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In Vitro to in Vivo Extrapolation for Drug-Induced Liver Injury Using a Pair Ranking Method

In Vitro to in Vivo Extrapolation for Drug-Induced Liver Injury Using a Pair Ranking Method

Liu et al.: In Vitro to In Vivo Extrapolation for Drug-Induced Injury Using a Pair Ranking Method

Supplementary Data

Tab. S1: The standard study protocol of TG-GATEs

Assays Species Tissues Number of Treatment Dose/ Abbreviation compounds* concentration** In vitro Human primary 120 2, 8, 24 h Low, middle, InVitro_Human hepatocytes high (1:5:25) Sprague-Dawley primary 131 2, 8, 24 h Low, middle, InVitro_Rat rat (6 weeks old) hepatocytes high (1:5:25) In vivo Sprague-Dawley liver 131 24 h after Low, middle, InVivo rat (6 weeks old) the last dose of high repeated (mainly 1:3:10) administration for 3, 7, 14 and 28 days

* There are a total of 170 compounds in the Open TG-GATEs database. In this study, only 131 compounds, which were generated in the first phase of TG-GATEs, were employed. ** For the in vivo assay, the highest dose was chosen to match the level that induces the minimum toxic effect in a 4-week toxicity study. Then, the ratio of the low, middle and high dose levels was set as 1:3:10. For the in vitro assay, the highest concentration was defined as the dose level generating an 80-90% relative survival ratio with a ratio of 1:5:25 for the low, middle and high concentration levels.

This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 International license (http://creativecommons.org/ licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium, provided the original work is appropriately cited. doi.org/10.14573/altex.1610201s

ALTEX 34(3), SUPPLEMENTARY DATA S1 Liu et al.

Tab. S2: Drug-induced liver injury endpoints

Categories Number of Compound names compounds

Drug induced liver injury (DILI)

Most DILI concern 46 ; coumarin; ; ethanol; hydroxyzine; tetracycline; vitamin A; ; allyl ; benzbromarone; ; ; chlormadinone; chlormezanone; chlorpheniramine; cimetidine; ciprofloxacin; clofibrate; cyclosporine A; danazol; ethambutol; fluphenazine; griseofulvin; ; hexachlorobenzene; ; ; ; methyldopa; methyltestosterone; moxisylyte; nicotinic acid; ; nitrofurazone; omeprazole; pemoline; phenylanthranilic acid; ; ; rifampicin; simvastatin; ; sulpiride; tamoxifen; ; Xu’s label 47 Acetaminophen; ; allopurinol; ; ; benzbromarone; captopril; chloramphenicol; chlorpheniramine; ciprofloxacin; ; cyclophosphamide; cyclosporine A; danazol; dantrolene; ; ; ethylsuccinate; ethionine; etoposide; fenofibrate; flutamide; ; gemfibrozil; griseofulvin; ; ; labetalol; mefenamic acid; methimazole; ; nicotinic acid; nifedipine; ; ; ; ; phenytoin; quinidine; sulfasalazine; sulindac; tamoxifen; tetracycline; thioacetamide; ticlopidine; trimethadione; vitamin A Sakatis’s label 51 Amitriptyline; tacrine; cimetidine; ranitidine; amiodarone; danazol; labetalol; nimesulide; acetaminophen; diclofenac; flutamide; azathioprine; tamoxifen; cyclophosphamide; erythromycin ethylsuccinate; benzbromarone; nifedipine; imipramine; nicotinic acid; dantrolene; isoniazid; sulindac; ; methyldopa; nitrofurantoin; valproic acid; cyclosporine A; etoposide; phenylbutazone; disulfiram; propylthiouracil; ibuprofen; rifampicin; fenofibrate; furosemide; quinidine; tetracycline; doxorubicin; ciprofloxacin; mefenamic acid; perhexiline; ticlopidine; ; iproniazid; sulfasalazine; allopurinol; phenytoin; carbamazepine; coumarin; ; sulpiride Hepatic failure 24 Acetazolamide; allopurinol; amitriptyline; azathioprine; carbamazepine; ciprofloxacin; dantrolene; diclofenac; disulfiram; doxorubicin; ; ibuprofen; mefenamic acid; omeprazole; propylthiouracil; ranitidine; simvastatin; sulfasalazine; sulindac; terbinafine; tetracycline; ticlopidine; triazolam; valproic acid Other hepatotoxic endpoints Biochemical parameters AST increased 13 Acetaminophen; amiodarone; carboplatin; ciprofloxacin; colchicine; diclofenac; diltiazem; fenofibrate; flutamide; nitrofurantoin; omeprazole; tamoxifen; valproic acid ALT increased 9 Amiodarone; ciprofloxacin; colchicine; diclofenac; fenofibrate; nitrofurantoin; omeprazole; ticlopidine; valproic acid Hepatic increased 8 Acarbose; diclofenac; disopyramide; furosemide; ibuprofen; mefenamic acid; terbinafine; valproic acid Blood bilirubin increased 6 Carboplatin; ciprofloxacin; doxorubicin; fenofibrate; gemfibrozil; tamoxifen Liver injury patterns Cholestasis 7 Captopril; glibenclamide; ibuprofen; nifedipine; sulindac; tamoxifen; thioridazine Hepatocellular injury 16 Acarbose; amiodarone; azathioprine; captopril; ciprofloxacin; colchicine; fluphenazine; isoniazid; methyldopa; omeprazole; phenobarbital; phenytoin; ranitidine; sulfasalazine; terbinafine; valproic acid Hepatobiliary abnormality Cholelithiasis 6 Fenofibrate; gemfibrozil; nicotinic acid; sulindac; tacrine; tamoxifen Foetor hepaticus 7 Amiodarone; ciprofloxacin; methyldopa; omeprazole; ranitidine; terbinafine; valproic acid Hepatomegaly 5 Allopurinol; amiodarone; ciprofloxacin; cyclophosphamide; gentamicin

