KR100408107B1 - Pharmaceutical compositions for protecting liver comprising leucocyanidin - Google Patents
Pharmaceutical compositions for protecting liver comprising leucocyanidin Download PDFInfo
- Publication number
- KR100408107B1 KR100408107B1 KR10-2000-0063536A KR20000063536A KR100408107B1 KR 100408107 B1 KR100408107 B1 KR 100408107B1 KR 20000063536 A KR20000063536 A KR 20000063536A KR 100408107 B1 KR100408107 B1 KR 100408107B1
- Authority
- KR
- South Korea
- Prior art keywords
- liver
- pharmaceutical composition
- acetaminophen
- phase
- activity
- Prior art date
Links
- 210000004185 liver Anatomy 0.000 title claims abstract description 30
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 25
- SBZWTSHAFILOTE-SOUVJXGZSA-N (2R,3S,4S)-leucocyanidin Chemical compound C1([C@H]2OC3=CC(O)=CC(O)=C3[C@H](O)[C@@H]2O)=CC=C(O)C(O)=C1 SBZWTSHAFILOTE-SOUVJXGZSA-N 0.000 title claims abstract description 9
- HMXJLDJMSRBOCV-UHFFFAOYSA-N Leucocyanidin Natural products OC1C(OC2C(O)C(Oc3cc(O)cc(O)c23)c4ccc(O)c(O)c4)c5c(O)cc(O)cc5OC1c6ccc(O)c(O)c6 HMXJLDJMSRBOCV-UHFFFAOYSA-N 0.000 title claims abstract description 9
- SBZWTSHAFILOTE-UHFFFAOYSA-N leucocianidol Natural products OC1C(O)C2=C(O)C=C(O)C=C2OC1C1=CC=C(O)C(O)=C1 SBZWTSHAFILOTE-UHFFFAOYSA-N 0.000 title claims abstract description 9
- 229940086558 leucocyanidin Drugs 0.000 title claims abstract description 9
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 claims abstract description 93
- 229960005489 paracetamol Drugs 0.000 claims abstract description 48
- 102000004190 Enzymes Human genes 0.000 claims abstract description 42
- 108090000790 Enzymes Proteins 0.000 claims abstract description 42
- 230000002503 metabolic effect Effects 0.000 claims abstract description 18
- 231100000304 hepatotoxicity Toxicity 0.000 claims abstract description 16
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 15
- 239000000126 substance Substances 0.000 claims abstract description 15
- 230000007056 liver toxicity Effects 0.000 claims abstract description 12
- 231100000334 hepatotoxic Toxicity 0.000 claims abstract description 10
- 230000003082 hepatotoxic effect Effects 0.000 claims abstract description 10
- 206010067125 Liver injury Diseases 0.000 claims abstract description 9
- 231100000234 hepatic damage Toxicity 0.000 claims abstract description 9
- 230000008818 liver damage Effects 0.000 claims abstract description 9
- 231100000331 toxic Toxicity 0.000 claims abstract description 9
- 230000002588 toxic effect Effects 0.000 claims abstract description 9
- 230000029142 excretion Effects 0.000 claims abstract description 5
- 206010019851 Hepatotoxicity Diseases 0.000 claims abstract description 4
- 230000007686 hepatotoxicity Effects 0.000 claims abstract description 4
- 102000008097 Aryl sulfotransferase Human genes 0.000 claims description 12
- 108060000550 Aryl sulfotransferase Proteins 0.000 claims description 12
- 108010070675 Glutathione transferase Proteins 0.000 claims description 11
- 102000005720 Glutathione transferase Human genes 0.000 claims description 11
- 239000003937 drug carrier Substances 0.000 claims description 4
- 239000003814 drug Substances 0.000 abstract description 11
- 238000000034 method Methods 0.000 abstract description 11
- 230000001988 toxicity Effects 0.000 abstract description 8
- 231100000419 toxicity Toxicity 0.000 abstract description 8
- 239000003907 antipyretic analgesic agent Substances 0.000 abstract description 4
- 230000002829 reductive effect Effects 0.000 abstract description 3
- 230000000694 effects Effects 0.000 description 62
- 101150053185 P450 gene Proteins 0.000 description 19
- 235000018102 proteins Nutrition 0.000 description 17
- 102000004169 proteins and genes Human genes 0.000 description 17
- 108090000623 proteins and genes Proteins 0.000 description 17
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 14
- 241000700159 Rattus Species 0.000 description 14
- 206010019692 hepatic necrosis Diseases 0.000 description 12
- UMFJAHHVKNCGLG-UHFFFAOYSA-N n-Nitrosodimethylamine Chemical compound CN(C)N=O UMFJAHHVKNCGLG-UHFFFAOYSA-N 0.000 description 12
- 231100000149 liver necrosis Toxicity 0.000 description 11
- 229940079593 drug Drugs 0.000 description 9
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 7
- 239000012380 dealkylating agent Substances 0.000 description 7
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 7
- 238000004519 manufacturing process Methods 0.000 description 7
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- 238000001000 micrograph Methods 0.000 description 6
- 210000002966 serum Anatomy 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 239000008280 blood Substances 0.000 description 5
- 210000004369 blood Anatomy 0.000 description 5
- 239000012649 demethylating agent Substances 0.000 description 5
- 229960003180 glutathione Drugs 0.000 description 5
- 239000006228 supernatant Substances 0.000 description 5
- 229930195730 Aflatoxin Natural products 0.000 description 4
- XWIYFDMXXLINPU-UHFFFAOYSA-N Aflatoxin G Chemical compound O=C1OCCC2=C1C(=O)OC1=C2C(OC)=CC2=C1C1C=COC1O2 XWIYFDMXXLINPU-UHFFFAOYSA-N 0.000 description 4
- FMMWHPNWAFZXNH-UHFFFAOYSA-N Benz[a]pyrene Chemical compound C1=C2C3=CC=CC=C3C=C(C=C3)C2=C2C3=CC=CC2=C1 FMMWHPNWAFZXNH-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 4
- URNSECGXFRDEDC-UHFFFAOYSA-N N-acetyl-1,4-benzoquinone imine Chemical compound CC(=O)N=C1C=CC(=O)C=C1 URNSECGXFRDEDC-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- 239000005409 aflatoxin Substances 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 210000000172 cytosol Anatomy 0.000 description 4
- 229960003276 erythromycin Drugs 0.000 description 4
- 230000004060 metabolic process Effects 0.000 description 4
- 230000003228 microsomal effect Effects 0.000 description 4
- LOUPRKONTZGTKE-LHHVKLHASA-N quinidine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@H]2[C@@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-LHHVKLHASA-N 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 239000003440 toxic substance Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 102000002004 Cytochrome P-450 Enzyme System Human genes 0.000 description 3
- 108010015742 Cytochrome P-450 Enzyme System Proteins 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- CXOFVDLJLONNDW-UHFFFAOYSA-N Phenytoin Chemical compound N1C(=O)NC(=O)C1(C=1C=CC=CC=1)C1=CC=CC=C1 CXOFVDLJLONNDW-UHFFFAOYSA-N 0.000 description 3
- 235000014787 Vitis vinifera Nutrition 0.000 description 3
- XJLXINKUBYWONI-DQQFMEOOSA-N [[(2r,3r,4r,5r)-5-(6-aminopurin-9-yl)-3-hydroxy-4-phosphonooxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [(2s,3r,4s,5s)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl phosphate Chemical compound NC(=O)C1=CC=C[N+]([C@@H]2[C@H]([C@@H](O)[C@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](OP(O)(O)=O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 XJLXINKUBYWONI-DQQFMEOOSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- -1 coatings Substances 0.000 description 3
- 230000001086 cytosolic effect Effects 0.000 description 3
- 235000003969 glutathione Nutrition 0.000 description 3
- 235000002532 grape seed extract Nutrition 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 210000001589 microsome Anatomy 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 229960002036 phenytoin Drugs 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 3
- 229960005080 warfarin Drugs 0.000 description 3
- PJVWKTKQMONHTI-UHFFFAOYSA-N warfarin Chemical compound OC=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 PJVWKTKQMONHTI-UHFFFAOYSA-N 0.000 description 3
- SNICXCGAKADSCV-JTQLQIEISA-N (-)-Nicotine Chemical compound CN1CCC[C@H]1C1=CC=CN=C1 SNICXCGAKADSCV-JTQLQIEISA-N 0.000 description 2
- VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 description 2
- HXEZIDSFDHEIIQ-UHFFFAOYSA-N 2-naphthyl sulfate Chemical compound C1=CC=CC2=CC(OS(=O)(=O)O)=CC=C21 HXEZIDSFDHEIIQ-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical class NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- 108010003415 Aspartate Aminotransferases Proteins 0.000 description 2
- 102000004625 Aspartate Aminotransferases Human genes 0.000 description 2
- TXVHTIQJNYSSKO-UHFFFAOYSA-N BeP Natural products C1=CC=C2C3=CC=CC=C3C3=CC=CC4=CC=C1C2=C34 TXVHTIQJNYSSKO-UHFFFAOYSA-N 0.000 description 2
- NBSCHQHZLSJFNQ-GASJEMHNSA-N D-Glucose 6-phosphate Chemical compound OC1O[C@H](COP(O)(O)=O)[C@@H](O)[C@H](O)[C@H]1O NBSCHQHZLSJFNQ-GASJEMHNSA-N 0.000 description 2
- VYZAHLCBVHPDDF-UHFFFAOYSA-N Dinitrochlorobenzene Chemical compound [O-][N+](=O)C1=CC=C(Cl)C([N+]([O-])=O)=C1 VYZAHLCBVHPDDF-UHFFFAOYSA-N 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 2
- VFRROHXSMXFLSN-UHFFFAOYSA-N Glc6P Natural products OP(=O)(O)OCC(O)C(O)C(O)C(O)C=O VFRROHXSMXFLSN-UHFFFAOYSA-N 0.000 description 2
- 108010024636 Glutathione Proteins 0.000 description 2
- WZUVPPKBWHMQCE-UHFFFAOYSA-N Haematoxylin Chemical compound C12=CC(O)=C(O)C=C2CC2(O)C1C1=CC=C(O)C(O)=C1OC2 WZUVPPKBWHMQCE-UHFFFAOYSA-N 0.000 description 2
