Protamine may be included as a peptide usable for the above mRNA delivery. Protamine is a small, cationic, arginine-rich nuclear protein that contributes to the stability of DNA during spermatogenesis in the testis. Protamine stabilizes mRNA molecules, enabling efficient delivery. A protamine-mRNA complex is specifically described in U.S. Patent No. 9,352,028, which is incorporated herein by reference. Cell-penetrating peptides (CPPs) may also be promising cationic molecules for mRNA delivery. Amphipathic CPPs, such as the arginine-rich RALA peptide (WEARLARALARALARHLARALARALRACEA), RALA, LAH4 (KKALLALALHHLAHLALHLALALKKA), and LAH4-L1 (KKALLAHALHLLALLALHLAHALKKA), can be used to deliver mRNA molecules. The nucleic acid can be delivered into a target cell without the aid of a carrier. The nucleic acid can be delivered directly into the cell without the aid of a carrier using electroporation, sonoporation, or a gene gun. In the present invention, the term "drug-induced hepatotoxicity disease" refers to a disease caused by damage to liver function due to long-term or short-term use of herbal medicines, Western medicines, health functional foods, etc., inhalation of chemical substances, injections, etc. The term "drug-induced hepatotoxicity disease" may be used interchangeably with "toxic liver disease" or "toxic hepatitis" in the same meaning. The above drug-induced hepatotoxicity disease-causing substances can theoretically refer to any substance that can be absorbed by the body and digested / detoxified by the liver. These substances include acetaminophen, erythromycin, antituberculosis drugs, oral contraceptives, various weight-loss health foods, and herbal medicines. In the present invention, the drug hepatotoxicity may be characterized as being caused by acetaminophen. Preferably, the drug-induced liver disease may be characterized as being caused by acetaminophen, and the daily dose of acetaminophen capable of causing the drug-induced liver disease may be characterized as being 1000 mg or more per day, preferably 2000 mg or more or 3000 mg or more, more preferably 4000 mg or more or 5000 mg or more. The composition of the present invention may further include a pharmaceutically acceptable additive, and at this time, the pharmaceutically acceptable additive may include starch, gelatinized starch, microcrystalline cellulose, lactose, povidone, colloidal silicon dioxide, calcium hydrogen phosphate, lactose, mannitol, maltose, gum arabic, pregelatinized starch, corn starch, powdered cellulose, hydroxypropyl cellulose, Opadry, sodium starch glycolate, carnauba wax, synthetic aluminum silicate, stearic acid, magnesium stearate, aluminum stearate, calcium stearate, white sugar, etc. The composition of the present invention can be administered in various dosage forms, such as parenteral or oral, during actual clinical administration. When formulating, it can be prepared using diluents or excipients such as commonly used fillers, bulking agents, binders, wetting agents, disintegrants, and surfactants. It is preferable to use suitable formulations known in the art as disclosed in the literature (Remington's Pharmaceutical Science, recently, Mack Publishing Company, Easton PA). Carriers, excipients and diluents that may be included in the composition include lactose, dextrose, sucrose, oligosaccharides, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxy benzoate, propylhydroxy benzoate, talc, magnesium stearate, mineral oil and the like. The above preparations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized preparations, and suppositories. Non-aqueous solvents and suspensions may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. Suppository bases may include witepsol, macrogol, tween 61, cacao butter, laurin butter, and glycerogelatin. The parenteral administration may be administered externally or by intraperitoneal injection, rectal injection, subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection. The above solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid preparations are prepared by mixing at least one excipient, such as starch, calcium carbonate, sucrose or lactose, gelatin, etc. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. In addition, the above liquid preparations for oral administration include suspensions, oral solutions, emulsions, syrups, etc., and in addition to commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, fragrances, preservatives, etc. may be included. The dosage of the pharmaceutical composition of the present invention varies depending on the patient's body weight, age, sex, health condition, diet, administration time, administration method, excretion rate, and disease severity. It may be administered once a day or divided into several times. The administration of the pharmaceutical composition of the present invention may be characterized by being administered before, simultaneously with, or after the administration of a hepatotoxic substance, preferably acetaminophen. In one embodiment of the present invention, it was confirmed that hepatotoxicity was suppressed when the Slit2 protein was administered at doses of 50 μg / kg and 100 μg / kg, and it was shown that the expression of liver damage markers AST and ALT was further reduced when 100 μg / kg was administered than when 50 μg / kg was administered. Therefore, in the present invention, the administration dose of the pharmaceutical composition may be characterized as being 10 to 200 μg / kg, 20 to 160 μg / kg or 30 to 140 μg / kg, more preferably 40 to 120 μg / kg, and most preferably 50 to 100 μg / kg for the Slit2 protein. The pharmaceutical composition of the present invention can be used alone or in combination with methods using surgery, radiation therapy, hormone therapy, chemotherapy, and biological response modifiers for the prevention and treatment of drug hepatotoxicity. In one embodiment of the present invention, when administering the Slit2 protein, changes in various indicators related to liver damage, such as AST and ALT, which are representative liver damage indicators, as well as inflammatory factors and immune cell activity, were confirmed. In the present invention, when administering Slit2 protein, it may be characterized by suppression of intralobular necrosis due to damage to hepatocytes, bleeding accompanied by congestion of the sinusoidal space, and central vein damage, but is not limited thereto. In the present invention, when administering Slit2 protein under the premise of administration of acetaminophen, it may be characterized by exhibiting one or more of the following characteristics compared to when Slit2 protein is not administered: i) Decreased expression of liver damage markers; ii) Reduced expression of inflammatory factors; iii) Decreased activity of immune cells; vi) reduction in cytotoxicity indicators (CYP2E1); and v) Reduction of reactive oxygen species (ROS) The above liver damage marker may be AST and / or ALT. The 'AST' and 'ALT' refer to aspartate aminotransferase and alanine aminotransferase, respectively, and are liver damage markers whose expression increases with liver damage. Assuming the administration of acetaminophen, the expression of the liver damage marker may be characterized by a decrease of 50% or less, preferably 40% or less, when the Slit2 protein is administered compared to when no administration is performed. The above inflammatory factor may be selected from the group consisting of IL1β, MyD88, IL6, TNFα and TLR4. The above "IL1β" refers to interleukin 1b, a key cytokine that regulates inflammation and immune responses to infection. Among the IL-1 family, IL-1b in particular is known to be involved in chronic inflammatory diseases and autoimmune symptoms. The above 'MyD88' refers to myeloid differentiation primary response gene 88, and is known to bind to all Toll-like receptors (TLRs) except TLR3 and induce the activity of NF-kB. The above 'IL6' refers to Interleukin 6, an interleukin that acts as both a pro-inflammatory cytokine and an anti-inflammatory myokine. It is present on the cell surface and intracellular compartments and induces intracellular signaling cascades that cause the production of inflammatory cytokines. The above 'TNFα' refers to tumor necrosis factor α, which is a cytokine produced by macrophages and other cells. It is produced by activated macrophages, natural killer cells (NK cells), some T cells, or some tumor cells. The above 'TLR4' refers to toll-like receptor 4. It is a protein similar to the toll protein of Drosophila, and the TLR4 has a receptor function for bacterial body components (lipopolysaccharides, peptidylglycans, lipoproteins, acid-fast glycolipids, etc.) and heat shock proteins, and activates cells to produce inflammatory cytokines and mediators (TNF, IL-1, IL-6, IL-8, NO, etc.). Assuming administration of acetaminophen, the expression of the inflammatory marker may be characterized by a decrease of 90% or less, preferably 80% or less, more preferably 70% or less, 60% or less, 50% or less, and most preferably 40% or less or 30% or less when the Slit2 protein is administered compared to when it is not administered. The activity of the above immune cells can be observed