S2 ALTEX 34(3), SUPPLEMENTARY DATA Liu et al.

Categories Number of Compound names compounds

Jaundice 49 Acarbose; acetazolamide; allopurinol; amitriptyline; captopril; carbamazepine; chlorpropamide; ciprofloxacin; cyclophosphamide; danazol; ; diclofenac; disopyramide; doxorubicin; famotidine; fenofibrate; fluphenazine; flutamide; furosemide; gemfibrozil; glibenclamide; haloperidol; ibuprofen; imipramine; isoniazid; labetalol; mefenamic acid; methimazole; methyldopa; methyltestosterone; nicotinic acid; nifedipine; nitrofurantoin; omeprazole; pemoline; ; propylthiouracil; quinidine; ranitidine; rifampicin; simvastatin; sulfasalazine; sulindac; terbinafine; thioridazine; ticlopidine; ; triazolam; valproic acid cholestatic 21 Acetazolamide; allopurinol; captopril; chlorpropamide; ciprofloxacin; danazol; disopyramide; doxorubicin; famotidine; fluphenazine; flutamide; furosemide; gemfibrozil; glibenclamide; labetalol; methyltestosterone; nitrofurantoin; ranitidine; simvastatin; sulfasalazine; ticlopidine Histologic findings Hyperbilirubinaemia 7 Allopurinol; ciprofloxacin; cyclophosphamide; doxorubicin; isoniazid; nicotinic acid; omeprazole Hepatitis 43 Acarbose; allopurinol; amiodarone; amitriptyline; captopril; carbamazepine; ciprofloxacin; clomipramine; dantrolene; diclofenac; disulfiram; doxorubicin; ethambutol; famotidine; fenofibrate; fluphenazine; flutamide; glibenclamide; ibuprofen; isoniazid; labetalol; mefenamic acid; metformin; methimazole; methyldopa; mexiletine; nicotinic acid; nifedipine; nitrofurantoin; omeprazole; papaverine; pemoline; phenytoin; propylthiouracil; quinidine; ranitidine; rifampicin; simvastatin; sulfasalazine; sulindac; tamoxifen; ticlopidine; valproic acid Hepatic 7 Amiodarone; diclofenac; fenofibrate; papaverine; simvastatin; sulfasalazine; valproic acid Liver disorder 8 Amiodarone; ciprofloxacin; glibenclamide; methyldopa; omeprazole; ranitidine; terbinafine; valproic acid Hepatic function abnormal 33 Acarbose; acetazolamide; amiodarone; azathioprine; carbamazepine; carboplatin; ciprofloxacin; clomipramine; cyclophosphamide; danazol; diclofenac; fenofibrate; fluphenazine; gemfibrozil; glibenclamide; haloperidol; ibuprofen; isoniazid; ketoconazole; methyldopa; mexiletine; nicotinic acid; omeprazole; pemoline; phenytoin; quinidine; rifampicin; simvastatin; sulfasalazine; sulindac; tamoxifen; terbinafine; ticlopidine Steatosis 13 Amitriptyline; colchicine; coumarin; diltiazem; disulfiram; ethanol; ethinylestradiol; hydroxyzine; imipramine; lomustine; methapyrilene; tetracycline; vitamin A Hepatic necrosis 13 Acetazolamide; allopurinol; ciprofloxacin; diclofenac; flutamide; ibuprofen; labetalol; mexiletine; nitrofurantoin; omeprazole; simvastatin; sulfasalazine; ticlopidine Cytolytic hepatitis 10 Acarbose; azathioprine; captopril; ciprofloxacin; colchicine; fluphenazine; isoniazid; phenobarbital; phenytoin; sulfasalazine

ALTEX 34(3), SUPPLEMENTARY DATA S3 Liu et al.

