1. Effect of SNPs: 1R9O ~ WT with bound flurbiprophen; 1OG5 with mutations K206E, I215V, C216Y, S220P, P221A, I223L, and I224L

2. R108 flurbiprophen heme iron WT CYP 2C9 bound to flurbiprophen

3. R108 heme iron S-warfarin Mutant CYP 2C9 complexed to S-warfarin

4. CYP1A2 allele nomenclature AlleleProteinNucleotide changes, Gene * Gene *Position 5347 should have a T and not a C to be considered *1A. Trivial name EffectEnzyme activityReferences In vivoIn vitro CYP1A2*1ACYP1A2.1NoneWild- type Normal Ikeya et al, 1989 Quattrochi and Tukey, 1989 CYP1A2*1BCYP1A2.15347T>C Nakajima et al, 1994 Welfare et al, 1999 CYP1A2*1CCYP1A2.1-3860G>A Decreased Nakajima et al, 1999 CYP1A2*1DCYP1A2.1-2467delT Japanese patent number 05719026 Chida et al, 1999 Chida et al, 1999 CYP1A2*1ECYP1A2.1-739T>G Japanese patent number 05719026 Chida et al, 1999 Chida et al, 1999 CYP1A2*1FCYP1A2.1-163C>A Higher inducibility Japanese patent number 05719026 Sachse et al, 1999 Chida et al, 1999 Han et al., 2002 Sachse et al, 1999 Chida et al, 1999 Han et al., 2002 http://www.imm.ki.se/CYPalleles/

5. SNPs matching: CYP1A2-03 Surrounding Sequence (GC Content=52%) CCTCAGTGTCACTGGGTAGGGGGAACTCCTGGTCCCTTGGGTAT ATGGAAGG TATCAGCAGAAAGCCAGCACTGGCAGGGACTCTTTGGTACAATA CCCAGCAT GCATGCTGTGSCAGGGGCTGACAAGGGTGCTGTCCTTGGCTTCC CCATTTTG GAGTGGTCACTTGCCTCTACTCCAGCCCCAGAAGTGGAAACTGA GATGATGT GTGGAGGAGAGASCCAGCGTTCATGTTGGGAATCTTGAGGCTCC TTTCCAGC TCTCAGATTCTGTGATGCTCAAAGGRTGAGCTCTGTGGGC(A/C )CMGGACG CAYGGTAGATGGAGCTTAGTCTTTCTGGTATCCAGCTGGGAGCC ARGCACAG AACACGCATCAGTGTTTATCAAATGACTGAGGAAATGAATGART GAATGTCT CCATCTCAACCCTCAGCCTGGTCCCTCCTKTTTTCCCTGCAGTT GGTACAGA TGGCATTGTCCCAGTCTGTTCCCTTCTCGGCCACAGAGCTTYTC CTGGCCTS TGCCATCTTSTGCCTGGTATTCTGGGTGCTCAAGGGTTTGAGGC CTCGGGTC CCCAAAGGCCTGAAAAGTCCACCARAGCCATGGS RA/CMYR KYS R To link to the SNP in the Genewindow genome browser, click on the red SNP. To view one of the other SNPs in this sequence, click on its IUPAC code. Some SNPs in this sequence are not currently in the database.IUPAC code dbSNP ID: rs762551 SNP500Cancer ID: CYP1A2- 03 Gene: CYP1A2 SNP Region: IVS1-154C>A Note: aka CYP1A2*1F CYP1A2IVS1-154C>A dbSNP NCBI map Ensembl mapdbSNP NCBI map Ensembl map Entrez GeneEntrez Gene

6. 1. Epoxidation of double bonds. 2.C and N hydroxylation: C-H  C-OH or N-H  N-OH 3.Oxidative dealkylation: C-X-CH 3  C-OH + CH 2 O; X= O, N, S C-NH 2 C-SH 4.Oxidative deamination: R-CH 2 -NH 2  R-CH=O + NH 3 5.N, S oxidation: R 3 N  R 3 N  O ; R 2 S  O Five reaction types of cytochrome P450

7. Oxidative dealkylation: C-hydroxylation followed by non-enzymatic hydrolysis of the gem-substituted adduct. Oxidative deamination: C-hydroxylation followed by non-enzymatic hydrolysis of the gem-substituted adduct. C-X-CH 3 C-X-CH 2 C-X-H + CH 2 =O X=O, N, S H-O X = O, hemiacetal X = N, gem amino hydrin X = S, thiohemiacetal

8. O O 1 2 3 4 5 6 7 8 9 10 11 12 benzo[a]pyrene 1-OH 6-OH 3-OH* 1,6-Q 6,12-Q 3,6-Q OH H H HO O H H diolepoxide Major metabolites of benzo[a]pyrene by MFO system 7-OH, 9-OH, 12-OH and the 4,5-Q have also been reported O O 7,8-quinone

9. Arene oxide  phenol rearrangement

10. Stereochemistry of hydration by epoxide hydrolase H2OH2O

11. BP diolepoxide stereo isomers (+)-anti: 7R,8S,9S,10R-BPDE

13. Adducts of anti-BPDE with exocyclic amino groups of nucleobases Heavy lines show the aromatic π-system conjugated with, and stabilizing the incipient positive charge resulting from attack at epoxide ring. This situation favors addition adjacent to aromatic ring.

