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1 5-4 5 () / / 30

2 / 30 2 DB DB -23 4/ 30

3 (1) (23) (2) (21) -23 5/ (21) -23 6/ 30

4 2. (21)( ) 21 p.5 / 60 CYP2E1-23 7/ / 30

5 3. (1) ( ) [DB] List of chemicals ChemIDPlus Names and synonyms Key words chemical name, metabolism, rat/mouse Scirus Google PubMed Journal of Biological Chemistry Drug Metabolism and Disposition The Journal of Toxicological Science -24 RESULTS 9/ (2) ( ) [DB] 307 chemicals for database (entered 424 maps) 138 original chemical (entered 210 maps) 164 structural analogues (entered 214 maps) No data found for 5 chemicals 133 chemicals have observed metabolism (entered 205 maps) chemicals are not metabolizing (entered only parent) 10 / 30

6 3. (3) ( ) [DB] / (4) ( ) [DB] CH3 CH3 CH3 CH 3 di-n-heptyl phthalate No. 43 from the list (no data) di-n-ctyl phthalate analogue S N N S S N N S S 2-(4-Morpholinyldithio)benzothiazole No.117 from the list (no data) (4-Morpholinylthio)benzothiazole analogue 12 / 30

7 3. (5) ( ) [] Substrate Principal transformations Metabolites Geminal diol decomposition H P = 1.00 C C H -oxidation P = 0.99 H H Match? - Yes! Cyclohexanone oxidation P = Ester hydrolysis H RESULT H P = 0.90 Amine decomposition H + C C NH 2 P = 0.75 C C -xidation CH 3 P = H / (6) ( ) [] : 85.2% / 30

8 3. (7) ( ) [] Comparison between observed (left part) and simulated (right part) metabolic maps of a parent chemical, belonging to the structural domain of the simulator / [DB] in vivo, in vitro DB in vitro S9-24~28 16 / 30