Tab. S3: Compound information

Names Name Abbr. CAS No. Pub CID SMILES code (From PubChem) acarbose ACA 56180-94-0 441184 C[C@@H]1[C@H]([C@@H]([C@H]([C@H](O1)O[C@@H]2[C@H] (O[C@@H]([C@@H]([C@H]2O)O)O[C@@H]3[C@H](O[C@H] ([C@@H]([C@H]3O)O)O)CO)CO)O)O)N[C@H]4C=C([C@@H] ([C@@H]([C@H]4O)O)O)CO acetamidofluorene AAF 9006-42-2 5897 CC(=O)NC1=CC2=C(C=C1)C3=CC=CC=C3C2 acetaminophen APAP 103-90-2 1983 CC(=O)NC1=CC=C(C=C1)O acetazolamide ACZ 59-66-5 1986 CC(=O)NC1=NN=C(S1)S(=O)(=O)N AJM 12/7/4360 20367 CCC1[C@H](N2C3CC1C4C2CC5([C@H]3N(C6=CC=CC=C65)C) [C@@H]4O)O allopurinol APL 315-30-0 2094 C1=C2C(=NC=NC2=O)NN1 allyl alcohol AA 107-18-6 7858 C=CCO amiodarone AM 1951-25-3 2157 CCCCC1=C(C2=CC=CC=C2O1)C(=O)C3=CC(=C(C(=C3)I)OCCN (CC)CC)I amitriptyline AMT 50-48-6 2160 CN(C)CCC=C1C2=CC=CC=C2CCC3=CC=CC=C31 ASA 50-78-2 2244 CC(=O)OC1=CC=CC=C1C(=O)O azathioprine AZP 446-86-6 2265 CN1C=NC(=C1SC2=NC=NC3=C2NC=N3)[N+](=O)[O-] BDZ 20187-55-7 2313 C1=CC=C(C=C1)CN2C3=CC=CC=C3C(=N2)OCC(=O)O benzbromarone BBr 3562-84-3 2333 CCC1=C(C2=CC=CC=C2O1)C(=O)C3=CC(=C(C(=C3)Br)O)Br benziodarone BZD 68-90-6 6237 CCC1=C(C2=CC=CC=C2O1)C(=O)C3=CC(=C(C(=C3)I)O)I bromobenzene BBZ 108-86-1 7961 C1=CC=C(C=C1)Br bromoethylamine BEA 107-09-5 7851 C(CBr)N bucetin BCT 1083-57-4 14130 CCOC1=CC=C(C=C1)NC(=O)CC(C)O caffeine CAF 8/2/1958 2519 CN1C=NC2=C1C(=O)N(C(=O)N2C)C captopril CAP 62571-86-2 44093 C[C@H](CS)C(=O)N1CCC[C@H]1C(=O)O carbamazepine CBZ 298-46-4 2554 C1=CC=C2C(=C1)C=CC3=CC=CC=C3N2C(=O)N carboplatin CBP 41575-94-4 38904 C1CC(C1)(C(=O)O)C(=O)O.N.N.[Pt] cephalothin CLT 58-71-9 5288660 CC1=C(N[C@@H](SC1)[C@@H](C(=O)O)NC(=O)CC2=CC=CS2) C(=O)O chloramphenicol CMP 56-75-7 298 C1=CC(=CC=C1C(C(CO)NC(=O)C(Cl)Cl)O)[N+](=O)[O-] chlormadinone CLM 1961-77-9 16065 CC(=O)[C@]1(CC[C@@H]2C1(CC[C@H]3C2C=C(C4=CC(=O) CCC34C)Cl)C)O chlormezanone CMN 80-77-3 2717 CN1C(S(=O)(=O)CCC1=O)C2=CC=C(C=C2)Cl chlorpheniramine CHL 132-22-9 2725 CN(C)CCC(C1=CC=C(C=C1)Cl)C2=CC=CC=N2 chlorpropamide CPP 94-20-2 2727 CCCNC(=O)NS(=O)(=O)C1=CC=C(C=C1)Cl cimetidine CIM 51481-61-9 2756 CC1=C(N=CN1)CSCCNC(=NC)NC#N ciprofloxacin CPX 85721-33-1 2764 C1CC1N2C=C(C(=O)C3=CC(=C(C=C32)N4CCNCC4)F)C(=O)O cisplatin CSP 15663-27-1 441203 N.N.Cl[Pt+2]Cl clofibrate CFB 637-07-0 2796 CCOC(=O)C(C)(C)OC1=CC=C(C=C1)Cl clomipramine CPM 303-49-1 2801 CN(C)CCCN1C2=CC=CC=C2CCC3=C1C=C(C=C3)Cl colchicine COL 64-86-8 6167 CC(=O)N[C@H]1CCC2=CC(=C(C(=C2C3=CC=C(C(=O)C=C13) OC)OC)OC)OC coumarin CMA 91-64-5 323 C1=CC=C2C(=C1)C=CC(=O)O2

S4 ALTEX 34(3), SUPPLEMENTARY DATA Liu et al.