- FLAQQSHRLBFIEZ-UHFFFAOYSA-N N-Methyl-N-nitroso-4-oxo-4-(3-pyridyl)butyl amine Chemical compound O=NN(C)CCCC(=O)C1=CC=CN=C1 FLAQQSHRLBFIEZ-UHFFFAOYSA-N 0.000 description 2
- 206010028851 Necrosis Diseases 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 229930012538 Paclitaxel Natural products 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical class C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 description 2
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 description 2
- JLRGJRBPOGGCBT-UHFFFAOYSA-N Tolbutamide Chemical compound CCCCNC(=O)NS(=O)(=O)C1=CC=C(C)C=C1 JLRGJRBPOGGCBT-UHFFFAOYSA-N 0.000 description 2
- 241000219095 Vitis Species 0.000 description 2
- 240000006365 Vitis vinifera Species 0.000 description 2
- 230000003187 abdominal effect Effects 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- YRKCREAYFQTBPV-UHFFFAOYSA-N acetylacetone Chemical compound CC(=O)CC(C)=O YRKCREAYFQTBPV-UHFFFAOYSA-N 0.000 description 2
- IAJILQKETJEXLJ-QTBDOELSSA-N aldehydo-D-glucuronic acid Chemical compound O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-QTBDOELSSA-N 0.000 description 2
- MWPLVEDNUUSJAV-UHFFFAOYSA-N anthracene Chemical compound C1=CC=CC2=CC3=CC=CC=C3C=C21 MWPLVEDNUUSJAV-UHFFFAOYSA-N 0.000 description 2
- 230000003078 antioxidant effect Effects 0.000 description 2
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 description 2
- 230000021615 conjugation Effects 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- AAOVKJBEBIDNHE-UHFFFAOYSA-N diazepam Chemical compound N=1CC(=O)N(C)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 AAOVKJBEBIDNHE-UHFFFAOYSA-N 0.000 description 2
- 229960003529 diazepam Drugs 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- 229930182833 estradiol Natural products 0.000 description 2
- 229960005309 estradiol Drugs 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 229940097043 glucuronic acid Drugs 0.000 description 2
- 230000002440 hepatic effect Effects 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- ODBLHEXUDAPZAU-UHFFFAOYSA-N isocitric acid Chemical compound OC(=O)C(O)C(C(O)=O)CC(O)=O ODBLHEXUDAPZAU-UHFFFAOYSA-N 0.000 description 2
- 210000001853 liver microsome Anatomy 0.000 description 2
- 210000005228 liver tissue Anatomy 0.000 description 2
- 238000006241 metabolic reaction Methods 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 230000017074 necrotic cell death Effects 0.000 description 2
- 229960002715 nicotine Drugs 0.000 description 2
- SNICXCGAKADSCV-UHFFFAOYSA-N nicotine Natural products CN1CCCC1C1=CC=CN=C1 SNICXCGAKADSCV-UHFFFAOYSA-N 0.000 description 2
- 229960001592 paclitaxel Drugs 0.000 description 2
- WEXRUCMBJFQVBZ-UHFFFAOYSA-N pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 description 2
- CPJSUEIXXCENMM-UHFFFAOYSA-N phenacetin Chemical compound CCOC1=CC=C(NC(C)=O)C=C1 CPJSUEIXXCENMM-UHFFFAOYSA-N 0.000 description 2
- 231100000614 poison Toxicity 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 229920002414 procyanidin Polymers 0.000 description 2
- AQHHHDLHHXJYJD-UHFFFAOYSA-N propranolol Chemical compound C1=CC=C2C(OCC(O)CNC(C)C)=CC=CC2=C1 AQHHHDLHHXJYJD-UHFFFAOYSA-N 0.000 description 2
- 229960001404 quinidine Drugs 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 2
- ZFXYFBGIUFBOJW-UHFFFAOYSA-N theophylline Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 description 2
- 229960005371 tolbutamide Drugs 0.000 description 2
- 231100000167 toxic agent Toxicity 0.000 description 2
- 210000003462 vein Anatomy 0.000 description 2
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 2
- SSEBTPPFLLCUMN-CYBMUJFWSA-N (1r)-2-(tert-butylamino)-1-(7-ethyl-1-benzofuran-2-yl)ethanol Chemical compound CCC1=CC=CC2=C1OC([C@H](O)CNC(C)(C)C)=C2 SSEBTPPFLLCUMN-CYBMUJFWSA-N 0.000 description 1
- XMAYWYJOQHXEEK-OZXSUGGESA-N (2R,4S)-ketoconazole Chemical compound C1CN(C(=O)C)CCN1C(C=C1)=CC=C1OC[C@@H]1O[C@@](CN2C=NC=C2)(C=2C(=CC(Cl)=CC=2)Cl)OC1 XMAYWYJOQHXEEK-OZXSUGGESA-N 0.000 description 1
- RTHCYVBBDHJXIQ-MRXNPFEDSA-N (R)-fluoxetine Chemical compound O([C@H](CCNC)C=1C=CC=CC=1)C1=CC=C(C(F)(F)F)C=C1 RTHCYVBBDHJXIQ-MRXNPFEDSA-N 0.000 description 1
- ALRLPDGCPYIVHP-UHFFFAOYSA-N 1-nitropyrene Chemical compound C1=C2C([N+](=O)[O-])=CC=C(C=C3)C2=C2C3=CC=CC2=C1 ALRLPDGCPYIVHP-UHFFFAOYSA-N 0.000 description 1
- SGTNSNPWRIOYBX-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-{[2-(3,4-dimethoxyphenyl)ethyl](methyl)amino}-2-(propan-2-yl)pentanenitrile Chemical compound C1=C(OC)C(OC)=CC=C1CCN(C)CCCC(C#N)(C(C)C)C1=CC=C(OC)C(OC)=C1 SGTNSNPWRIOYBX-UHFFFAOYSA-N 0.000 description 1
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- GACDQMDRPRGCTN-KQYNXXCUSA-N 3'-phospho-5'-adenylyl sulfate Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OS(O)(=O)=O)[C@@H](OP(O)(O)=O)[C@H]1O GACDQMDRPRGCTN-KQYNXXCUSA-N 0.000 description 1
- GOLORTLGFDVFDW-UHFFFAOYSA-N 3-(1h-benzimidazol-2-yl)-7-(diethylamino)chromen-2-one Chemical compound C1=CC=C2NC(C3=CC4=CC=C(C=C4OC3=O)N(CC)CC)=NC2=C1 GOLORTLGFDVFDW-UHFFFAOYSA-N 0.000 description 1
- ZPSOKQFFOYYPKC-UHFFFAOYSA-N 7-pentoxyphenoxazin-3-one Chemical compound C1=CC(=O)C=C2OC3=CC(OCCCCC)=CC=C3N=C21 ZPSOKQFFOYYPKC-UHFFFAOYSA-N 0.000 description 1
- NLHHRLWOUZZQLW-UHFFFAOYSA-N Acrylonitrile Chemical class C=CC#N NLHHRLWOUZZQLW-UHFFFAOYSA-N 0.000 description 1
- 102100036475 Alanine aminotransferase 1 Human genes 0.000 description 1
- 108010082126 Alanine transaminase Proteins 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- DGAKHGXRMXWHBX-ONEGZZNKSA-N Azoxymethane Chemical compound C\N=[N+](/C)[O-] DGAKHGXRMXWHBX-ONEGZZNKSA-N 0.000 description 1
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 1
- 102000018832 Cytochromes Human genes 0.000 description 1
- 108010052832 Cytochromes Proteins 0.000 description 1
- ODBLHEXUDAPZAU-ZAFYKAAXSA-N D-threo-isocitric acid Chemical compound OC(=O)[C@H](O)[C@@H](C(O)=O)CC(O)=O ODBLHEXUDAPZAU-ZAFYKAAXSA-N 0.000 description 1
- OGDVEMNWJVYAJL-LEPYJNQMSA-N Ethyl morphine Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OCC OGDVEMNWJVYAJL-LEPYJNQMSA-N 0.000 description 1
- OGDVEMNWJVYAJL-UHFFFAOYSA-N Ethylmorphine Natural products C1C(N(CCC234)C)C2C=CC(O)C3OC2=C4C1=CC=C2OCC OGDVEMNWJVYAJL-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- LPHGQDQBBGAPDZ-UHFFFAOYSA-N Isocaffeine Natural products CN1C(=O)N(C)C(=O)C2=C1N(C)C=N2 LPHGQDQBBGAPDZ-UHFFFAOYSA-N 0.000 description 1
- ODBLHEXUDAPZAU-FONMRSAGSA-N Isocitric acid Natural products OC(=O)[C@@H](O)[C@H](C(O)=O)CC(O)=O ODBLHEXUDAPZAU-FONMRSAGSA-N 0.000 description 1
- PWKSKIMOESPYIA-BYPYZUCNSA-N L-N-acetyl-Cysteine Chemical compound CC(=O)N[C@@H](CS)C(O)=O PWKSKIMOESPYIA-BYPYZUCNSA-N 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- WBNQDOYYEUMPFS-UHFFFAOYSA-N N-nitrosodiethylamine Chemical compound CCN(CC)N=O WBNQDOYYEUMPFS-UHFFFAOYSA-N 0.000 description 1
- CIJBKNZDKBKMFU-UHFFFAOYSA-N N-nitrosomethanamine Chemical compound CNN=O CIJBKNZDKBKMFU-UHFFFAOYSA-N 0.000 description 1
- CWEZAWNPTYBADX-UHFFFAOYSA-N Procyanidin Natural products OC1C(OC2C(O)C(Oc3c2c(O)cc(O)c3C4C(O)C(Oc5cc(O)cc(O)c45)c6ccc(O)c(O)c6)c7ccc(O)c(O)c7)c8c(O)cc(O)cc8OC1c9ccc(O)c(O)c9 CWEZAWNPTYBADX-UHFFFAOYSA-N 0.000 description 1
- 102000007562 Serum Albumin Human genes 0.000 description 1
- 108010071390 Serum Albumin Proteins 0.000 description 1
- 108090000340 Transaminases Proteins 0.000 description 1
- 102000003929 Transaminases Human genes 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- BZHJMEDXRYGGRV-UHFFFAOYSA-N Vinyl chloride Chemical class ClC=C BZHJMEDXRYGGRV-UHFFFAOYSA-N 0.000 description 1
- 235000009392 Vitis Nutrition 0.000 description 1
- 235000009754 Vitis X bourquina Nutrition 0.000 description 1
- 235000012333 Vitis X labruscana Nutrition 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000002790 anti-mutagenic effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical class [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 description 1
- 239000003613 bile acid Substances 0.000 description 1
- 230000008033 biological extinction Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 229950006886 bufuralol Drugs 0.000 description 1
- 229960001948 caffeine Drugs 0.000 description 1
- VJEONQKOZGKCAK-UHFFFAOYSA-N caffeine Natural products CN1C(=O)N(C)C(=O)C2=C1C=CN2C VJEONQKOZGKCAK-UHFFFAOYSA-N 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 230000000711 cancerogenic effect Effects 0.000 description 1
- FFGPTBGBLSHEPO-UHFFFAOYSA-N carbamazepine Chemical compound C1=CC2=CC=CC=C2N(C(=O)N)C2=CC=CC=C21 FFGPTBGBLSHEPO-UHFFFAOYSA-N 0.000 description 1
- 229960000623 carbamazepine Drugs 0.000 description 1
- 231100000357 carcinogen Toxicity 0.000 description 1
- 239000003183 carcinogenic agent Substances 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229960003633 chlorzoxazone Drugs 0.000 description 1
- TZFWDZFKRBELIQ-UHFFFAOYSA-N chlorzoxazone Chemical compound ClC1=CC=C2OC(O)=NC2=C1 TZFWDZFKRBELIQ-UHFFFAOYSA-N 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 229960001380 cimetidine Drugs 0.000 description 1