histologically by confirming the expression of CD11b, an immune cell marker, through immunoprecipitation. In one embodiment, it was confirmed that when the Slit2 protein of the present invention was administered, the activity of the immune cells was reduced and a small number of immune cells were observed. From another perspective, the present invention relates to a health functional food for preventing or improving drug hepatotoxicity disease, comprising Slit2 protein as an active ingredient. In the present invention, the Slit2 protein may be characterized as being a recombinant human SLIT2 protein. In the present invention, the SLIT2 protein may be characterized by having an amino acid sequence of sequence number 1. In the present invention, "health functional food" refers to a food having a bioregulatory function such as disease prevention and improvement, biodefense, immunity, recovery after illness, and anti-aging, and must be harmless to the human body when consumed over a long period of time. When the Slit2 protein of the present invention is used as a food additive, the Slit2 protein can be added as is or used together with other foods or food ingredients, and can be used appropriately according to a conventional method. The amount of the active ingredient can be appropriately determined depending on the purpose of use (prevention, health, or therapeutic treatment). Generally, when manufacturing a food or beverage, the Slit2 protein of the present invention can be added in an amount of 15% by weight or less, preferably 10% by weight or less, based on the raw material. However, in the case of long-term intake for the purpose of health and hygiene or health control, the amount can be below the above range, and the active ingredient can be used in an amount above the above range as long as there is no problem in terms of safety. The health beverage composition of the present invention can contain various flavorings or natural carbohydrates as additional ingredients, like a conventional beverage. The natural carbohydrates described above may include monosaccharides such as glucose and fructose, disaccharides such as maltose and sucrose, and natural sweeteners such as dextrin and cyclodextrin, or synthetic sweeteners such as saccharin and aspartame. The proportion of the natural carbohydrate may generally be about 0.01 to 10 g, preferably about 0.01 to 0.1 g, per 100 ml of the composition of the present invention, but is not limited thereto. In addition to the above, the composition of the present invention may include various nutrients, vitamins, electrolytes, flavoring agents, coloring agents, pectic acid and its salts, alginic acid and its salts, organic acids, protective colloid thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol, carbonating agents used in carbonated beverages, etc. In addition, the composition of the present invention may include fruit pulp for the production of natural fruit juice, fruit juice drinks, and vegetable drinks. These components may be used independently or in combination. The proportion of these additives is not particularly critical, but is typically selected in the range of 0.01 to 0.1 parts by weight per 100 parts by weight of the composition of the present invention. Hereinafter, the present invention will be described in detail with examples and the like to aid understanding. However, the examples according to the present invention may be modified in various different forms, and the scope of the present invention should not be construed as being limited to the following examples. Example Example 1: Confirmation of the drug hepatotoxicity inhibitory effect of Slit2 protein in an animal model. Example 1-1: Experimental administration of acetaminophen and / or Slit2 protein to animal models Mice (C57BL / 6 male) were used as models for animal experiments. Slit2 protein was administered intraperitoneally to the animal model on days 0, 1, 2, and 3. The experimental groups were administered 50 μg / kg and 100 μg / kg of Slit2 protein, while the control group was administered 1× PBS (Fig. 1). On day 3, 400 mg / kg of acetaminophen was administered orally as a hepatotoxic agent. On day 4, the model mice were sacrificed, and liver tissues were obtained, and histological, hematological, and genetic data were obtained according to the following examples. The Slit2 protein used in the animal model was mouse Slit2 (R&D system, 5444-SL-050), and acetaminophen was purchased from Sigma (A5000). The amino acid sequence of the mouse Slit2 protein used in the experiment is as follows. msgigwqtls lslglvlsil