Names Name Abbr. CAS No. Pub CID SMILES code (From PubChem) cyclophosphamide CPA 6055-19-2 2907 C1CNP(=O)(OC1)N(CCCl)CCCl cyclosporine A CSA 59865-13-3 2909 CCC1C(=O)N(CC(=O)N(C(C(=O)NC(C(=O)N(C(C(=O)NC(C(=O) NC(C(=O)N(C(C(=O)N(C(C(=O)N(C(C(=O)N(C(C(=O)N1)C(C(C) CC=CC)O)C)C(C)C)C)CC(C)C)C)CC(C)C)C)C)C)CC(C)C)C)C(C) C)CC(C)C)C)C danazol DNZ 17230-88-5 28417 C[C@]12CC[C@H]3[C@H]([C@@H]1CC[C@]2(C#C)O) CCC4=CC5=C(C[C@]34C)C=NO5 dantrolene DTL 7261-97-4 6914273 C1C(=O)NC(=O)N1/N=C/C2=CC=C(O2)C3=CC=C(C=C3)[N+](=O) [O-] diazepam DZP 439-14-5 3016 CN1C(=O)CN=C(C2=C1C=CC(=C2)Cl)C3=CC=CC=C3 diclofenac DFNa 15307-86-5 3033 C1=CC=C(C(=C1)CC(=O)O)NC2=C(C=CC=C2Cl)Cl diltiazem DIL 42399-41-7 39186 CC(=O)O[C@@H]1[C@@H](SC2=CC=CC=C2N(C1=O)CCN(C)C) C3=CC=C(C=C3)OC disopyramide DIS 9/5/3737 3114 CC(C)N(CCC(C1=CC=CC=C1)(C2=CC=CC=N2)C(=O)N)C(C)C disulfiram DSF 97-77-8 3117 CCN(CC)C(=S)SSC(=S)N(CC)CC doxorubicin DOX 23214-92-8 31703 C[C@H]1[C@H]([C@H](C[C@@H](O1)O[C@H]2C[C@@] (CC3=C(C4=C(C(=C23)O)C(=O)C5=C(C4=O)C=CC=C5OC)O) (C(=O)CO)O)N)O enalapril ENA 75847-73-3 5362032 CCOC(=O)[C@@H](CCC1=CC=CC=C1)N[C@@H](C)C(=O) N2CCC[C@H]2C(=O)O erythromycin EME 114-07-8 12560 CC[C@@H]1[C@@]([C@@H]([C@H](C(=O)[C@@H] ethylsuccinate (C[C@@]([C@@H]([C@H]([C@@H]([C@H](C(=O)O1)C) O[C@H]2C[C@@]([C@H]([C@@H](O2)C)O)(C)OC)C) O[C@H]3[C@@H]([C@H](C[C@H](O3)C)N(C)C)O)(C)O)C)C)O) (C)O ethambutol EBU 74-55-5 3279 CCC(CO)NCCNC(CC)CO ethanol ETN 64-17-5 702 CCO ethinylestradiol EE 57-63-6 5991 C[C@]12CC[C@H]3[C@H]([C@@H]1CC[C@]2(C#C)O) CCC4=C3C=CC(=C4)O ethionine ET 13073-35-3 25674 CCSCC[C@@H](C(=O)O)N etoposide ETP 33419-42-0 36462 C[C@@H]1OC[C@@H]2[C@@H](O1)[C@@H]([C@H]([C@@H] (O2)O[C@H]3[C@H]4COC(=O)[C@@H]4[C@@H](C5=CC6=C (C=C35)OCO6)C7=CC(=C(C(=C7)OC)O)OC)O)O famotidine FAM 76824-35-6 5702160 C1=C(N=C(S1)N=C(N)N)CSCC/C(=N/S(=O)(=O)N)/N fenofibrate FFB 49562-28-9 3339 CC(C)OC(=O)C(C)(C)OC1=CC=C(C=C1)C(=O)C2=CC=C(C=C2) Cl fluphenazine FP 69-23-8 3372 C1CN(CCN1CCCN2C3=CC=CC=C3SC4=C2C=C(C=C4)C(F)(F)F) CCO flutamide FT 13311-84-7 3397 CC(C)C(=O)NC1=CC(=C(C=C1)[N+](=O)[O-])C(F)(F)F furosemide FUR 54-31-9 3440 C1=COC(=C1)CNC2=CC(=C(C=C2C(=O)O)S(=O)(=O)N)Cl gemfibrozil GFZ 25812-30-0 3463 CC1=CC(=C(C=C1)C)OCCCC(C)(C)C(=O)O gentamicin GMC 1403-66-3 3467 CC(C1CCC(C(O1)OC2C(CC(C(C2O)OC3C(C(C(CO3)(C)O)NC)O) N)N)N)NC glibenclamide GBC 10238-21-8 3488 COC1=C(C=C(C=C1)Cl)C(=O)NCCC2=CC=C(C=C2)S(=O)(=O) NC(=O)NC3CCCCC3 griseofulvin GF 126-07-8 441140 C[C@@H]1CC(=O)C=C([C@]12C(=O)C3=C(O2)C(=C(C=C3OC) OC)Cl)OC

ALTEX 34(3), SUPPLEMENTARY DATA S5 Liu et al.