- CCGSUNCLSOWKJO-UHFFFAOYSA-N cimetidine Chemical compound N#CNC(=N/C)\NCCSCC1=NC=N[C]1C CCGSUNCLSOWKJO-UHFFFAOYSA-N 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 238000004737 colorimetric analysis Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 229960004397 cyclophosphamide Drugs 0.000 description 1
- 230000020335 dealkylation Effects 0.000 description 1
- 238000006900 dealkylation reaction Methods 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- CYQFCXCEBYINGO-IAGOWNOFSA-N delta1-THC Chemical compound C1=C(C)CC[C@H]2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3[C@@H]21 CYQFCXCEBYINGO-IAGOWNOFSA-N 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 229960001259 diclofenac Drugs 0.000 description 1
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- MCWXGJITAZMZEV-UHFFFAOYSA-N dimethoate Chemical compound CNC(=O)CSP(=S)(OC)OC MCWXGJITAZMZEV-UHFFFAOYSA-N 0.000 description 1
- 239000002612 dispersion medium Substances 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 229960004242 dronabinol Drugs 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- YQGOJNYOYNNSMM-UHFFFAOYSA-N eosin Chemical compound [Na+].OC(=O)C1=CC=CC=C1C1=C2C=C(Br)C(=O)C(Br)=C2OC2=C(Br)C(O)=C(Br)C=C21 YQGOJNYOYNNSMM-UHFFFAOYSA-N 0.000 description 1
- 229960004578 ethylmorphine Drugs 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 229960002464 fluoxetine Drugs 0.000 description 1
- 239000010200 folin Substances 0.000 description 1
- 239000000417 fungicide Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 229940087603 grape seed extract Drugs 0.000 description 1
- 230000007866 hepatic necrosis Effects 0.000 description 1
- 210000003494 hepatocyte Anatomy 0.000 description 1
- 230000002443 hepatoprotective effect Effects 0.000 description 1
- 229960002456 hexobarbital Drugs 0.000 description 1
- UYXAWHWODHRRMR-UHFFFAOYSA-N hexobarbital Chemical compound O=C1N(C)C(=O)NC(=O)C1(C)C1=CCCCC1 UYXAWHWODHRRMR-UHFFFAOYSA-N 0.000 description 1
- 238000000265 homogenisation Methods 0.000 description 1
- BCGWQEUPMDMJNV-UHFFFAOYSA-N imipramine Chemical compound C1CC2=CC=CC=C2N(CCCN(C)C)C2=CC=CC=C21 BCGWQEUPMDMJNV-UHFFFAOYSA-N 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 229960000905 indomethacin Drugs 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 229960003350 isoniazid Drugs 0.000 description 1
- QRXWMOHMRWLFEY-UHFFFAOYSA-N isoniazide Chemical compound NNC(=O)C1=CC=NC=C1 QRXWMOHMRWLFEY-UHFFFAOYSA-N 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 229960004125 ketoconazole Drugs 0.000 description 1
- 238000000691 measurement method Methods 0.000 description 1
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 description 1
- RFKMCNOHBTXSMU-UHFFFAOYSA-N methoxyflurane Chemical compound COC(F)(F)C(Cl)Cl RFKMCNOHBTXSMU-UHFFFAOYSA-N 0.000 description 1
- 229960002455 methoxyflurane Drugs 0.000 description 1
- MCPLVIGCWWTHFH-UHFFFAOYSA-L methyl blue Chemical compound [Na+].[Na+].C1=CC(S(=O)(=O)[O-])=CC=C1NC1=CC=C(C(=C2C=CC(C=C2)=[NH+]C=2C=CC(=CC=2)S([O-])(=O)=O)C=2C=CC(NC=3C=CC(=CC=3)S([O-])(=O)=O)=CC=2)C=C1 MCPLVIGCWWTHFH-UHFFFAOYSA-L 0.000 description 1
- BJNBRIBHKLJMAG-ARJAWSKDSA-N methylazoxymethanol Chemical compound C\[N+]([O-])=N\CO BJNBRIBHKLJMAG-ARJAWSKDSA-N 0.000 description 1
- CXKWCBBOMKCUKX-UHFFFAOYSA-M methylene blue Chemical compound [Cl-].C1=CC(N(C)C)=CC2=[S+]C3=CC(N(C)C)=CC=C3N=C21 CXKWCBBOMKCUKX-UHFFFAOYSA-M 0.000 description 1
- 229960000907 methylthioninium chloride Drugs 0.000 description 1
- 238000000386 microscopy Methods 0.000 description 1
- 230000000116 mitigating effect Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- CCYHKRWGLAJQTB-UHFFFAOYSA-N n-hydroxy-n-(4-hydroxyphenyl)acetamide Chemical group CC(=O)N(O)C1=CC=C(O)C=C1 CCYHKRWGLAJQTB-UHFFFAOYSA-N 0.000 description 1
- 230000018791 negative regulation of catalytic activity Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 1
- HYIMSNHJOBLJNT-UHFFFAOYSA-N nifedipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1[N+]([O-])=O HYIMSNHJOBLJNT-UHFFFAOYSA-N 0.000 description 1
- 229960001597 nifedipine Drugs 0.000 description 1
- XKLJHFLUAHKGGU-UHFFFAOYSA-N nitrous amide Chemical compound ON=N XKLJHFLUAHKGGU-UHFFFAOYSA-N 0.000 description 1
- SBQLYHNEIUGQKH-UHFFFAOYSA-N omeprazole Chemical compound N1=C2[CH]C(OC)=CC=C2N=C1S(=O)CC1=NC=C(C)C(OC)=C1C SBQLYHNEIUGQKH-UHFFFAOYSA-N 0.000 description 1
- 229960000381 omeprazole Drugs 0.000 description 1
- 238000001543 one-way ANOVA Methods 0.000 description 1
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 229960001412 pentobarbital Drugs 0.000 description 1
- 125000004115 pentoxy group Chemical group [*]OC([H])([H])C([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- 229960003893 phenacetin Drugs 0.000 description 1
- DDBREPKUVSBGFI-UHFFFAOYSA-N phenobarbital Chemical compound C=1C=CC=CC=1C1(CC)C(=O)NC(=O)NC1=O DDBREPKUVSBGFI-UHFFFAOYSA-N 0.000 description 1
- 229960002695 phenobarbital Drugs 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 238000005375 photometry Methods 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000008057 potassium phosphate buffer Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000011533 pre-incubation Methods 0.000 description 1
- 229960003387 progesterone Drugs 0.000 description 1
- 239000000186 progesterone Substances 0.000 description 1
- SSOLNOMRVKKSON-UHFFFAOYSA-N proguanil Chemical compound CC(C)\N=C(/N)N=C(N)NC1=CC=C(Cl)C=C1 SSOLNOMRVKKSON-UHFFFAOYSA-N 0.000 description 1
- 229960005385 proguanil Drugs 0.000 description 1
- 150000003815 prostacyclins Chemical class 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 230000002000 scavenging effect Effects 0.000 description 1
- DUIOPKIIICUYRZ-UHFFFAOYSA-N semicarbazide Chemical compound NNC(N)=O DUIOPKIIICUYRZ-UHFFFAOYSA-N 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 208000018655 severe necrosis Diseases 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000012064 sodium phosphate buffer Substances 0.000 description 1
- CIJQGPVMMRXSQW-UHFFFAOYSA-M sodium;2-aminoacetic acid;hydroxide Chemical compound O.[Na+].NCC([O-])=O CIJQGPVMMRXSQW-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000010421 standard material Substances 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229960003604 testosterone Drugs 0.000 description 1
- 229960000278 theophylline Drugs 0.000 description 1
- 150000003595 thromboxanes Chemical class 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 230000003966 vascular damage Effects 0.000 description 1
- 229960001722 verapamil Drugs 0.000 description 1
- 239000001717 vitis vinifera seed extract Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000002676 xenobiotic agent Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y205/00—Transferases transferring alkyl or aryl groups, other than methyl groups (2.5)
- C12Y205/01—Transferases transferring alkyl or aryl groups, other than methyl groups (2.5) transferring alkyl or aryl groups, other than methyl groups (2.5.1)
- C12Y205/01018—Glutathione transferase (2.5.1.18)
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y208/00—Transferases transferring sulfur-containing groups (2.8)
- C12Y208/02—Sulfotransferases (2.8.2)
- C12Y208/02001—Aryl sulfotransferase (2.8.2.1)
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Veterinary Medicine (AREA)
- General Engineering & Computer Science (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Zoology (AREA)
- Animal Behavior & Ethology (AREA)
- Wood Science & Technology (AREA)
- Public Health (AREA)
- Genetics & Genomics (AREA)
- Biochemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Gastroenterology & Hepatology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
본 발명은 류코시아니딘의 간 보호제로서의 의약 용도에 관한 것이다. 본 발명은 해열 진통제로서 유용한 아세트아미노펜에 의한 간 독성을 억제하는 데 류코시아니딘을 사용하는 방법과 그 약학 조성물을 제공한다. 또한 본 발명은 아세트아미노펜 이외에, 제I상 대사 효소들에 의해 독성 본체로 대사되는 간 독성 물질에 의한 간 독성을 억제하는 데 류코시아니딘을 사용하는 방법과 그 약학 조성물을 제공한다. 본 발명에 의하면, 간 독성 물질에 의한 간 손상을 현저하게 감소시킬 수 있다. 본 발명은 제I상 대사 효소에 의해 대사되어 독성을 나타내는 물질은 물론, 제II상 대사 효소에 의해 배설 속도가 촉진되는 모든 물질의 독성을 억제(경감)하는 데 적용할 수 있다.The present invention relates to the use of leucocyanidin as a medicament for liver protection. The present invention provides a method of using leucocyanidine and a pharmaceutical composition thereof for inhibiting liver toxicity by acetaminophen useful as an antipyretic analgesic. The present invention also provides a pharmaceutical composition and a method of using leucocyanidine in addition to acetaminophen to inhibit hepatotoxicity caused by hepatotoxic substances metabolized to toxic bodies by phase I metabolic enzymes. According to the present invention, liver damage caused by hepatotoxic substances can be significantly reduced. The present invention can be applied to suppressing (reducing) the toxicity of not only substances metabolized by phase I metabolizing enzymes, but also all substances whose excretion rate is promoted by phase II metabolizing enzymes.
