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

2. Arene oxide  phenol rearrangement

3. Stereochemistry of hydration by epoxide hydrolase
H2O

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

6. 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.

8. (+)-trans-anti--BPDE:N2-dGuo adduct at primer-template junction5'

10. Oxidized angular ring
Distal end of pyrene system

11. adduct of (-)-trans-anti-BPDE with N6-dAdo: opposite dThyd from N-Ras fragment
5 face of dAdo
Looking down helix axis
Looking perpendicular to helix axis

12. cis adduct of (+)-anti-BPDE at N6 of dAdo
5 face of dAdo

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

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

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

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

17. transition state for opening of bay region epoxide
BAY REGION THEORY
If a PAH has a bay region and shows genotoxic activity, the ultimate active metabolite will be the bay region diolepoxide. O d
transition state for opening of bay region epoxide
heavy lines indicate the aromatic p-
aromatic system Nu

18. Aflatoxin B1 activation
human CYP3A4

19. Albumin
lysine

20. Reactions of AFB1-dGuo adduct
hydrolysis
depurination

21. AFB1-FAPy dGuo adduct N7 N9

22. Vinyl chloride activation

23. +

24. ACTIVATION OF DIMETHYLNITROSAMINE
GENERAL STRUCTURE
monomethyl nitrosamine
azotic acid

25. Activation of 2-AAF (general for amines)
other amines of commercial importance

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

27. Other important environmental nitro-PAH
Activation of nitroaromatics-multiple pathways, MFO and nitroreductase N H 2 R O - + C 3
NH+
reduce
P450
carbonium ion
binding to DNA
NAT
OAT
nitrenium ion
R = OH
OAT =
acetyltransferase
NAT =
Pathway A
Pathway B
Pathway C
Pathway D

28. Deamination via diazotization reaction

29. Deamination by bisulfite reaction

30. Direct acting mutagens