Names Name Abbr. CAS No. Pub CID SMILES code (From PubChem) haloperidol HPL 52-86-8 3559 C1CN(CCC1(C2=CC=C(C=C2)Cl)O)CCCC(=O)C3=CC=C(C=C3)F hexachlorobenzene HCB 118-74-1 8370 C1(=C(C(=C(C(=C1Cl)Cl)Cl)Cl)Cl)Cl hydroxyzine HYZ 68-88-2 3658 C1CN(CCN1CCOCCO)C(C2=CC=CC=C2)C3=CC=C(C=C3)Cl ibuprofen IBU 15687-27-1 3672 CC(C)CC1=CC=C(C=C1)C(C)C(=O)O imipramine IMI 50-49-7 3696 CN(C)CCCN1C2=CC=CC=C2CCC3=CC=CC=C31 iproniazid IPA 54-92-2 3748 CC(C)NNC(=O)C1=CC=NC=C1 isoniazid INAH 54-85-3 3767 C1=CN=CC=C1C(=O)NN ketoconazole KC 65277-42-1 47576 CC(=O)N1CCN(CC1)C2=CC=C(C=C2)OC[C@@H]3CO[C@@] (O3)(CN4C=CN=C4)C5=C(C=C(C=C5)Cl)Cl labetalol LBT 36894-69-6 3869 CC(CCC1=CC=CC=C1)NCC(C2=CC(=C(C=C2)O)C(=O)N)O lomustine LS 13010-47-4 3950 C1CCC(CC1)NC(=O)N(CCCl)N=O mefenamic acid MEF 61-68-7 4044 CC1=C(C(=CC=C1)NC2=CC=CC=C2C(=O)O)C metformin MFM 657-24-9 4091 CN(C)C(=N)N=C(N)N methapyrilene MP 91-80-5 8667 CN(C)CCN(CC1=CC=CS1)C2=CC=CC=N2.Cl methimazole MTZ 60-56-0 1349907 CN1C=CNC1=S methyldopa MDP 555-30-6 38853 C[C@](CC1=CC(=C(C=C1)O)O)(C(=O)O)N methyltestosterone MTS 58-18-4 6429880 C[C@]1(CCC2C1(CCC3C2CCC4=CC(=O)CCC34C)C)O mexiletine MEX 31828-71-4 4178 CC1=C(C(=CC=C1)C)OCC(C)N moxisylyte MXS 54-32-0 4260 CC1=CC(=C(C=C1OC(=O)C)C(C)C)OCCN(C)C naphthyl isothiocyanate ANIT 551-06-4 11080 C1=CC=C2C(=C1)C=CC=C2N=C=S nicotinic acid NIC 59-67-6 938 C1=CC(=CN=C1)C(=O)O nifedipine NIF 21829-25-4 4485 CC1=C(C(C(=C(N1)C)C(=O)OC)C2=CC=CC=C2[N+](=O)[O-]) C(=O)OC nimesulide NIM 51803-78-2 4495 CS(=O)(=O)NC1=C(C=C(C=C1)[N+](=O)[O-])OC2=CC=CC=C2 nitrofurantoin NFT 67-20-9 5353830 C1C(=O)NC(=O)N1/N=C\C2=CC=C(O2)[N+](=O)[O-] nitrofurazone NFZ 59-87-0 5447130 C1=C(OC(=C1)[N+](=O)[O-])/C=N/NC(=O)N omeprazole OPZ 73590-58-6 4594 CC1=CN=C(C(=C1OC)C)CS(=O)C2=NC3=C(N2)C=C(C=C3)OC papaverine PAP 61-25-6 4680 COC1=C(C=C(C=C1)CC2=NC=CC3=CC(=C(C=C32)OC)OC)OC pemoline PML 2152-34-3 4723 C1=CC=C(C=C1)C2C(=O)N=C(O2)N PEN 52-67-5 5852 CC(C)([C@H](C(=O)O)N)S perhexiline PH 6621-47-2 4746 C1CCC(CC1)C(CC2CCCCN2)C3CCCCC3 phenacetin PCT 62-44-2 4754 CCOC1=CC=C(C=C1)NC(=O)C phenobarbital PB 6/6/1950 4763 CCC1(C(=O)NC(=O)NC1=O)C2=CC=CC=C2 phenylanthranilic acid NPAA 91-40-7 4386 C1=CC=C(C=C1)NC2=CC=CC=C2C(=O)O phenylbutazone PhB 50-33-9 4781 CCCCC1C(=O)N(N(C1=O)C2=CC=CC=C2)C3=CC=CC=C3 phenytoin PHE 57-41-0 1775 C1=CC=C(C=C1)C2(C(=O)NC(=O)N2)C3=CC=CC=C3 promethazine PMZ 60-87-7 4927 CC(CN1C2=CC=CC=C2SC3=CC=CC=C31)N(C)C propylthiouracil PTU 51-52-5 657298 CCCC1=CC(=O)NC(=S)N1 quinidine QND 56-54-2 441074 COC1=CC2=C(C=CN=C2C=C1)[C@@H]([C@H]3C[C@@H] 4CCN3C[C@@H]4C=C)O

S6 ALTEX 34(3), SUPPLEMENTARY DATA Liu et al.