Description
본 발명은 류코시아니딘(leucocyanidin)의 새로운 의약 용도에 관한 것이다. 구체적으로 본 발명은 류코시아니딘의 간 보호제로서의 의약 용도에 관한 것이다. 보다 구체적으로, 본 발명은 해열 진통제로서 유용한 아세트아미노펜에 의한 간 독성을 억제하는 데 류코시아니딘을 사용하는 방법과 그것을 위한 약학 조성물에 관한 것이다. 또한 본 발명은 아세트아미노펜 이외에, 제1상 대사 효소들에 의한 독성 본체로 대사되는 간 독성 물질에 의한 간 독성을 억제하는 데 류코시아니딘을 사용하는 방법과 그것을 위한 약학 조성물에 관한 것이다.The present invention relates to new medicinal uses of leucocyanidin. Specifically, the present invention relates to the use of leucocyanidin as a medicament for liver protection. More specifically, the present invention relates to a method of using leucocyanidine for inhibiting liver toxicity by acetaminophen useful as an antipyretic analgesic and a pharmaceutical composition therefor. The present invention also relates to a method for using leucocyanidins for inhibiting liver toxicity by a hepatotoxic substance which is metabolized into a toxic body by first phase metabolic enzymes, in addition to acetaminophen, and a pharmaceutical composition therefor.
류코시아니딘은 포도(학명: 비티스 비니페라(Vitis vvinifera) 씨 추출물에 함유되어 있는 트로시아니돌 올리고머의 하나로서, 하기 구조식을 갖는 화합물이다: Leucocyanidin is one of the trocyanidol oligomers contained in grape ( Vitis vvinifera ) seed extract and is a compound having the following structural formula:
상기 류코시아니딘은 혈관 손상 보호 효과, 항산화 작용, 돌연 변이 억제 효과를 갖는 물질로 알려져 있다[참고 문헌: Masquelier, J.: Oligomeres procyanidoliques.Perfumes, cosmetiques, aromesOct-Nov, 89-97, 1997; Facino, R. M., Carini, M., Aldini, G., Bombardelli, E., Morazzoni, P. 및 Morelli, R.: Free radicals scavenging action and anti-enzyme activities of procyanidinesfrom Vitis vinifera.Drug Res. (Germany)44(1), 5, 592-601, 1994; Nuttall, S. L., Kendall, M. J., Bombardelli, E., 및 Morazzoni, P.: An evaluation of the antioxidant activity of a standardized grape seed extract, Leucoselect,J. Clin. Pharm. Ther.23(5), 385-389, 1998; Morazzoni, P. 및 Bombardelli, E.: Antimutagenic activity of procyanidins from Vitis vinifera, Fitoterapia LXV(3), 203-208, 1994].The leucocyanidins are known to have a vascular damage protection effect, an antioxidant action, and a mutation inhibiting effect. Masquelier, J .: Oligomeres procyanidoliques. Perfumes, cosmetiques, aromes Oct-Nov, 89-97, 1997; Facino, RM, Carini, M., Aldini, G., Bombardelli, E., Morazzoni, P. and Morelli, R .: Free radicals scavenging action and anti-enzyme activities of procyanidines from Vitis vinifera. Drug Res. (Germany) 44 (1), 5, 592-601, 1994; Nuttall, SL, Kendall, MJ, Bombardelli, E., and Morazzoni, P .: An evaluation of the antioxidant activity of a standardized grape seed extract, Leucoselect, J. Clin. Pharm. Ther. 23 (5), 385-389, 1998; Morazzoni, P. and Bombardelli, E .: Antimutagenic activity of procyanidins from Vitis vinifera, Fitoterapia LXV (3), 203-208, 1994].
한편, 아세트아미노펜은 해열 진통제로 널리 사용되는 약물로서 고용량으로 사용할 경우 간 독성이 있음이 사람과 동물 시험 결과 밝혀졌다[참고 문헌: Davidson, D. G. D. 및 Eastham, W. N.: Acute liver necrosis following overdose of paracetamol.Br. Med. J.2 497-499, 1966; Boyd, E. M. and Bereezky, G. M,: Liver necrosis from paracetamol.Br. J. Pharmacol.Chemother. 26, 606-614, 1966]. 아세트아미노펜은 체내에서 주로 제II상 대사 반응인 글루쿠론산 포합 반응(conjugation)과 황산 포합 반응을 통해 배설된다[참고 문헌: Nelson, S. D.: Metabolic activation and drug toxicityJ. Med. Chem.25, 753-765, 1982].On the other hand, acetaminophen is a drug widely used as an antipyretic analgesic and has been shown to be hepatotoxic when used in high doses [Davidson, D. G. D. and Eastham, W. N .: Acute liver necrosis following overdose of paracetamol.Br. Med. J.2 497-499, 1966; Boyd, E. M. and Bereezky, G. M ,: Liver necrosis from paracetamol.Br. J. Pharmacol.Chemother. 26, 606-614, 1966. Acetaminophen is excreted in the body primarily through phase II metabolic reactions, such as glucuronic acid conjugation and sulfuric acid conjugation [Reference: Nelson, S. D .: Metabolic activation and drug toxicityJ. Med. Chem.25, 753-765, 1982.
한편, 아세트아미노펜의 제I상 대사 반응에 의해 생성된 N-아세틸-p-벤조퀴논이민(NAPQI)은 간 독성을 나타내는 활성 본체로서, 글루타치온 포합 반응을 통해 배설되어 해독된다[참고 문헌: Corcoran, G .B., Mitchell, J. R., Vaishnav, Y. N. 및 Horning, E. C.: Evidence that acetaminophen and N-hydroxyacetaminophen form a common arylating intermediate, N-Acetyl-p-Benzoquinoneimine.Mol. Pharmacol.18, 536-542, 1980]. 따라서, 아세트아미노펜이 과량 투여되면 글루쿠론산 포합 반응과 황산 포합 반응이 포화될 뿐만 아니라 간세포내 글루타치온을 소모시키게되며, 이 때 과량으로 생성된 NAPQI가 간세포내 고분자인 단백질(효소), DNA에 결합하여 간 손상을 일으키게 된다.On the other hand, N-acetyl-p-benzoquinoneimine (NAPQI) produced by phase I metabolic reaction of acetaminophen is an active body showing hepatotoxicity, which is excreted and detoxified by a glutathione reaction reaction [Corcoran, G.B., Mitchell, JR, Vaishnav, YN and Horning, EC: Evidence that acetaminophen and N-hydroxyacetaminophen form a common arylating intermediate, N-Acetyl-p-Benzoquinoneimine. Mol. Pharmacol. 18, 536-542, 1980]. Therefore, excessive administration of acetaminophen not only saturates the glucuronic acid synthesis and sulfuric acid synthesis reactions, but also consumes hepatocyte glutathione, and the NAPQI produced in excess binds to proteins (enzymes) and DNA, which are intracellular polymers. This will cause liver damage.
본 발명자들은 간에서 제I상 대사에 의해 활성화되어 독성을 나타내는 매우 다양한 물질들에 의한 간 독성은, 그 물질 자체를 독성 본체로 대사하는 효소 활성을 억제하고 독성 물질의 배설을 촉진하는 제II상 효소의 활성을 높여줌으로써 가능해짐을 밝혀내고 본 발명을 완성하기에 이르렀다.The inventors of the present invention found that hepatic toxicity by a wide variety of substances activated by phase I metabolism in the liver, resulting in phase II inhibition of enzyme activity that metabolizes the substance itself into the toxic body and promotes excretion of the toxic substance The present invention was found to be possible by increasing the activity of the enzyme and to complete the present invention.
따라서, 본 발명의 목적은 간 독성 물질에 의한 간 손상을 억제하는 방법과 그것을 위한 약학 조성물을 제공하는 데 있다.Accordingly, it is an object of the present invention to provide a method for inhibiting liver damage by liver toxic substances and a pharmaceutical composition therefor.
본 발명의 다른 목적은 해열 진통제로서 유용한 아세트아미노펜에 의한 간 독성을 억제하는 방법과 그것을 위한 약학 조성물을 제공하는 데 있다.Another object of the present invention is to provide a method for inhibiting liver toxicity by acetaminophen useful as an antipyretic analgesic and a pharmaceutical composition therefor.
본 발명의 또 다른 목적은 제I상 대사 효소들에 의해 독성 본체로 대사되는 아세트아미노펜 이외의 간 독성 물질에 의한 간 독성을 억제하는 방법과 그것을 위한 약학 조성물을 제공하는 데 있다.Still another object of the present invention is to provide a method for inhibiting liver toxicity by a hepatotoxic substance other than acetaminophen, which is metabolized to a toxic body by phase I metabolic enzymes, and a pharmaceutical composition therefor.
도 1은 정상 간과 아세트아미노펜 투여에 의해 괴사된 간을 비교하기 위한 현미경 사진으로서,1 is a micrograph for comparing normal liver with liver necrosis by acetaminophen administration,
도 1a는 대조군 마우스의 간 소엽 사진(50 배율)이고,1A is a liver lobule photograph (50 magnification) of a control mouse,
도 1b는 150 mg/kg/일의 류코시아니딘 단독 투여군 마우스의 간 소엽 사진(50 배율)이며,1B is a photograph of liver lobule (50 magnification) of 150 mg / kg / day leucocyanidine alone group mice,
도 1c는 아세트아미노펜 투여에 의한 간 괴사 등급 1의 현미경 사진(100 배율)이고,1C is a micrograph (100 magnification) of liver necrosis grade 1 by acetaminophen administration,
도 1d는 간 괴사 등급 2의 현미경 사진(50 배율)이며,1D is a micrograph (50 magnification) of liver necrosis grade 2,
도 1e는 간 괴사 등급 3의 현미경 사진(50 배율)이고,1E is a micrograph (50 magnification) of liver necrosis grade 3,
도 1f는 간 괴사 등급 4의 현미경 사진(50 배율)이다.1F is a micrograph (50 magnification) of liver necrosis grade 4. FIG.
도 2는 래트 간에서의 P450 1A1의 활성에 대한 류코시아니딘의 효과를 나타내기 위한 그래프로서, 효소의 활성은 레소루핀 생성량(nmol)/분/mg(단백질)으로서 나타낸다.Figure 2 is a graph showing the effect of leucocyanidine on the activity of P450 1A1 in rat liver, the activity of the enzyme is expressed as the amount of lesorupin production (nmol) / min / mg (protein).
도 3은 래트 간에서의 P450 1A2의 활성에 대한 류코시아니딘의 효과를 나타내기 위한 그래프로서, 효소의 활성은 레소루핀 생성량(nmol)/분/mg(단백질)으로서나타낸다.Figure 3 is a graph showing the effect of leucocyanidine on the activity of P450 1A2 in rat liver, the activity of the enzyme is shown as the amount of lesorupin production (nmol) / min / mg (protein).
도 4는 래트 간에서의 P450 2B1의 활성에 대한 류코시아니딘의 효과를 나타내기 위한 그래프로서, 효소의 활성은 레소루핀 생성량(nmol)/분/mg(단백질)으로서 나타낸다.4 is a graph showing the effect of leucocyanidine on the activity of P450 2B1 in rat liver, the activity of the enzyme is expressed as the amount of lesorupin production (nmol) / min / mg (protein).