nkvapqacpa qcscsgstvd chglalrsvp rniprnterl dlngnnitri tkidfaglrh lrvlqlmenr istiergafq dlkelerlrl nrnnlqlfpe llflgtakly rldlsenqiq aiprkafrga vdiknlqldy nqisciedga fralrdlevl tlnnnnitrl svasfnhmpk lrtfrlhsnn lycdchlawl sdwlrqrprv glytqcmgps hlrghnvaev qkrefvcsgh qsfmapscsv lhcpaactcs nnivdcrgkg lteiptnlpe titeirleqn sirvippgaf spykklrrld lsnnqisela pdafqglrsl nslvlygnki telpkslfeg lfslqlllln ankinclrvd afqdlhnlnl lslydnklqt vakgtfsalr aiqtmhlaqn pficdchlkw ladylhtnpi etsgarctsp rrlankrigq ikskkfrcsg tedyrsklsg dcfadlacpe kcrcegttvd csnqrlnkip dhipqytael rlnnneftvl eatgifkklp qlrkinfsnn kitdieegaf egasgvneil ltsnrlenvq hkmfkglesl ktlmlrsnri scvgndsfig lgsvrllsly dnqittvapg afdslhslst lnllanpfnc nchlawlgew lrrkrivtgn prcqkpyflk eipiqdvaiq dftcddgndd nscsplsrcp sectcldtvv rcsnkglkvl pkgipkdvte lyldgnqftl vpkelsnykh ltlidlsnnr istlsnqsfs nmtqlltlil synrlrcipp rtfdglkslr llslhgndis vvpegafndl salshlaiga nplycdcnmq wlsdwvksey kepgiarcag pgemadklll ttpskkftcq gpvditiqakcnpclsnpck ndgtcnndpv dfyrctcpyg fkgqdcdvpi hacisnpckh ggtchlkege nagfwctcad gfegencevn iddcedndce nnstcvdgin nytclcppey tgelceekld fcaqdlnpcq hdskciltpk gfkcdctpgy igehcdidfd dcqdnkckng ahctdavngy tcvcpegysg lfcefsppmv lprtspcdnf dcqngaqcii rinepicqcl pgylgekcek lvsvnfvnke sylqipsakv rpqtnitlqi atdedsgill ykgdkdhiav elyrgrvras ydtgshpasa iysvetindg nfhivelltl dsslslsvdg gspkvitnls kqstlnfdsp lyvggmpgkn nvaslrqapg qngtsfhgci rnlyinselq dfrkmpmqtg ilpgcepchk kvcahgmcqp ssqsgftcec eegwmgplcd qrtndpclgn kcvhgtclpi nafsysckcl eghggvlcde eedlfnpcqm ikckhgkcrl sgvgqpycec nsgftgdscd reiscrgeri rdyyqkqqgy aacqttkkvs rlecrggcag gqccgplrsk rrkysfectd gssfvdevek vvkcgcarca s (SEQ ID NO: 2) Example 1-2: Histological analysis of the effect of inhibiting liver damage The liver tissue obtained in Example 1-1 was fixed by treating with a fixative (1% formalin) for 24 hours. After making a paraffin block using the fixed liver tissue, the nucleus and cytoplasm were stained and observed under a microscope to determine the degree of hepatocyte damage. As a result, when acetaminophen was treated alone without the Slit2 protein pretreatment process, severe hemorrhage accompanied by extensive intralobular necrosis and congestion of the sinusoidal space was confirmed. When the Slit2 protein pretreatment process was preceded, the condition of the liver tissue appeared similar to the control group, and it was confirmed that there was no liver damage (Fig. 2). In addition, the aging model of the above mouse (age: 20 months) was established and the presence of liver damage was confirmed by treating with 300 mg / kg of acetaminophen. As a result, similarly, when acetaminophen was treated alone without Slit2 protein pretreatment, severe hemorrhage accompanied by extensive intralobular necrosis and sinusoidal space congestion was confirmed, and when 100 μg / kg of Slit2 protein pretreatment was preceded, the condition of the liver tissue appeared similar to the control group, and it was confirmed that there was no liver damage (Fig. 3). Example 1-3: Blood analysis for expression of liver damage markers (AST / ALT) Blood was collected from the animal model according to Example 1-1, centrifuged at 11,000 rpm for 5 minutes to obtain a supernatant. The supernatant was analyzed for the activities of aminotransferases aspartate aminotransferase (AST) and alanine aminotransferase (ALT) using an AST kit (GOT-AM103-K; Asan Pharmaceutical) and an ALT kit (GTP-AM102-K; Asan Pharmaceutical). As a result, compared to the untreated control group, when acetaminophen was administered, high AST and ALT activities of approximately 2000 IU / L and approximately 5000 IU / L were observed. This indicates that acetaminophen administration causes liver damage. In contrast, when Slit2 was administered at 50 and 100 μg / kg, despite the administration of acetaminophen, the activities of AST and ALT were significantly reduced by approximately 50% to 1000 IU / L to 800 IU / L and 2200 IU / L to 1800 IU / L, respectively (Fig. 4). In addition, the aging model of the above mouse (age: 20 months) was established, treated with acetaminophen, and the activities of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were analyzed. As a result, compared to the untreated control group, when 300 mg / kg of acetaminophen was administered, high AST and ALT activities of approximately 500 IU / L and approximately 1000 IU / L were observed. This indicates that acetaminophen administration causes liver damage. In contrast, when 100 μg / kg of Slit2 was administered, the activities of AST and ALT were significantly reduced by approximately 50% to 300 IU / L