Names Name Abbr. CAS No. Pub CID SMILES code (From PubChem) ranitidine RAN 66357-35-5 3001055 CN/C(=C\[N+](=O)[O-])/NCCSCC1=CC=C(O1)CN(C)C rifampicin RIF 13292-46-1 5360416 C[C@H]1C=CC=C(C(=O)NC\2=C(C3=C(C(=C4C(=C3C(=O)/C2= C/NN5CCN(CC5)C)C(=O)[C@](O4)(OC=C[C@@H]([C@H]([C@H] ([C@@H]([C@@H]([C@@H]([C@H]1O)C)O)C)OC(=O)C)C)OC)C) C)O)O)C simvastatin SST 79902-63-9 6419910 CCC(C)(C)C(=O)O[C@H]1C[C@H](C=C2[C@H]1[C@H]([C@H] (C=C2)C)CCC3C[C@H](CC(=O)O3)O)C sulfasalazine SS 599-79-1 5359476 C1=CC=NC(=C1)NS(=O)(=O)C2=CC=C(C=C2)N/N=C\3/C=CC (=O)C(=C3)C(=O)O sulindac SUL 38194-50-2 1548885 CC\1=C(C2=C(/C1=C/C3=CC=C(C=C3)S(=O)C)C=CC(=C2)F) CC(=O)O sulpiride SLP 15676-16-1 5355 CCN1CCCC1CNC(=O)C2=C(C=CC(=C2)S(=O)(=O)N)OC tacrine TAC 321-64-2 1935 C1CCC2=NC3=CC=CC=C3C(=C2C1)N tamoxifen TMX 10540-29-1 2733526 CC/C(=C(\C1=CC=CC=C1)/C2=CC=C(C=C2)OCCN(C)C)/C3= CC=CC=C3 tannic acid TAN 18483-17-5 16129778 C1=C(C=C(C(=C1O)O)O)C(=O)OC2=CC(=CC(=C2O)O)C(=O) OC[C@@H]3[C@H]([C@@H]([C@H]([C@@H](O3)OC(=O) C4=CC(=C(C(=C4)OC(=O)C5=CC(=C(C(=C5)O)O)O)O)O)OC(=O) C6=CC(=C(C(=C6)OC(=O)C7=CC(=C(C(=C7)O)O)O)O)O)OC(=O) C8=CC(=C(C(=C8)OC(=O)C9=CC(=C(C(=C9)O)O)O)O)O)OC(=O) C1=CC(=C(C(=C1)OC(=O)C1=CC(=C(C(=C1)O)O)O)O)O terbinafine TBF 91161-71-6 1549008 CC(C)(C)C#C/C=C/CN(C)CC1=CC=CC2=CC=CC=C21 tetracycline TC 60-54-8 5280962 C[C@@]1([C@H]2C[C@H]3[C@@H](C(=O)/C(=C(\N)/O)/C(=O) [C@]3(C(=O)C2=C(C4=C1C=CC=C4O)O)O)N(C)C)O theophylline TEO 58-55-9 2153 CN1C2=C(C(=O)N(C1=O)C)NC=N2 thioacetamide TAA 62-55-5 2723949 CC(=S)N thioridazine TRZ 50-52-2 5452 CN1CCCCC1CCN2C3=CC=CC=C3SC4=C2C=C(C=C4)SC ticlopidine TCP 55142-85-3 5472 C1CN(CC2=C1SC=C2)CC3=CC=CC=C3Cl tiopronin TIO 2/2/1953 5483 CC(C(=O)NCC(=O)O)S TLB 64-77-7 5505 CCCCNC(=O)NS(=O)(=O)C1=CC=C(C=C1)C triamterene TRI 396-01-0 5546 C1=CC=C(C=C1)C2=NC3=C(N=C2N)N=C(N=C3N)N triazolam TZM 28911-01-5 5556 CC1=NN=C2N1C3=C(C=C(C=C3)Cl)C(=NC2)C4=CC=CC=C4Cl trimethadione TMD 127-48-0 5576 CC1(C(=O)N(C(=O)O1)C)C valproic acid VPA 99-66-1 3121 CCCC(CCC)C(=O)O vitamin A VA 68-26-8 445354 CC1=C(C(CCC1)(C)C)/C=C/C(=C/C=C/C(=C/CO)/C)/C WY-14643 WY 50892-23-4 5694 CC1=C(C(=CC=C1)NC2=CC(=NC(=N2)SCC(=O)O)Cl)C

ALTEX 34(3), SUPPLEMENTARY DATA S7 Liu et al.