도 5는 래트 간에서의 P450 3A4의 활성에 대한 류코시아니딘의 효과를 나타내기 위한 그래프로서, 효소의 활성은 포름알데히드 생성량(pmol)/분/mg(단백질)으로서 나타낸다.5 is a graph showing the effect of leucocyanidine on the activity of P450 3A4 in rat liver, the activity of the enzyme is shown as formaldehyde production (pmol) / min / mg (protein).
도 6은 래트 간에서의 P450 2E1의 활성에 대한 류코시아니딘의 효과를 나타내기 위한 그래프로서, 효소의 활성은 포름알데히드 생성량(nmol)/분/mg(단백질)으로서 나타낸다.6 is a graph showing the effect of leucocyanidin on the activity of P450 2E1 in rat liver, the activity of the enzyme is shown as formaldehyde production (nmol) / min / mg (protein).
도 7은 래트 간에서의 치토크롬 P450 총량에 대한 류코시아니딘의 효과를 나타내기 위한 그래프로서, 효소의 함량은 nmol/mg(단백질)로서 나타낸다.FIG. 7 is a graph showing the effect of leucocyanidine on the total amount of chitochrome P450 in rat liver, in which the enzyme content is expressed as nmol / mg (protein).
도 8은 래트 간에서의 GST의 활성에 대한 류코시아니딘의 효과를 나타내기 위한 그래프로서, 효소의 활성은 CDNB-GS 생성량(μmol)/분/mg(단백질)로서 나타낸다.8 is a graph showing the effect of leucocyanidine on the activity of GST in rat liver, the activity of the enzyme is shown as CDNB-GS production (μmol) / min / mg (protein).
도 9는 래트 간에서의 PST의 활성에 대한 류코시아니딘의 효과를 나타내기 위한 그래프로서, 효소의 활성은 β-나프틸설페이트 생성량(nmol)/분/mg(단백질)로서 나타낸다.9 is a graph showing the effect of leucocyanidine on the activity of PST in rat liver, and the activity of the enzyme is expressed as β-naphthyl sulfate production amount (nmol) / min / mg (protein).
전술한 본 발명의 목적은 간 보호제로서 류코시아니딘을 사용하여 간 독성 물질의 대사에 관여하는 제I상 대사 효소의 활성을 억제하고 제II상 대사 효소를 활성화시킴으로써 달성된다.The above object of the present invention is achieved by using leucocyanidin as a liver protectant to inhibit the activity of phase I metabolic enzymes involved in the metabolism of hepatotoxic substances and to activate phase II metabolic enzymes.
따라서, 본 발명은 간 손상을 억제하는 데 유효한 분량의 류코시아니딘과 약학적으로 허용 가능한 담체를 포함하는 간 보호용 약학 조성물을 제공한다.Accordingly, the present invention provides a pharmaceutical composition for protecting liver, comprising an effective amount of leucocyanidine and a pharmaceutically acceptable carrier to inhibit liver damage.
본 발명의 바람직한 한 가지 실시 상태에 의하면, 상기 약학 조성물은 아세트아미노펜에 의한 간 독성을 억제하는 데 사용할 수 있다. 다른 실시 상태에 의하면, 본 발명의 약학 조성물은 제I상 대사 효소에 의해 독성 본체로 대사되는 간 독성 물질에 의한 간 독성을 억제하는 데 사용할 수 있다. 상기 제I상 대사 효소는 치토크롬 P450 1A1, 1A2, 2B1, 3A4 또는 2E1인 것이 바람직하다.According to one preferred embodiment of the present invention, the pharmaceutical composition can be used to suppress liver toxicity by acetaminophen. According to another embodiment, the pharmaceutical composition of the present invention can be used to suppress liver toxicity by liver toxic substances that are metabolized into toxic bodies by phase I metabolic enzymes. The phase I metabolic enzyme is preferably chitochrome P450 1A1, 1A2, 2B1, 3A4 or 2E1.
본 발명의 또 다른 실시 상태에 의하면, 상기 약학 조성물은 제II상 대사 효소에 의해 배설 속도가 빨라지는 간 독성 물질에 의한 간 독성을 억제하는 데 사용할 수 있다. 상기 제II상 대사 효소는 페놀 설포트랜스퍼라제(PST) 및 글루타치온 S-트랜스퍼라제(GST)인 것이 바람직하다.According to another exemplary embodiment of the present invention, the pharmaceutical composition may be used to suppress liver toxicity caused by hepatotoxic substances whose excretion rate is accelerated by phase II metabolic enzymes. Phase II metabolic enzymes are preferably phenol sulfotransferase (PST) and glutathione S-transferase (GST).
류코시아니딘의 유효량은 적어도 부분적으로 목적하는 간 보호 효과를 달성할 수 있는 분량으로서 투여 대상의 간 손상 정도에 따라 다르나, 일반적으로 체중 1 kg 당 하루에 0.1 내지 1500 mg, 바람직하게는 10 내지 1000 mg, 더욱 바람직하게는 20 내지 500 mg, 가장 바람직하게는 50 내지 150 mg이다.The effective amount of leucocyanidine is at least in part dependent on the extent of liver damage in the subject to which the desired liver protective effect can be achieved, but is generally from 0.1 to 1500 mg per kg body weight per day, preferably from 10 to 1000 mg, more preferably 20 to 500 mg, most preferably 50 to 150 mg.
본 발명의 약학 조성물은 당업계에 공지된 방법에 따라 정제, 캡슐제, 과립제, 산제, 시럽제, 액제, 유제, 현탁제, 주사제, 캅셀제, 환제 등으로 제제화할 수 있다. 본 발명의 약학 조성물을 제제화하는 데 사용하기에 적합한 약학적으로 허용 가능한 담체로서는 제약 분야에서 통상적으로 사용되는 임의의 모든 용매, 분산 매질, 충전제, 고형 담체, 수용액, 코팅제, 살균제, 항균제, 등장제 및 흡수 지연제 등을 들 수 있다. 약학적 활성 성분에 그러한 담체를 사용하는 것은 당업계에 공지되어 있으며, 예를 들면 문헌[Remington's Pharmaceutical Sciences, 18판, 미국 펜실베니아 소재 맥출판사]에 기재되어 있다. 활성 성분과 상용성이 없는 경우를 제외하고는, 본 발명의 약학 조성물을 제조하는 데 어떤 담체를 사용해도 좋다. 보조 활성 성분 또한 약학 조성물에 첨가할 수 있다. 활성 성분과 약학적으로 허용 가능한 담체와의 배합 비율은 당업자가 경험적으로 용이하게 결정할 수 있다.The pharmaceutical composition of the present invention may be formulated into tablets, capsules, granules, powders, syrups, solutions, emulsions, suspensions, injections, capsules, pills and the like according to methods known in the art. Pharmaceutically acceptable carriers suitable for use in formulating the pharmaceutical compositions of the invention include any and all solvents, dispersion media, fillers, solid carriers, aqueous solutions, coatings, fungicides, antibacterial agents, isotonic agents commonly used in the pharmaceutical arts. And absorption retardants. The use of such carriers in pharmaceutically active ingredients is known in the art and described, for example, in Remington's Pharmaceutical Sciences, 18th edition, McPublisher, Pennsylvania, USA. Except incompatibility with the active ingredient, any carrier may be used to prepare the pharmaceutical composition of the present invention. Supplementary active ingredients can also be added to the pharmaceutical compositions. The proportion of the active ingredient combined with the pharmaceutically acceptable carrier can be readily determined empirically by those skilled in the art.
본 발명의 약학 조성물은 간 보호가 필요한 동물, 바람직하게는 사람에게 경구 또는 비경구 투여할 수 있다. 간 독성을 일으키는 약물, 예를 들면 아세트아미노펜을 투여하기 전에, 예를 들면 1 주일 전에, 경구 투여하는 것이 바람직하다.The pharmaceutical composition of the present invention can be administered orally or parenterally to an animal, preferably a human, in need of liver protection. It is preferred to administer orally before the drug causing the liver toxicity, for example acetaminophen, for example one week before.
실시예Example
다음은 실시예에 의거하여 본 발명을 일층 상세히 설명하고자 하나, 본 발명이 이들에 의해 한정되는 것은 아니다.The following is intended to explain the present invention in more detail based on examples, but the present invention is not limited thereto.
각 실시예의 결과는 일방향 변수 분석법(one way analysis of variance)를 사용하여 모든 지표의 통계적 유의성을 검증하고 p<0.05를 유의성 한계로 하여 나타내었다.The results of each example were shown using the one way analysis of variance to verify the statistical significance of all indicators and with p <0.05 as the significance limit.
실시예 1Example 1
간 보호 효과의 평가Evaluation of Hepatoprotective Effects
이 실시예는 류코시아니딘의 투여에 의해 제I상 및 제II상 효소들의 활성이 어떻게 변하는가를 보고 이들 효소에 의해서 독성 본체에 의해 유발되는 아세트아미노펜의 독성이 억제되는지를 생체내 시험을 통해 확인하기 위한 것이다. 아세트아미노펜의 독성 감소는, 고용량의 아세트아미노펜 투여에 의해 간 손상이 일어남으로써 혈액 중에 유출되는 혈청 트랜스아미나제, 즉 알라닌 아미노트랜스퍼라제(ALT) 및 아스파테이트 아미노트랜스퍼라제(AST) 효소의 활성에 대한, 그리고 그로 인한 간 조직 괴사에 대한 류코시아니딘의 억제 효과인 것으로 간주된다.This example shows how the activities of phase I and II enzymes change by administration of leucocyanidine and through in vivo testing whether these enzymes inhibit the toxicity of acetaminophen induced by the toxic body. It is to confirm. Toxicity reduction of acetaminophen is associated with the activity of serum transaminase (ALT) and aspartate aminotransferase (AST) enzymes that leak into the blood due to liver damage caused by high doses of acetaminophen. And the inhibitory effect of leucocyanidins on resulting liver tissue necrosis.
(1) 동물 처치(1) animal kills
35∼40 g의 숫컷 ICR-마우스에게 7일 동안 류코시아니딘(LC; 50, 100, 150, mg/kg/일) 또는 류코시아니딘을 녹이는 데 사용한 것과 같은 양의 프로필렌 글리콜을 경구로 투여하고, 염수에 녹인 아세트아미노펜(400 mg/kg)을 복강내 투여하였다. 18 시간 후에, 마우스를 디에틸에테르로 마취한 다음, 복대 정맥에서 혈액을 채취하고 간을 절개하였다.35-40 g male ICR-mouse is orally given the same amount of propylene glycol as used to dissolve leucocyanidine (LC; 50, 100, 150, mg / kg / day) or leucocyanidine for 7 days. And acetaminophen (400 mg / kg) dissolved in saline was administered intraperitoneally. After 18 hours, mice were anesthetized with diethyl ether, and blood was drawn from the abdominal vein and the liver was dissected.