14. 3’-OH

15. 5' (+)-trans-anti--BPDE:N 2 -dGuo adduct at primer-template junction

17. Oxidized angular ring Distal end of pyrene system

18. adduct of (-)-trans-anti-BPDE with N 6 -dAdo: opposite dThyd from N-Ras fragment Looking down helix axis Looking perpendicular to helix axis 5 face of dAdo

19. cis adduct of (+)-anti-BPDE at N 6 of dAdo 5 face of dAdo

21. (-)-trans-anti-5-methylchrysene:dGuo adduct at the hindered bay region 5' 3'

22. (+)-trans-anti-benzo[g]chrysene:dAdo Inset: benzo[g]chrysene skeleton

23. R,S-trans-anti-benzo[c]phenanthrene:dGuo SR

24. classical intercalation 5-insertion S-trans-anti-B[c]Ph 1(S) 5…C[G*]C… normal duplex classical intercalation 3-insertion R-trans-anti-B[c]Ph 1(R) 5…C[G*]C… normal duplex

25. BAY REGION THEORY O  transition state for opening of bay region epoxide heavy lines indicate the aromatic  aromatic system  Nu If a PAH has a bay region and shows genotoxic activity, the ultimate active metabolite will be the bay region diolepoxide.

26. Aflatoxin B 1 activation human CYP3A4

27. Reactions of AFB 1 -dGuo adduct depurination hydrolysis

28. AFB 1 -Fapy dGuo adduct N7 N9

29. Vinyl chloride activation

30. +

31. ACTIVATION OF DIMETHYLNITROSAMINE GENERAL STRUCTURE azotic acid monomethyl nitrosamine

32. Activation of 2-AAF (general for amines) other amines of commercial importance  2-aminonaphthalene -naphthylamine 4,4'-aminobiphenyl 4,4'-diamino-3,3'-dichlorodiphenylmethane methylene bis(o-chloroaniline) MOCA NH 2 H 2 N NH 2 CH 2 NH 2 Cl H 2 N Cl

33. Nitrenium ion adducts C8 adduct of AAF C1 adduct of AAF C8 adduct 1-aminopyrene

34. Activation of nitroaromatics-multiple pathways, MFO and nitroreductase Other important environmental nitro- PAH

35. Deamination via diazotization reaction

36. Deamination by bisulfite reaction

37. Direct acting mutagens

38. P450 catalytic cycle “compound I” “compound 0”

40. Proposed mode of action of PCBs

42. 2O 2 + 2H + H 2 O 2 + 0 2 H 2 0 2 + M n+ M (n+1)+ + HO - + HO SOD - Hydroxyl radical from action of superoxide dismutase followed by Fenton chemistry Fenton reaction

43. Reductive dehalogenation of carbon tetrachloride

44. LIPID PEROXIDATION RADICAL CHAIN

45. α β β-CLEAVAGE TO UNSATURATED ALDEHYDES

46. Formation of Malondialdehyde

47. OH O malondialdehyde (enol form) N N N O N N dR 1,N 2 -propeno dG O N OH N N O N N dR NHO N N O N N dR acrolein CH 3 O NH 3 C OH N N O N N dR crotonaldehyde O OH N OH N N O N N dR HO 4-hydroxy-2-nonenal 4 isomers O OH O 4-hydroxy-2,3-epoxynonanal N O N N dR N N N O N N dR N N O 1,N 2 -etheno dG 4 isomers + + 1,N 2 -propano dG, two isomers OH (M 1 G)

48.  dGuo from initial 2,3-epoxy-4-hydroxynonanal adducts

49. HN N N N H 2 N O dR HN N N H N H 2 N O dR O HN N NH NH H 2 N O dR H O N N NH dR O H 2 N O N NH dR O H 2 N H 2 N HO HO HO 8-oxodGuo FapyGuo Hydroxyl radical oxidation of dGuo 2,2-diamino-4-[(2’-deoxyribosyl)- amino]-5(2H)-oxazolone dZ

50. HN N N N O dR H 2 N HN N N H N O dR H 2 N O N N NH O dR H 2 N N O H 2 N H 2 N O NH dR 2,2-diamino-4-[(2’-deoxyribosyl)- amino]-5(2H)-oxazolone dZ H 2 O 1-electron oxidation products of dGuo NH N H N H N dR H 2 N O O H guanidinohydantoin Gh -e - -e -

51. N N NH 2 O dR OH OH H H HN N O O dR OH OH CH 3 H N N NH 2 OH O dR 5-hydroxy dCyd 5,6-dihydroxy-5,6-dihydro dCyd dThyd glycol Products of Hydroxyl Radical Oxidation of Bases

54. Formation of base propenal Reaction of base propenal with dGuo to form M 1 G

55. M 1 G FROM BASE PROPENAL

57. Cation radicals from 1-electron oxidation of BP and 6-MePB benzo[a]pyrene cation radical6-methylbenzo[a]pyrene cation radical

58. Adducts of the cation radicals of BP and 7,12-DMBA with dAdo and dGuo

59. Pathway for formation of adducts of dGuo from the cation radical of DMBA

60. Pathway to adducts of dAdo from 1-electron oxidation of dibenzo[a,l]pyrene

61. “ene-diyne” class of antineoplastic drugs H1´ abstraction from deoxyribose From: Chem. Rev. 1998, 98, 1089-1107