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AFB1-dGuo Adduct Opposite dCyd
Reactions of AFB1-dGuo adduct
depurination
hydrolysis
OOP
O
O OH
HO
O
apurinic site
O
O
O
N
NHN
H2N
O
OHH
H
OCH3
OO
N
O
H O
H
H O
H
O
O O C H3
O
O
O
H O
HH
O
O O C H3
O
O
N
H N
O
H2
N N
N
O
N
N
HN
N
dR
H2N
O
HO
HH
O
N
NH
HN
N
dR
H2N
O
HO
HH
CHOH2O
formamidopyrimidine
(Fapy)
Ring-opened formamido pyrimidine (FAPy) of AFB1 adduct at dGuo N7
HN
N
O
H2N N
N
dR
CH2
O
H
O Cl
HN
N
O
H2N N
N
dR
HN
N
O
H2N N
N
dR
CH2
O
Cl
H
N7-(2-oxoethyl)dGuo
N
dR
O
N
NHN
O
N
N
dRN N
N N
N
dR
N
N
N2,3-dGuo 1,N6-dAdo 3,N4-dCyd
ADDUCT OF 2-CHLOROOXIRANE WITH dGuo AND OTHER dNUCLEOSIDES
= “etheno”
3,N4-Etheno-dC opposite dGuo adduct
FORMATION OF 2-AAF ADDUCT
HN
N
N
N
O
H2NN
AcN
Ac
HN
N
N
N
O
H2N
H
N
Ac
HN
N
N
N
O
H2N
2-AAF-dGuo C8 adduct
2-AF-dGuo adduct at template junction
Common direct acting alkylating agents H2N N
O
CH3
NO
H2O
HNCH3
NO+ H2N OH
O
N-methyl-N-nitrosourea (MNU)
methylnitrosamine carbamic acid
HN N
NH
CH3
NOO2N
N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)
H2O
methylnitrosamine
HNCH3
NONH2
O
O2NN
H
+
nitrourea
H3C S OCH3
O
O
methylmethanesulfonate
H3CO S OCH3
O
O
dimethyl sulfate
O
H2C CH2
O
propiolactone
NP
O N CH2CH2Cl
O
CH2CH2Cl
cyclophosphamide
H2C CH2
O
OH3C
ethylene oxide
propylene oxide
Deamination via diazotization reaction
REACTIVE ALDEHYDES FROM LIPID PEROXIDATION AND TRICYCLIC ADDUCTS
OH
O
malondialdehyde (enol form)
N
N
N
O
N
N
dR
1,N2-propeno dG
O
N
OH
N
N
O
N
N
dR
NHO
N
N
O
N
N
dR
acrolein CH3
O
NH3C
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
NN
O
N
N
dR
N
N
O
1,N2-etheno dG 4 isomers
+
+
1,N2-propano dG, two isomers
R = CH2 CH3
N
R
OH
OH
N
N
O
N
N
N
HO
OH
N
R
HO
O
HO
H
N
N
O
N
N
O
HO
OH
HN N
N
O
N
N
N
HO
OH
H
CHOCHR
HO
+
dGuo from initial 2,3-epoxy-4-hydroxynonanal adducts
Quinone redox cycling is a source of reactive oxygen species (ROS)
2O2-/ + 2H+ H2O2 + O2
H2O2 + Mn+ HO + HO- + M(n+1)+
GENERATION OF HYDROXYL RADICAL (HO•) BY SUPEROXIDE DISMUTASE
(eq. 1) and the FENTON REACTION (eq. 2)
SOD(1)
(2)
N
N
NH2
OH
O
dR
N
N
NH2
O
dR
OH
OH
H
H
5-hydroxy dCyd 5,6-dihydroxy-5,6-dihydrodCyd
HN
N
O
O
dR
OH
OH
CH3
H
dThyd glycol
PRODUCTS OF ATTACK OF HYDROXYL RADICAL ON NUCLEOBASES
HN
N N
N
O
H2N
HN
N N
N
H2NOH
N
N N
N
O
H2N N
N
NH
O
NH2N
O
NH
O NH2
NH2
HN
N N
N
O
H2N
OH
H
HN
N N
HN
O
H2N
O
HN
N NH
HN
O
H2N
CHO
HO
HO
O2, H2O H2O
O2
reduction
- H2O
dZdIz
Fa pyG
8-oxo-dGuodGuo
phosphoglycolate
base propenal
nucleotide 5'-aldehyde
furfural
aerobic anaerobicboth
RO3PO HO O
CH3H
OPO3R'
O O
HO H
OPO3R'
O O
CH3 HO O
PRODUCTS OF 4' AND 5',5'' DEOXYRIBOSE HYDROGEN ABSTRACTION
R, R'= DNA strand
RO3PO H
OPO3R'
O O
HO H
OH
O O
O-
O
RO3PO
B
HH
O
O BH
OPO3R'
O
OHO
OHCH
OPO3R'
O O
OHCH
OH
O O
4'
5',5''
Formation of base propenal
Reaction of base propenal with dAdo to form M1G
N
NHN
NH
OO
OH2N
dR
HN
N N
HN
O
H2N
O
spiroiminodihydantoin(Sp)
1O2
dGuo
Oxidation of 8-oxodGuo by singlet oxygen (1O2)
Review of PAH adduct structures by NMR spectrometry:
Nicholas E. Geacintov, et al., Chem. Res. Toxicol., 1997, 10, 112.
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