(2) 알라닌 아미노트랜스퍼라제(sALT)(2) Alanine Aminotransferase (sALT)
전혈을 실온에서 30분 동안 방치하고, 4℃에서, 3,000 rpm으로 10분 동안 원심 분리하여 혈청을 분리하였다. 혈청에서의 ALT 활성은 ALT 시약(시그마 케미칼 코포레이션 제품)을 사용하였다.Whole blood was left at room temperature for 30 minutes, and at 4 ° C., centrifuged at 3,000 rpm for 10 minutes to separate serum. ALT activity in serum was used ALT reagent (Sigma Chemical Corporation).
(3) 조직 병리학적 검사(3) histopathological examination
간의 파라핀 섹션을 중성 10% 포르말린으로 고정시킨 후, 헤마톡실린과 에오신(HE)으로 염색하였다. 간 절편은 보통 광학 현미경으로 분석하였다.Paraffin sections of the liver were fixed with neutral 10% formalin and then stained with hematoxylin and eosin (HE). Liver sections were usually analyzed by light microscopy.
결과 - 아세트아미노펜 유도 간 독성 및 사망률에 대한 보호 효과Results-Protective effect on acetaminophen-induced liver toxicity and mortality
(1) 사망율(1) mortality
마우스에 7 일간 LC를 전처리하고 8 일째에 아세트아미노펜을 400 mg/kg 복강내 주사하고, 아세트아미노펜 투여 후 18 시간 동안 사망률을 관찰한 결과, 아세트아미노펜 단독 투여군, LC 50, 100, 150 mg/kg 전처리군에 있어서의 사망률은 하기 표 1에 나타낸 바와 같았다.Mice were pretreated with LC for 7 days and 400 mg / kg intraperitoneal injection of acetaminophen on day 8, and mortality was observed for 18 hours after acetaminophen administration, and acetaminophen alone, LC 50, 100, 150 mg / kg Mortality in the pretreatment group was as shown in Table 1 below.
상기 표에서 알 수 있는 바와 같이, 아세트아미노펜의 독성으로 인한 사망률은 LC 용량 의존적으로 감소함을 확인할 수 있다.As can be seen from the table, it can be seen that the mortality due to the toxicity of acetaminophen decreases in a LC dose dependent manner.
(2) 간 손상(2) liver damage
마우스에 아세트아미노펜을 투여하고 간 조직을 현미경하에서 관찰하여, 간 손상 정도를 등급 1(도 1c)에서 등급 4(도 1d)까지의 스코어링 시스템을 사용하여 나타내었다. 도 1에 예시되어 있는 현미경 사진으로부터 아세트아미노펜 투여에 의한 간괴사 상태를 정상 간과 비교해 볼 수 있다. 정상 간은 등급 0(도 1a)로 나타내었다. 각 군 10마리에 대해 시험한 결과, 각 등급에 해당하는 동물의 수는 하기 표 2에 나타낸 바와 같았다.Mice were administered acetaminophen and liver tissue was observed under a microscope, and the extent of liver damage was shown using a scoring system from grade 1 (FIG. 1C) to grade 4 (FIG. 1D). From the micrograph shown in FIG. 1, hepatic necrosis by acetaminophen administration can be compared with normal liver. Normal livers are shown as grade 0 (FIG. 1A). As a result of testing for 10 groups, the number of animals corresponding to each grade was as shown in Table 2 below.
상기 표에서 알 수 있는 바와 같이, 아세트아미노펜 단독 투여군의 70%가 등급 4의 심각한 괴사를 나타내었고, LC 100, 150 mg/kg 투여군에서는 60%, 20%의 등급 3 또는 4의 괴사를 나타내었으며, 150 mg/kg 투여군에서는 30%가 간 괴사를 전혀 나타내지 않았다. 이러한 결과로부터 LC 용량 의존적으로 간 괴사가 억제됨을 알 수 있다.As can be seen from the table, 70% of acetaminophen alone group showed severe necrosis of grade 4, and LC 100, 150 mg / kg group showed 60%, 20% grade 3 or 4 necrosis. , 30% showed no liver necrosis in the 150 mg / kg group. From these results, it can be seen that liver necrosis is suppressed in LC dose-dependent manner.
(3) 혈청 ALT 효소 활성(3) serum ALT enzyme activity
각 시험군의 혈청 중의 ALT 활성은 하기 표 3에 나타낸 바와 같았다.ALT activity in serum of each test group was as shown in Table 3 below.
상기 표에서 알 수 있는 바와 같이, 아세트아미노펜 단독 투여군에 있어서는정상군과 비교하여 혈중 ALT 활성이 현저히 증가하였으나 대개는 사망하였으며, LC 투여군 중에서는 150 mg/kg/일 투여군에 있어 현저한 간 독성 억제 효과를 나타내었다.As can be seen from the above table, in the acetaminophen alone group, blood ALT activity was significantly increased in comparison with the normal group, but most of them died. In the LC-administered group, a significant inhibitory effect on liver toxicity was observed in the 150 mg / kg / day-administered group. Indicated.
실시예 2Example 2
효소 활성에 대한 류코시아니딘의 효과Effect of Leucocyanidins on Enzyme Activity
이 실시예에서는 류코시아니딘 투여에 의한 제I상, 제II상 대사 효소들의 활성 변화를 봄으로써 아세토아미노펜 이외의, 이들 효소에 의해 독성 본체로 대사되는 간 독성 물질에 대한 억제 효과를 알아 보고자 한다.In this example, the inhibitory effect on the hepatotoxic substances metabolized to the toxic body by these enzymes other than acetoaminophen by looking at the activity changes of the Phase I and II metabolizing enzymes by leucocyanidine administration do.
(1) 동물 처치(1) animal kills
200∼250 g의 수컷 SD-래트에게 7일 동안 류코시아니딘(LC; 50, 100 mg/kg) 또는 류코시아니딘을 녹이는 데 사용한 것과 같은 양의 프로필렌 글리콜을 경구 투여하였다. 24 시간 후에 래트를 펜토바비탈(50 mg/kg, 복강 투여)로 마취하고 방혈사시켰다.200-250 g of male SD-rat were orally administered the same amount of propylene glycol as was used to dissolve leucocyanidine (LC; 50, 100 mg / kg) or leucocyanidine for 7 days. After 24 hours rats were anesthetized with pentobarbital (50 mg / kg, intraperitoneal) and bled to death.
(2) 간 시토솔과 마이크로솜의 분리(2) Separation of liver cytosol and microsomes
복대 정맥으로 혈액을 제거한 후, 얼음 냉각시킨 0.9% 염수로 세척하고 절개하여 무게를 측정하였다. 간 마이크로솜과 시토솔은 다음과 같이 준비하였다. 일정 분량의 간을 1 mM EDTA를 함유하는 차가운 0.1 M 트리스-KCI 완충액(pH 7.4)로 균질화시켰다. 균등액을 40분 동안 10,000 ×g으로 원심 분리하고 상등액은 60분 동안 105,000 ×g으로 초원심 분리하였다. 상등액은 시토솔 효소의 분획으로 사용하였다. 침전물은 균질화할 때 사용한 완충액에 재현탁시킨 후 다시 초원심 분리하였다. 상등액을 제거한 후, 50 mM 트리스-완충액(1 mM EDTA, 20% 글리세롤, pH 7.4) 또는 0.1 M 인산칼슘 완충액(20% 글리세롤, pH 7.4)에 침전물을 현탁시켰다. 모든 원심 분리 과정은 4℃에서 수행하였으며, 모든 샘플은 측정할 때까지 -70℃로 보관하였다.Blood was removed from the abdominal vein, then washed with ice-cold 0.9% saline and incised to weigh. Liver microsomes and cytosol were prepared as follows. A portion of liver was homogenized with cold 0.1 M Tris-KCI buffer (pH 7.4) containing 1 mM EDTA. The homogenate was centrifuged at 10,000 × g for 40 minutes and the supernatant was ultracentrifuged at 105,000 × g for 60 minutes. The supernatant was used as a fraction of cytosol enzyme. The precipitate was resuspended in the buffer used for homogenization and then ultracentrifuged again. After removing the supernatant, the precipitate was suspended in 50 mM Tris-buffer (1 mM EDTA, 20% glycerol, pH 7.4) or 0.1 M calcium phosphate buffer (20% glycerol, pH 7.4). All centrifugation procedures were performed at 4 ° C. and all samples were stored at −70 ° C. until measurement.
(3) 효소 측정법(3) enzyme measurement method
(i) 에톡시레소루핀 0-탈알킬화제(i) Ethoxyresorupine 0-Dealkylating Agent
에톡시레소루핀 O-탈알킬화제(P450 1A1) 활성은 루벳 등의 문헌[Lubet, R. A., Mayer, R. T., Cameron, J. W., Nims, R. W., Burke, M. S., Wolfe, T. 및 Guengerich, F. P.: Dealkylation of pentoxyresorufin: a raped and sensitive assay for measuring induction of cytochrome(s) P-450 by phenobarbital and other xenobiotics in rat. Arch. Biochem. Biophys. 238, 43-48, 1985]에 기재된 방법에 따라 레소루핀의 생성량을 형광 측정법으로 측정하였다. 반응 혼합물은 5 mM 트리스-HCl(pH 8.4), 5 mM MgCl2, 0.5 mM NADP, 7.5 mM DL-이소시트르산, 이소시트르산 탈수소화제 1 유닛, 1 mg 마이크로솜 단백질로 만들었다. 잘 흔들어 주면서 37℃에서 5분 동안 예비 배양한 후, 5 μM 7-에톡시레소루핀을 첨가하고 잘 흔들어 주면서 37℃에서 10분 동안 배양하였다. 5% ZnSO4와 포화 수산화바륨을 첨가하여 반응을 종료시켰다. 이어서 혼합물을 4℃에서 3,000×g으로 10분 동안 원심 분리하였다. 제단백 상등액에 0.5 M 글리신-NaOH(pH 8.5) 2배 용량을 첨가하였다. 4 내지 5분 동안 형광의 증가를 기록하였다(여기 파장=535 nm, 방출 파장=582 nm).효소 활성은 레소루핀 표준 곡선과 비교하여 측정하였다.Ethoxyresorufine O-dealkylating agent (P450 1A1) activity is described by Rubet et al., Lubet, RA, Mayer, RT, Cameron, JW, Nims, RW, Burke, MS, Wolfe, T. and Guengerich, FP: Dealkylation of pentoxyresorufin: a raped and sensitive assay for measuring induction of cytochrome (s) P-450 by phenobarbital and other xenobiotics in rat. Arch. Biochem. Biophys. 238, 43-48, 1985] was determined by the fluorescence measurement of the amount of lesorupine produced. The reaction mixture was made with 5 mM Tris-HCl (pH 8.4), 5 mM MgCl 2 , 0.5 mM NADP, 7.5 mM DL-isocitric acid, 1 unit of isocitric acid dehydrogenator, 1 mg microsome protein. After pre-incubation for 5 minutes at 37 ℃ shaking well, 5 μM 7-ethoxy resorphin was added and incubated for 10 minutes at 37 ℃ shaking well. The reaction was terminated by addition of 5% ZnSO 4 and saturated barium hydroxide. The mixture was then centrifuged at 4 ° C. at 3,000 × g for 10 minutes. Two-fold doses of 0.5 M glycine-NaOH (pH 8.5) were added to the algal supernatant. The increase in fluorescence was recorded for 4-5 minutes (excitation wavelength = 535 nm, emission wavelength = 582 nm). Enzyme activity was measured compared to the resorphin standard curve.