9 / (1) ( ) [DB] Google Scholar / 30

10 3. (2) ( ) [DB] / (3) ( ) [DB] / 30

11 3. (4) ( ) [DB] Template for interaction of CYP2E1 with substrates 6-Aminochrysene (as inhibitor) NH 2 7,12-Dimethylbenzo[a]anthracene Benzo[a]pyrene N H H Benzo[a]pyrene 7,8-dihydrodiol NH 2 H H Pyrene N 1-Methylpyrene A B C D E 1-Nitropyrene xidized site Dibenzo[a,h]anthracene Boundary A core space of CYP2E1 active site was extracted t from polycyclic li aromatic hydrocarbons substrates t and inhibitor. Arrows indicate the major site of the oxidation (interaction with heme - oxygen). Assumed space boundary is shown as chain / (5) ( ) [DB] List of chemicals associated with CYP2E1 Acetaminophen, Acetone, Acetonitrile, 2-Acetylbenzothiophene Acetylbenzothiophene, Acrylonitrile, S-adenosyl-l-methionine l methionine, Ametryne, 6-Aminochrysene, Amino[a]carboline, 3-Amino-1,2,4-triazole, Aniline, 2-Anisidine, Anisole, Anthracene-9-carboxaldehyde, 9-Anthraldehyde, Arachidonic acid, Atrazine, Benzo[a]pyrene, Benzo[a]pyrene-7,8-dihydrodiol, 2,2'-Bipyridine, 1,3-Butadiene, t-butylacetylene, N-Butylaniline, t-butyl ethyl ether, 4-tert-Butyltoluene, Caffeine, Carbamazepine, 4-Chloroaniline, 2-Chloro-4-toluidine, 4-Chloro-2- toluidine, Chlorzoxazone, Coumarin, 4-Cyclopropylanisole, 4-Cymene, 4-Cresol, Dacarbazine, cis- Crotononitrile, Dapsone, Deprenyl, Diallylsulfone, 2,4-Diaminoanisole, 2,4- and 2,6-Diaminotoluene, Dibenzo[a,h]anthracene, 1,2- and 1,4-Dichlorobenzene 1,2-Dichloro-1-fluoroethane, 1,1-Dichloro-2,2,2- trifluoroethane, Diethyl ether, N,N-Diethylthiocarbamate, 2,5-Difluoroaniline, 2,3- and 2,6-Dimethylaniline, 712-Dimethylbenzo[a]anthracene 7,12-Dimethylbenzo[a]anthracene, 26-Dimethylnaphthalene 2,6-Dimethylnaphthalene, Dimethylsulfoxide, 1,3-Dinitrobenzene, Enflurane, Estragole, Ethosuximide, Ethylbenzene, Ethyl isocyanide, Ethylmorphine, 1-Ethylpyrene, Flutamide, Furan, Genistein, 1,1,2,3,3,3-Hexafluoropropyl methyl ether, 13-Hydroperoxy-9,11- octadecadienoic acid, 3-Hydroxypyridine, Isoflurane, Isoprene, Isoquinoline, Lauric acid, (R+)-Menthofuran, 7-Methoxy-4-trifluoromethylcoumarin, 3-Methylacetanilide, Methylamino[a]carboline, 2- and 4- Methylanisole, Methyleugenol, N-Methylformamide, 3-Methylindole, 6-Methylnorharman, 4-Methylpyrazole, 1-Methylpyrene, 4-Methyltriazole, Nabumetone, Naphthalene, 2- and 4-Nitroanisole, Nitrobenzene, 6- Nitrochrysene, 4-Nitrophenol, 1-Nitropyrene, N-Nitrosobenzylmethylamine, N-Nitrosodimethylamine, N- Nitrosodiethylamine, N-Nitrosodipropylamine, N-Nitrosodiamylamine, N-Nitrosoethylmethylamine, 2-, 3- and 4-Nitrotoluene, Norharman, leic acid, 13-xo-9,11-tridecadienoic 911tridecadienoic acid, Pargyline, Phenanthrene, Phenethyl isothiocyanate, Phenylacetylene, 5-Phenyl-1-pentyne, Propofol, 2-n-Propyl-quinoline, Pulegone, Pyrene, Quinoline, Safrole, Styrene, 4-Vinylcyclohexene, 1,2,3,5-Tetrachlorobenzene, Theobromine, Theophylline, Toluene, 2-Toluidine, Tranylcypromine, 1,2,4-Trichlorobenzene, 1,1,2-Trichloro-2- fluoroethane, 2,2,2-Trifluoroethanol, 1,2,4-trimethylbenzene, Urethane, Vinylcarbamate, 1,2-, 1,3- and 1,4- Xylene. (Total 125 chemicals) / 30

12 3. (6) ( ) [DB] CYP2E1(125) CYP2E1(125) / (7) ( ) [DB] Cl Cl 1,2-Dichlorobenzene Cl H Cl Cl Cl H / 30

13 3. (8) ( ) [DB] 5 in vitro (safrole) (t-butyltoluene) (o-methylaniline deriv.) / (9) ( ) [DB] -29~32 26 / 30

14 3. [DB] DB CYP2E1 DB -28~32 27 / [DB] 2DB -24~32 28 / 30

15 / p.6 / CYP1A2 CYP1A2 DB -32,33 30 / 30

Appendix A1 Analytical Method, CAS Number and Chemical Name HSA-8N and 8S Analytical Method CAS Number Chemical Name Alternative Chemical Name

Appendix A1 Analytical Method, CAS Number and Chemical Name HSA-8N and 8S Analytical Method CAS Number Chemical Name Alternative Chemical Name Analytical Method CAS Number Chemical Name Alternative Chemical Name 300 14797-55-8 Nitrate [as N] 300 14797-55-8 Nitrate 300 16984-48-8 Fluoride 9012B 57-12-5 Cyanide 6010B 7429-90-5 Aluminum 6010B 7439-89-6