Tab. S4: Compound pairs with chemical similarity more than 0.4*

Drug pairs Chemical Similarity Similarity Similarity Therapeutic DILI concern similarity in in InVivo in categories InVitro_ InVitro_ Rat Human benzbromarone 1.000 0.510 0.560 0.288 M04 vs C01 Most-DILI-Concern vs Most-DILI-Concern vs benziodarone mefenamic acid 0.826 0.290 0.370 0.340 M01 vs NA Less-DILI-Concern vs NA vs phenylanthranilic acid clomipramine 0.806 0.6 0.378 0.373 N06 vs N06 Most-DILI-Concern vs Less-DILI-Concern vs imipramine bucetin vs phenacetin 0.741 0.243 0.383 0.148 N02 vs N02 NA vs NA iproniazid vs isoniazid 0.708 0.183 0.235 0.203 N06 vs J04 Most-DILI-Concern vs Most-DILI-Concern chlorpropamide 0.667 0.283 0.238 0.315 A10 vs A10 Less-DILI-Concern vs Less-DILI-Concern vs tolbutamide clofibratevs fenofibrate 0.656 0.468 0.533 0.313 C10 vs C10 Less-DILI-Concern vs Less-DILI-Concern dantrolene 0.652 0.290 0.168 0.188 M03 vs J01 Most-DILI-Concern vs Most-DILI-Concern vs nitrofurantoin chlormadinone 0.629 0.193 0.233 0.13 G03 vs G03 NA vs Less-DILI-Concern vs methyltestosterone amiodarone 0.549 0.293 0.390 0.178 C01 vs M04 Most-DILI-Concern vs Most-DILI-Concern vs benzbromarone amiodarone 0.549 0.310 0.383 0.340 C01 vs C01 Most-DILI-Concern vs Most-DILI-Concern vs benziodarone acetaminophen 0.538 0.088 0.375 0.305 N02 vs N02 Most-DILI-Concern vs NA vs phenacetin phenobarbital 0.538 0.068 0.205 0.100 N03 vs N03 Less-DILI-Concern vs Most-DILI-Concern vs phenytoin aspirin vs coumarin 0.519 0.120 0.135 0.113 A01 vs NA No-DILI-Concern vs NA diclofenac 0.516 0.23 0.338 0.218 M01 vs NA Most-DILI-Concern vs NA vs phenylanthranilic acid nitrofurantoin 0.512 0.565 0.215 0.295 J01 vs J01 Most-DILI-Concern vs NA vs nitrofurazone allyl alcohol vs ethanol 0.500 0.013 0.200 0.025 NA vs D01 NA vs No-DILI-Concern ethanol vs thioacetamide 0.500 0.293 0.093 0.115 D01 vs NA No-DILI-Concern vs NA promethazine 0.486 0.29 0.23 0.293 R06 vs N05 Less-DILI-Concern vs Less-DILI-Concern vs thioridazine diclofenac 0.485 0.235 0.405 0.205 M01 vs M01 Most-DILI-Concern vs Less-DILI-Concern vs mefenamic acid acetamidofluorene 0.483 0.103 0.213 0.168 NA vs N02 NA vs Most-DILI-Concern vs acetaminophen chlorpropamide 0.478 0.195 0.195 0.158 A10 vs A10 Less-DILI-Concern vs Less-DILI-Concern vs glibenclamide ethionine 0.478 0.163 0.153 0.078 V03 vs M01 NA vs Less-DILI-Concern vs penicillamine amitriptyline 0.469 0.63 0.42 0.488 N06 vs N06 Less-DILI-Concern vs Less-DILI-Concern vs imipramine acetamidofluorene 0.452 0.085 0.295 0.298 NA vs N02 NA vs NA vs phenacetin

S8 ALTEX 34(3), SUPPLEMENTARY DATA Liu et al.