(ii) 메톡시레소루핀 O-탈알킬화제 및 펜톡시레소루핀 O-탈알킬화제(ii) Methoxyresorufine O-Dealkylating Agent and Penthoxy Resorphin O-Dealkylating Agent
메톡시레소루핀 O-탈알킬화제(P450 1A2)와 펜톡시레소루핀 O-탈알킬화제(P450 1B1) 활성은, 기질 농도를 메톡시레소루핀 5 μM과 펜톡시레소루핀 10 μM로 한 것을 제외하고는, 에톡시레소루핀 O-탈알킬화제 분석에서 설명한 것과 동일한 방법으로 측정하였다.The methoxy resolupine O-dealkylating agent (P450 1A2) and pentoxy resorphin O-dealkylating agent (P450 1B1) activity are the same except that the substrate concentration is 5 μM of methoxy resolupine and 10 μM of pentoxyresolupine. , Was measured in the same manner as described in the ethoxyresorufine O-dealkylating agent analysis.
(iii) N-니트로소디메틸아민 N-탈메틸화제(iii) N-nitrosodimethylamine N-demethylating agent
N-니트로소디메틸아민 N-탈메틸화제(P450 2E1) 활성은 손(Sohn) 등의 문헌[Sohn, O,S., Fiala, E. S., Puz, C., Hamilton, S. R, 및 Williams, G. M.: Enhancement of rat liver microsomal metabolism of azoxymethane to methylazoxymethanol by chronic ethanol administration: similarity to the microsomal metabolism of N-nitrosomethylamine,Cancer Res, 47, 3123-3129,1987]과 투(Tu)와 양(Yang)의 문헌[Tu, Y. Y., 및 Yang, C. S.: High-affinity nitrosamine dealkylase system in rat liver microsomes and its induction by fasting.Cancer Res. 43, 623-629, 1983]에 기재된 방법에 의해서 N-니트로소디메틸아민으로부터 포름알데히드의 생성량을 자외선 흡광 광도법으로 측정하였다. 배양 혼합물은 NADPH-생성계(3.5 mM 글루코스 글루코스-6-포스페이트, 1.5 mM NADP, 글루코스-6-포스페이트 탈수소화제 5 유닛과 3.5 mM MgCl2), 1 mM N-니트로소디메틸아민과 0.1 M 포스페이트 완충액(pH 7.4) 1 ml에 혼탁시킨 2 mg마이크로솜 단백질로 만들었다. 잘 흔들어 주면서 10분 동안 37℃에서 혼합액을 배양한 후, 20% 트리클로로아세트산(TCA) 0.5 ml를 첨가하여 반응을 종료시키고 원심 분리하였다. TCA 상등액 1 ml에 Nash 시약(38.8 mM 아세틸아세톤, 0.6% (v/v) 아세트산에 용해시킨 4 M 아세트산암모늄) 0.4 ml를 첨가하였다. 37℃에서 60분 동안 발색되었고 흡광도는 405 nm에서 측정하였다. 효소 활성은 포름알데히드 표준 곡선과 비교하여 측정하였다.N-nitrosodimethylamine N-demethylating agent (P450 2E1) activity is described by Sohn et al., Sohn, O, S., Fiala, ES, Puz, C., Hamilton, S. R, and Williams, GM: Enhancement of rat liver microsomal metabolism of azoxymethane to methylazoxymethanol by chronic ethanol administration: similarity to the microsomal metabolism of N-nitrosomethylamine, Cancer Res , 47, 3123-3129,1987] and Tu and Yang Tu, YY, and Yang, CS: High-affinity nitrosamine dealkylase system in rat liver microsomes and its induction by fasting. Cancer Res . 43, 623-629, 1983], the amount of formaldehyde produced from N-nitrosodimethylamine was measured by ultraviolet absorption photometry. The culture mixture was NADPH-producing system (3.5 mM glucose glucose-6-phosphate, 1.5 mM NADP, 5 units of glucose-6-phosphate dehydrogenating agent and 3.5 mM MgCl 2 ), 1 mM N-nitrosodimethylamine and 0.1 M phosphate buffer. (pH 7.4) made up to 2 mg microsomal protein turbid in 1 ml. The mixture was incubated at 37 ° C. for 10 minutes with shaking, and 0.5 ml of 20% trichloroacetic acid (TCA) was added to terminate the reaction and centrifuged. To 1 ml of TCA supernatant was added 0.4 ml of Nash reagent (38.8 mM acetylacetone, 4 M ammonium acetate dissolved in 0.6% (v / v) acetic acid). Color development at 37 ° C. for 60 minutes and absorbance were measured at 405 nm. Enzyme activity was measured compared to the formaldehyde standard curve.
(iv) 에리트로마이신 N-탈메틸화제(iv) erythromycin N-demethylating agent
에리트로마이신 N-탈메틸화제(P450 3A4) 활성은, 포름알데히드를 포획하도록 4 mM 세미카르바지드를 반응 혼합물에 첨가하고, 배양 시간을 30분으로 증가시키며 기질로서 1 mM 에리트로마이신을 사용한 것을 제외하고는 N-니트로소디메틸아민 N-탈메틸화제 측정법과 동일한 방법으로 측정하였다.Erythromycin N-demethylating agent (P450 3A4) activity, except that 4 mM semicarbazide was added to the reaction mixture to capture formaldehyde, the incubation time was increased to 30 minutes and 1 mM erythromycin was used as the substrate. And it was measured by the same method as the N-nitrosodimethylamine N-demethylating agent measuring method.
(v) 글루타치온 S-트랜스퍼라제(v) glutathione S-transferase
시토솔에서의 글루타치온 S-트랜스퍼라제 (GST) 활성은 하이비그(Hibig) 등의 문헌[Habig, W. H., Pabst, M. J. 및 Jakoby, W. B.: Glutathion S-Trans ferases: The first enzymatic step in mercapturic acid formation.J. Biol. Chem.249(22), 7130-7139, 1974]에 기재된 방법으로 측정하였다. 반응 혼합물은 0.1 M 인산칼륨 완충액(pH 6.5) 2 ml에 1 mM GSH와 1 mM 1-클로로-2,4-디니트로벤젠(CDNB)로 만들었다. 반응은 10 μg 시토솔 단백질을 첨가하여 개시하고, CDNB-GSH 포합체의 형성으로 인한 340 nm에서의 증가를 4분 동안 기록하였다. 활성은9.6 mM-1cm-1의 흡광 계수를 이용하여 계산하였다. 시토솔 단백질 없이 측정한 백그라운드 활성은 각각의 수치에서 공제하였다.Glutathione S-transferase (GST) activity in cytosol is described by Hibig et al., Habig, WH, Pabst, MJ and Jakoby, WB: Glutathion S-Trans ferases: The first enzymatic step in mercapturic acid formation. J. Biol. Chem. 249 (22), 7130-7139, 1974]. The reaction mixture was made with 1 mM GSH and 1 mM 1-chloro-2,4-dinitrobenzene (CDNB) in 2 ml of 0.1 M potassium phosphate buffer (pH 6.5). The reaction was initiated by the addition of 10 μg cytosolic protein and the increase at 340 nm due to the formation of the CDNB-GSH conjugate was recorded for 4 minutes. Activity was calculated using an extinction coefficient of 9.6 mM −1 cm −1 . Background activity measured without cytosolic protein was subtracted from each value.
(vi) 페놀 설포트랜스퍼라제(vi) phenol sulfotransferases
페놀 설포트랜스퍼라제 (PST) 활성은 세쿠라(Sekura)와 재코비(Jakoby)의 문헌[Sekura, R. D. 및 Jakoby, W. B,: Phenol sulfotransferases.J. Biol. Chem.254(13), 5658-5663, 1979]에 기재되어 있는 방법을 약간 변형하여 비색 방법으로 측정하였다. 반응 혼합물은 0.4 ml를 총량으로 하여 0.25 M 인산나트륨 완충액(pH 7.4), 0.25 Mβ-나프톨, 5% (v/v) 아세톤, 5 mM 2-머캅토에탄올과 0.2 mM PAPS를 함유하게 하였다. 반응은 시토솔 단백질을 첨가하여 개시한다. 잘 흔들어 주면서 37℃에서 30분 동안 배양한 후, 메틸 블루 시약(증류수 1L에 메틸렌 블루 250 mg, 무수황산나트륨 50 g과 c-H2SO410 ml 함유) 0.5 ml와 클로로포름 3 ml를 첨가하여 반응을 종료시켰다. 두개의 상을 20초 동안 소용돌이 혼합 방식으로 강하게 섞어주고, 4℃에서 2,000×g으로 10분 동안 원심 분리하였다. 클로로포름 층은 무수 황산나트륨 50 내지 100 mg이 들어있는 또 다른 튜브로 옮겼다. 흡광도는 653 nm에서 측정하였으며 β-황산나프틸을 표준 물질로 사용하였다.Phenol sulfotransferase (PST) activity is described by Sekura and Jakoby in Sekura, RD and Jakoby, W. B ,: Phenol sulfotransferases. J. Biol. Chem. 254 (13), 5658-5663, 1979] was slightly modified and measured by the colorimetric method. The reaction mixture was made up to 0.4 ml in total to contain 0.25 M sodium phosphate buffer (pH 7.4), 0.25 Mβ-naphthol, 5% (v / v) acetone, 5 mM 2-mercaptoethanol and 0.2 mM PAPS. The reaction is initiated by the addition of cytosolic protein. After incubation at 37 ° C for 30 minutes with shaking, 0.5 ml of methyl blue reagent (250 ml of methylene blue, 50 g of anhydrous sodium sulfate and 10 ml of cH 2 SO 4 ) was added to 1 L of distilled water and 3 ml of chloroform to terminate the reaction. I was. The two phases were vigorously mixed by vortex mixing for 20 seconds and centrifuged at 2,000 × g for 10 minutes at 4 ° C. The chloroform layer was transferred to another tube containing 50-100 mg of anhydrous sodium sulfate. Absorbance was measured at 653 nm and β-naphthyl sulfate was used as a standard material.
(vii) 단백질 측정(vii) protein measurement
단백질은 소 혈청 알부민(BSA)를 표준 물질로 사용하여 로우리(Lowry) 등의 문헌[Lowry, O. H., Rosebrough, N. J., Farr, A. L. 및 Randall, R. T: Protein measurment with the folin phenol reagent.J. Biol. Chem.193. 265-275, 1951]에 기재된 방법으로 측정하였다.Proteins were prepared using Low Serum Albumin (BSA) as a standard, Lowry et al., Lowry, OH, Rosebrough, NJ, Farr, AL and Randall, R. T: Protein measurment with the folin phenol reagent. J. Biol. Chem. 193. 265-275, 1951].