and 550 IU / L, respectively, despite the administration of acetaminophen (Fig. 5). Example 1-4: Genetic analysis for cytotoxicity markers (CYP2E1) CYP2E1 is an enzyme belonging to the cytochrome P450 family, specifically the E subfamily, polypeptide 1. CYP2E1 is involved in the oxidative metabolism of several endogenous and exogenous compounds, including ethanol, acetaminophen (paracetamol), various solvents, and anesthetics, and is an enzyme that converts carcinogens and toxins into reactive metabolites that can potentially cause cell damage. CYP2E1 is an enzyme involved in the metabolism of various substances in the body, especially in the liver, and is a protein that increases when hepatocytes are damaged. GAPDH is a representative housekeeping gene. Liver tissue obtained according to Example 1-1 was lysed to extract proteins, and the amounts of CYP2E1 and GAPDH proteins were confirmed through Western blotting. CYP2E1 antibodies (ab28146) and GAPDH antibodies (ab8245) were used for the Western blotting. As a result, when only acetaminophen was treated, the CYP2E1 protein line appeared dark in the electrophoresis gel, indicating a large amount, and when both acetaminophen and Slit2 protein were treated, the expression of CYP2E1 protein was found to be low, similar to the case where hepatotoxicity was not induced (Fig. 6). The results of Examples 1-2 to 1-4 indicate that Slit 2 protein inhibits liver damage caused by acetaminophen. Example 2: Confirmation of the drug hepatotoxicity inhibitory effect of SLIT2 protein in a cell model. Example 2-1: Experimental administration of acetaminophen and / or SLIT2 protein to cell models Human hepatocyte (HH) cells and Chang liver cells were used as cell models to examine the effects of Slit2 protein. To induce hepatotoxicity, HH cells were treated with 250 μM acetaminophen, and Chang liver cells with 500 μM acetaminophen. The experimental group was treated with Slit2 protein (human SLIT2 (pepro tech, 150-11) at a concentration of 100 ng / ml. Example 2-2: Confirmation of the effect of SLIT2 protein in a liver injury cell model Human hepatocyte cell lines and liver cells were thawed and passaged three times to stabilize the cells. 1 × 10 of the cells were seeded in 6-wells. 4 After 24 hours of inoculation with the number of cells, DMSO was administered as a control group, acetaminophen (250 μM for human hepatocyte cell line, 500 μM for Chang Liver cells) and / or 100 ng / ml of SLIT2 protein was administered as an experimental group. The morphology of the cells was observed and the cells were harvested 24 hours after the treatment. As a result, when hepatotoxicity was induced by treating with acetaminophen, it was observed that the cells spread and grew (arrows in Figure 7), but when SLIT2 protein was treated together with acetaminophen, it was confirmed that the shape of the cells did not change (Figure 7). Example 2-3: Confirmation of the effect of Slit2 protein on inhibiting the expression of inflammatory factors. Hepatocytes obtained according to the methods of Examples 2-1 and 2-2 were disrupted, RNA was extracted, and cDNA was synthesized. Real-time PCR (real-time PCR) was then performed on the IL1β, MyD88, IL6, TNFα, and TLR4 genes to determine their expression levels. The β-actin gene was used as a reference gene. The primer sequences used to confirm the level of expression of inflammatory factors are as shown in Table 1 below. As a result, when treated with acetaminophen, the expression of inflammatory factors IL1β1, MyD88, TNF-α, IL6, and TLR4 increased in human hepatocyte cell lines and Chang Liver cells, and when treated with SLIT2 protein together, no increase in the expression of the inflammatory factors due to acetaminophen treatment was observed in human hepatocyte cell lines and Chang Liver cells (Figs. 8, 9). Example 2-4: Confirmation of the anti-oxidant effect of SLIT2 protein in a liver injury cell model. We confirmed that acetaminophen treatment induces the generation of reactive oxygen species in liver cells (HepG2), and that simultaneous administration of SLIT2 inhibits the generation of reactive oxygen species induced by acetaminophen. Specifically, 5 mM acetaminophen and / or 100 ng / mL SLIT2 were administered to liver cells (HepG2), and the reactive oxygen species (ROS) generated in each experimental group were confirmed using DCF-DA. As a result, it was confirmed that when acetaminophen was administered, the production of reactive oxygen species increased by approximately 10% compared to the control group, and when SLIT2 was administered together, the production of reactive