Drug pairs Chemical Similarity Similarity Similarity Therapeutic DILI concern similarity in in InVivo in categories InVitro_ InVitro_ Rat Human chlorpheniramine 0.452 0.185 0.190 0.178 R06 vs B01 No-DILI-Concern vs Most-DILI-Concern vs ticlopidine fluphenazine 0.452 0.520 0.273 0.233 N05 vs N06 Less-DILI-Concern vs Less-DILI-Concern vs imipramine bromobenzene 0.444 0.110 0.305 0.073 NA vs NA NA vs NA vs hexachlorobenzene bromoethylamine 0.444 0.063 0.228 – NA vs D01 NA vs No-DILI-Concern vs ethanol caffeine 0.429 0.56 0.328 0.655 N06 vs R03 No-DILI-Concern vs No-DILI-Concern vs theophylline carbamazepine 0.429 0.203 0.233 0.333 N03 vs NA Most-DILI-Concern vs NA vs coumarin wy-14643 0.429 0.210 0.153 0.228 NA vs M01 NA vs Less-DILI-Concern vs mefenamic acid clomipramine 0.426 0.583 0.223 0.178 N06 vs N05 Most-DILI-Concern vs Less-DILI-Concern vs fluphenazine moxisylyte vs tamoxifen 0.425 0.148 0.158 0.173 C04 vs L02 Most-DILI-Concern vs Most-DILI-Concern imipramine vs tamoxifen 0.421 0.105 0.238 0.193 N06 vs L02 Less-DILI-Concern vs Most-DILI-Concern captopril vs enalapril 0.419 0.085 0.268 0.148 C09 vs C09 Less-DILI-Concern vs Less-DILI-Concern ibuprofen vs methyldopa 0.419 0.16 0.193 0.090 C01 vs C02 Less-DILI-Concern vs Most-DILI-Concern imipramine vs thioridazine 0.415 0.268 0.275 0.223 N06 vs N05 Less-DILI-Concern vs Less-DILI-Concern aspirin 0.414 0.283 0.175 0.270 A01 vs NA No-DILI-Concern vs NA vs phenylanthranilic acid chlorpheniramine 0.413 0.558 0.235 0.313 R06 vs C01 No-DILI-Concern vs Less-DILI-Concern vs disopyramide chlorpheniramine 0.409 0.645 0.265 0.29 R06 vs N06 No-DILI-Concern vs Most-DILI-Concern vs clomipramine chlorpheniramine 0.409 0.183 0.148 0.245 R06 vs R06 No-DILI-Concern vs NA vs methapyrilene fluphenazine 0.408 0.365 0.26 0.420 N05 vs N05 Less-DILI-Concern vs Less-DILI-Concern vs thioridazine isoniazid vs nicotinic acid 0.407 0.103 0.165 0.060 J04 vs C04 Most-DILI-Concern vs Most-DILI-Concern acetaminophen vs bucetin 0.406 0.065 0.298 0.050 N02 vs N02 Most-DILI-Concern vs NA phenobarbital 0.406 0.085 0.300 0.118 N03 vs A10 Less-DILI-Concern vs Less-DILI-Concern vs tolbutamide diazepam vs fenofibrate 0.405 0.105 0.200 0.068 N05 vs C10 Less-DILI-Concern vs Less-DILI-Concern glibenclamide vs sulpiride 0.404 0.16 0.115 0.128 A10 vs N05 Less-DILI-Concern vs NA

* The second level of WHO ATC code was employed: A01 = Stomatological preparations; A10 = Drugs used in diabetes; B01 = Antithrombotic agents; C01 = Cardiac therapy; C02 = Antihypertensives; C04 = Peripheral vasodilators; C09 = Agents acting on the renin-angiotensin system; C10 = Lipid modifying agents; D01 = Antifungals for dermatological use; G03 = Sex hormones and modulators of the genital system; J01 = Antibacterials for systemic use; J04 = Antimycobacterials; L02 = Endocrine therapy; M01 = Anti-inflammatory and antirheumatic products; M03 = Muscle relaxants; M04 = Antigout preparations; N02 = ; N03 = Antiepileptics; N05 = Psycholeptics; N06 = Psychoanaleptics; R03 = Drugs for obstructive airway diseases; R06 = Antihistamines for systemic use; V03 = All other therapeutic products. DILI concern was cited from FDA Liver Toxicity Knowledge Base (LTKB): http://www.fda.gov/ScienceResearch/BioinformaticsTools/ LiverToxicityKnowledgeBase/ucm2024036.htm

ALTEX 34(3), SUPPLEMENTARY DATA S9 Liu et al.

Fig. S1: Hierarchical clustering analysis for the three assay systems (i.e., InVitro_Rat, InVitro_Human, and InVivo) based on the number of differentially expressed genes generated from matched treatment vs control with the criterion fold change of ≥ 1.5 and p ≤ 0.05

S10 ALTEX 34(3), SUPPLEMENTARY DATA Liu et al.

Fig. S2: Distribution of number of DEGs in each toxicogenomic assay system In each compound/time/dose (or concentration)/assay setting, the number of DEGs was calculated with the criteria fold change ≥ 1.5 and p ≤ 0.05. Then, the box plot was made within the assay system and the average and standard deviation of DEG numbers was calculated for each assay system.

Fig. S3: The stability of ranked similarity list for each assay system The data points denote the Spearman’s correlation coefficient, which was calculated by comparing the ranked similarity list with different numbers of DEGs.

ALTEX 34(3), SUPPLEMENTARY DATA S11 Liu et al.

Fig. S4: Concordance among the three different toxicogenomic assay systems with PRank methodology using MAS summary preprocessing

Fig. S5: The distribution of chemical similarity based on Tanimoto coefficient (TC) and drug pairs example for different chemical similarity

S12 ALTEX 34(3), SUPPLEMENTARY DATA

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