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Major metabolites of benzo[a]pyrene by MFO system
O
OH
O
H
H
HO
H OH
H
9,10-DHDO
9,10-oxide
O
1,6-Q
1-OH
O
11
12
1
2
10
3
9
8
O
7
OH
6,12-Q
H
H
4
5
6
benzo[a]pyrene
OH
HO
H
O
3,6-Q
H
4,5-DHDO
4,5-oxide
6-OH
O
HO
O
OH
H
3-OH*
H
O
H
H OH
7,8-DHDO
7,8-oxide
7-OH, 9-OH, 12-OH and the 4,5-Q have also
been reported
O
H
H
HO
HH
OH
diolepoxide
Arene oxide  phenol rearrangement
OH
H
O
H
OH
H
O
H
Stereochemistry of hydration by epoxide hydrolase
H
HO
O
H
H
OH
H
BP diolepoxide stereo isomers
H
HO
HO H
_ -7,8-dihydrodiol
(+)
H
O
H
H
H
HO
HO H
O
H
H
HO
HO H
_ -syn
(+)
_ -anti
(+)
(+)-anti: 7R,8S,9S,10R-BPDE
R, S CONVENTION
A
D
B
C
A>B>C
S
A>C>B
R
Lowest priority atom oriented towards rear, direction of
rotation is determined on the front face. Priority is assigned
by atomic number; when atoms are of equal atomic number,
the atoms bonded to the atoms under consideration are
considered.
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.
.N. H
+
2
O
-
N
d R
N
O
H N
d R
N
H N
N
N
N
H
N
H N
H
H
O H
H
O H
H
O H
H
O H
H
O H
H
O H
(+)-trans-anti--BPDE:N2-dGuo adduct at primer-template
junction
5'
Oxidized
angular
ring
Distal
end of
pyrene
system
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
cis adduct of (+)-anti-BPDE at N6 of dAdo
5 face of
dAdo
(-)-trans-anti-5-methylchrysene:dGuo
adduct at the hindered bay region
5'
3'
1
2
3
4
5 CH3
(+)-trans-anti-benzo[g]chrysene:dAdo
Inset: benzo[g]chrysene skeleton
R,S-trans-anti-benzo[c]phenanthrene:dGuo
S
R
benzo[ c]phenanthrene
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
BAY REGION THEORY
If a PAH has a bay region and shows genotoxic activity, the ultimate
active metabolite will be the bay region diolepoxide.
d
O
Nu
transition state for opening of bay region epoxide
heavy lines indicate the aromatic p-aromatic system
Aflatoxin B1 activation
O
O
O
2
O 1
O
3
O
9
5
O
O
7
O
O
4 OCH3
O
8
OCH3
endo (minor)
human
CYP3A4
6
O
O
aflatoxin B 1
AFB1
O
OCH3
O
O
Carcinogenic potency determined by:
O
1. Intrinsic activity of ultimate active metabolite
2. Proportion of metabolic pathway leading to
ultimate active metabolite
exo (major)
AFB1-8,9-oxide
Albumin
lysine
lysine
lysine
Reactions of AFB1-dGuo adduct
O
O
O
OCH3
HO
H
H
HO
O
O
hydrolysis
O
O
O
O
N
HN
H2N
HO
H
H
N
OCH3
O
O
N
depurination
AFB1-FAPy dGuo adduct
N9
N7
Vinyl chloride activation
ETHENO ( ADDUCTS FROM VINYL CHLORIDE
O
O
N
HN
N
N
N
N
N
N
N2,3-dGuo
N
N
1,N2-dGuo
N
N
N
N
N
N
N
O
3,N4-dCyd
1,N6-dAdo
N7-ADDUCT
O
O
H2C CH
N+
N
N
HN
H2N
N
N7-(2-oxoethyl)-dGuo
ACTIVATION OF DIMETHYLNITROSAMINE
GENERAL
STRUCTURE
R
N N
H3C
N N O
H3C
dimethylnitrosamine
(DMN)
O
R'
C-hydroxylation
by MFO
HOH2C
N N O
H3C
non-enzymatic
H
N N O
H3C
monomethyl
nitrosamine
+
N N OH
H3C
azotic acid
CH2O
H3C+ + N 2 + HO -
Activation of 2-AAF (general for amines)
other amines of commercial
importance
N H
2
2 - a m in o n a p h th a le n e
 - n a p h th y la m in e
H
2
N
N H
2
4 , 4 '- a m in o b ip h e n y l
C l
H
2
N
C l
C H
2
N H
2
4 , 4 '- d ia m in o - 3 , 3 '- d ic h lo r o d ip h e n y lm e t h a n e
m e th y le n e b is ( o - c h lo r o a n ilin e )
M O C A
Nitrenium ion adducts
O
NH
NH
2
N
N
N
dR
NH
O
NH
C8 adduct of AAF
H 2N
NH
N
N
C1 adduct of AAF
N
dR
O
NH
NH
2
N
N
N
NH
dR
C8 adduct 1-aminopyrene
Activation of nitroaromatics-multiple pathways,
MFO and nitroreductase
Other important
environmental nitroPAH
H N OCOCH3
Pathway A
Pathway B
R
Pathway C
Pathway D
1
OAT
NO
NO2
NH+
H N OH
2
3
reduce
R
R
reduce
R
P450
nitrenium ion
P450 reduce
NH2
NO2
binding to DNA
R
R
NO2
3-nitrofluoranthene
R
O
NAT
H N COCH3
NO2
NO2
2-nitrofluoranthene
R
R
binding to DNA
P450
-
O
+
carbonium ion
+ N COCH3
HO N COCH3
R
R
binding to DNA
R = -OH
OAT =O-acetyltransferase
NAT =N-acetyltransferase
nitrenium ion
CH3COO N COCH3
OAT
R
Deamination via diazotization reaction
Deamination by bisulfite reaction
Direct acting
mutagens
O
H2N
CH3
N
NO
H 2O
N-methyl- N-nitrosourea
(MNU)
NH
HN
O2N
CH3
N
NO
O
CH3
HN
NO
+
methylnitrosamine
H2O
N-methyl- N'-nitro-N-nitrosoguanidine
(MNNG)
H2N
OH
carbamic acid
O
CH3
HN
NO
+
methylnitrosamine
O2NN
NH2
H
nitrourea
O
H3C S OCH3
O
H3C
O
methylmethanesulfonate
O
H3CO S OCH3
O
dimethyl sulfate
propylene oxide
O
O
H2C CH2
-propiolactone
CH2CH2Cl
O
O
H2C
P
CH2
ethylene oxide
N
N CH CH Cl
2
2
O
cyclophosphamide