결과result
(1) 제I상 대사 효소에 미치는 류코시아니딘의 영향(1) Effect of Leucocyanidins on Phase I Metabolic Enzymes
LC를 7일 동안 50, 100 mg/kg 용량으로 경구 투여한 흰쥐의 간 마이크로솜 분획을 분리하여 치토크롬 P450 효소들의 활성 변화를 관찰한 결과, 도 2, 도 3 및 도 4에서 알 수 있는 바와 같이, 100 mg/kg 투여군에 있어서는 P450 1A1, 1A2, 2B1의 활성이 정상 대조군에 비해 각각 55.7%, 44.5%, 56.1%로 현저히 저하된 것으로 나타났다. 50 mg/kg 투여군에 있어서는 P450 1A1, 2B1의 활성은 약간 저하되었으나 통계적 유의성은 없었다.Hepatic microsomal fractions of rats orally administered with LC at 50, 100 mg / kg dose for 7 days were isolated and observed for changes in activity of the chitochrome P450 enzymes, as shown in FIGS. 2, 3 and 4. Likewise, the P450 1A1, 1A2, 2B1 activity was significantly reduced to 55.7%, 44.5% and 56.1%, respectively, in the 100 mg / kg administration group. In the 50 mg / kg administration group, the activity of P450 1A1 and 2B1 decreased slightly, but there was no statistical significance.
또 다른 치토크롬 P450 효소인 P450 3A4의 경우는, 도 5 및 도 6에서 알 수 있는 바와 같이 50, 100 mg/kg 투여군의 경우 정상군의 84.0%, 77.9%로 저하되었으며, P450 2E1에는 영향을 주지 않았다.As shown in FIGS. 5 and 6, another chitochrome P450 enzyme, P450 3A4, was reduced to 84.0% and 77.9% of the normal group in the 50 and 100 mg / kg administration groups. Did not give.
도 7에서 알 수 있는 바와 같이 치토크롬 P450 총량에는 변화가 없었는데, 이것은 LC 투여에 의해 효소 활성 자체가 영향을 받는다는 것을 의미하는 것이다.As can be seen in Figure 7, there was no change in the total amount of chitochrome P450, which means that the enzyme activity itself is affected by LC administration.
(2) 제II상 대사 효소에 미치는 영향(2) Effect on phase II metabolic enzyme
LC를 50, 100 mg/kg 용량으로 7일간 경구로 예비 투여한 흰쥐 마이크로솜에 대해 제II상 대사 효소인 포합 반응 관련 효소들의 활성을 측정한 결과, 도 8 및 도 9에서 알 수 있는 바와 같이, GST 활성은 정상 대조군의 각각 111.9%, 117.3%로 현저하게 증가되었으며, PST도 100 mg/kg 투여군에 있어 118.0%로 증가하였다.As shown in FIGS. 8 and 9, the activity of the enzymatic reaction associated with the phase II metabolic enzyme was measured on the rat microsomes pretreated orally with LC at 50, 100 mg / kg for 7 days. , GST activity was significantly increased to 111.9% and 117.3% of the normal control, respectively, PST also increased to 118.0% in the 100 mg / kg administration group.
류코시아니딘은 아세트아미노펜의 독성 본체를 생성시키는 효소인 치토크롬 P450 1A2 효소 활성을 현저하게 억제하며 빠른 시간내 배설되도록 도와주는 제II상 대사 효소 GST, PST 등의 활성을 높여줌으로써 간 보호 효과를 나타내는 것으로 확인되었다. 또한, 류코시아니딘은 아세트아미노펜 뿐만 아니라 하기 표 4에 나타낸 치토크롬 P450, 1A1, 1A2, 2B1, 3A4에 의해 대사되어 독성을 나타내는 다른 모든 물질에 대해서도 독성 억제(경감) 효과가 있으며, 제II상 대사 효소 중 PST, GST 등에 의해 배설 속도가 빨라지는 모든 물질에 대해서도 독성 억제(경감) 효과를 기대할 수 있다.Leucocyanidin significantly inhibits the activity of chitochrome P450 1A2, an enzyme that produces the toxic body of acetaminophen, and increases the activity of the Phase II metabolic enzymes GST and PST, which help to be excreted in a short time. It was confirmed to represent. In addition, leucocyanidine has a toxicity inhibitory (mitigating) effect on not only acetaminophen but also all other substances metabolized by chitochrome P450, 1A1, 1A2, 2B1, and 3A4 shown in Table 4 below and exhibiting toxicity. Among all metabolizing enzymes, PST, GST, etc. can be expected to suppress the toxicity (reduction) effect also for the excretion speed is faster.
이상은 특정 실시예에 의거하여 본 발명을 설명하였으나, 이들은 설명을 목적으로 예시한 것에 불과하며, 본 발명은 청구 범위에 한정된 발명의 범위 내에서 다양하게 변경 및 수정 가능함은 당업자들에게 자명한 것이다.Although the above has been described the present invention based on the specific embodiments, these are only for illustrative purposes, the present invention will be apparent to those skilled in the art that various changes and modifications within the scope of the invention as defined by the claims. .
Claims (6)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR10-2000-0063536A KR100408107B1 (en) | 2000-10-27 | 2000-10-27 | Pharmaceutical compositions for protecting liver comprising leucocyanidin |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR10-2000-0063536A KR100408107B1 (en) | 2000-10-27 | 2000-10-27 | Pharmaceutical compositions for protecting liver comprising leucocyanidin |
Publications (2)
Publication Number | Publication Date |
---|---|
KR20020032837A KR20020032837A (en) | 2002-05-04 |
KR100408107B1 true KR100408107B1 (en) | 2003-12-01 |
Family
ID=19695811
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
KR10-2000-0063536A KR100408107B1 (en) | 2000-10-27 | 2000-10-27 | Pharmaceutical compositions for protecting liver comprising leucocyanidin |
Country Status (1)
Country | Link |
---|---|
KR (1) | KR100408107B1 (en) |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4094969A (en) * | 1973-10-29 | 1978-06-13 | Sandoz, Inc. | Pesticide compositions stabilized with sulfonated catechin/leucocyanidin copolymer and method of using same |
US5474757A (en) * | 1992-10-16 | 1995-12-12 | Rutgers University | Prevention of acetaminophen overdose toxicity with organosulfur compounds |
KR19980017914A (en) * | 1996-08-31 | 1998-06-05 | 김낙두 | New Soy Protectors |
KR19980703214A (en) * | 1995-03-24 | 1998-10-15 | 벡 제임스 엘 | How to treat or prevent a nonviral bacterial infection |
-
2000
- 2000-10-27 KR KR10-2000-0063536A patent/KR100408107B1/en not_active IP Right Cessation
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4094969A (en) * | 1973-10-29 | 1978-06-13 | Sandoz, Inc. | Pesticide compositions stabilized with sulfonated catechin/leucocyanidin copolymer and method of using same |
US5474757A (en) * | 1992-10-16 | 1995-12-12 | Rutgers University | Prevention of acetaminophen overdose toxicity with organosulfur compounds |
KR19980703214A (en) * | 1995-03-24 | 1998-10-15 | 벡 제임스 엘 | How to treat or prevent a nonviral bacterial infection |
KR19980017914A (en) * | 1996-08-31 | 1998-06-05 | 김낙두 | New Soy Protectors |
Also Published As
Publication number | Publication date |
---|---|
KR20020032837A (en) | 2002-05-04 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Jollow et al. | Acetaminophen-induced hepatic necrosis: VI. Metabolic disposition of toxic and nontoxic doses of acetaminophen | |
Reid et al. | Metabolism and binding of aromatic hydrocarbons in the lung: relationship to experimental bronchiolar necrosis | |
Mitchell et al. | Metabolic activation of drugs to toxic substances | |
French et al. | Effect of ethanol on cytochrome P450 2E1 (CYP2E1), lipid peroxidation, and serum protein adduct formation in relation to liver pathology pathogenesis | |
Conti et al. | Protective activity of silipide on liver damage in rodents | |
Thompson et al. | Sex and strain differences in response to ***e | |
Gessner et al. | Elevated pentose cycle and glucuronyltransferase in daunorubicin-resistant P388 cells | |
Siemens et al. | Effect of cannabis on pentobarbital-induced sleeping time and pentobarbital metabolism in the rat | |
Sumioka et al. | Mechanisms of protection by S-allylmercaptocysteine against acetaminophen-induced liver injury in mice | |
Orrego et al. | Protection by propylthiouracil against carbon tetrachloride-induced liver damage | |
Hwang et al. | Production of membrane whorls in rat liver by some inhibitors of protein synthesis | |
Younes et al. | Effect of deferrioxamine and diethyldithiocarbamate on paracetamol‐induced hepato‐and nephrotoxicity. The role of lipid peroxidation | |
KR100408107B1 (en) | Pharmaceutical compositions for protecting liver comprising leucocyanidin | |
Jollow et al. | Biochemical aspects of toxic metabolites: Formation, detoxication, and covalent binding | |
Lash et al. | S-(1, 2-dichlorovinyl)-L-homocysteine-induced cytotoxicity in isolated rat kidney cells | |
Raheja et al. | Hepatotoxicity and metabolism of acetaminophen in male and female rats | |
Madan et al. | Characterization of diethyldithiocarbamate methyl ester sulfine as an intermediate in the bioactivation of disulfiram. | |
Tyce | Metabolism of 3, 4-dihydroxyphenylalanine by isolated perfused rat liver | |
Wojcicki et al. | The effect of cernitins on galactosamine-induced hepatic injury in rat | |
Shivashangari et al. | Evaluation of the protective efficacy of Asteracantha longifolia on acetaminophen-induced liver damage in rats | |
Lim et al. | Protective effects of acetylbergenin against carbon tetrachloride-induced hepatotoxicity in rats | |
Chakrabarti et al. | In vivo nephrotoxic action of an isomeric mixture of S-(1-phenyl-2-hydroxyethyl) glutathione and S (2-phenyl-2-hydroxyethyl) glutathione in Ficher-344 rats | |
Eriksson et al. | 3-Aminobenzamide: effects on cytochrome P450-dependent metabolism of chemicals and on the toxicity of dichlobenil in the olfactory mucosa | |
Cravedi et al. | Chloramphenicol oxamylethanolamine as an end product of chloramphenicol metabolism in rat and humans: evidence for the formation of a phospholipid adduct | |
Darbar et al. | Antioxidant and hepatoprotective effect of Andrographis paniculata leaf extract on diclofenac induced hepatotoxicity in rats |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A201 | Request for examination | ||
N231 | Notification of change of applicant | ||
E902 | Notification of reason for refusal | ||
E701 | Decision to grant or registration of patent right | ||
GRNT | Written decision to grant | ||
FPAY | Annual fee payment |
Payment date: 20111215 Year of fee payment: 9 |
|
FPAY | Annual fee payment |
Payment date: 20121221 Year of fee payment: 10 |
|
LAPS | Lapse due to unpaid annual fee |