oxygen species was similar to the control group (Fig. 10). Example 3: Confirmation of the anti-inflammatory effect of Slit2 protein in an animal model. Example 3-1: Histological analysis using immune cell markers A portion of the liver tissue obtained according to Example 1-1 was fixed in a fixative (1% formalin) for 24 hours, and then paraffin blocks were prepared. The expression of CD11b (an immune cell marker) was observed using an immunoprecipitation method using CD11b antibody (ab13357) on the paraffin blocks to confirm the activity of immune cells. When treated with acetaminophen, the number of immune cells increased, but when treated with Slit2 protein, the number of immune cells did not increase even with acetaminophen treatment (Fig. 11). This indicates that Slit2 protein can suppress the activity of immune cells induced by acetaminophen. Example 3-2: Confirmation of expression of inflammatory genes Liver tissue obtained according to Example 1-1 was disrupted, RNA was extracted, and cDNA was synthesized based on this. The expression of inflammatory genes, IL1β, MyD88, IL6, TNFα, and TLR4, was observed using the synthesized cDNA. The primer sequences used to confirm the expression of inflammatory factors are shown in Table 2. As a result, the expression of inflammatory factors IL1β1, MyD88, TNF-α, IL6, and TLR4 all increased when treated with acetaminophen, and when treated together with SLIT2 protein, no increase in the expression of the inflammatory factors due to acetaminophen treatment was observed (Fig. 12). This indicates that the Slit2 protein has an anti-inflammatory effect. Example 4: Confirmation of inhibition of CYP2E1 expression following SLIT2 administration in animal and cell models. When 100 ng / mL of SLIT2 and / or 2 mM of acetaminophen were administered to an aging mouse model (age: 20 months) and a hepatic cell line (HepG2), the expression level of CYP2E1 was checked. When only acetaminophen was treated, the expression level of CYP2E1 was confirmed to be approximately 1.5 times higher than that of the control group. However, when SLIT2 was treated together with acetaminophen, the expression level of CYP2E1 was confirmed to be lower than that of the control group (Fig. 13). This means that the administration of SLIT2 can effectively reduce the expression level of CYP2E1, which can induce cytotoxicity. The Slit2 protein according to the present invention suppresses the expression of inflammatory factors, suppresses the expression of hepatotoxicity markers AST and ALT, and is useful for the prevention or treatment of drug-induced hepatotoxicity, particularly drug-induced hepatotoxicity caused by acetaminophen overdose. While specific aspects of the present invention have been described in detail above, it will be apparent to those skilled in the art that these specific descriptions merely represent preferred embodiments and are not intended to limit the scope of the present invention. Therefore, the substantial scope of the present invention is defined by the appended claims and their equivalents. Electronic file attached.

Claims

1. A pharmaceutical composition for preventing or treating drug hepatotoxicity disease, comprising a Slit2 protein or a nucleic acid encoding the same as an active ingredient.

2. A pharmaceutical composition for preventing or treating drug hepatotoxicity disease, characterized in that the Slit2 protein in claim 1 is a recombinant human SLIT2 protein.

3. A pharmaceutical composition for preventing or treating drug hepatotoxicity disease, characterized in that the SLIT2 protein in the second paragraph has an amino acid sequence of sequence number 1.

4. A pharmaceutical composition for preventing or treating drug hepatotoxicity disease, characterized in that the drug hepatotoxicity disease in paragraph 1 is caused by acetaminophen.

5. A health functional food composition for preventing or improving drug hepatotoxicity disease, comprising Slit2 protein as an active ingredient.

6. A health functional food composition for preventing or improving drug hepatotoxicity, characterized in that the Slit2 protein in paragraph 5 is a recombinant human SLIT2 protein.

7. A health functional food composition for preventing or improving drug hepatotoxicity, characterized in that the SLIT2 protein in claim 6 has an amino acid sequence of sequence number 1.

8. A health functional food composition for preventing or improving drug-induced liver toxicity, characterized in that the drug-induced liver toxicity disease in paragraph 5 is caused by acetaminophen.

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