Chemistry Reference
In-Depth Information
Toeg 1982; Krushinskaya 1983; Kapp and Smith 1970; Ullrich and Hagen 1971;
Janicek et al. 1985; Rashid et al. 1999). Nearly all the TBA-activity attributable
to low-molecular-weight (DNA-free) material is due to malonaldehyde (Rashid
et al. 1999), and there is no indication for the formation of base propenals which
dominate the products of the BLM reaction (Sect. 12.9). Moreover, at low doses
the major fraction is due to TBA-active material bound to DNA (Fig. 12.11).
Mechanistically, the formation of malonaldehyde and TBA-active DNA-
bound material is not yet fully understood. While free malonaldehyde increases
linearly with dose (
G
= 0.1
10
−7
mol J
−1
= 1.7% of
•
OH), the efficiency of form-
ing TBA-active DNA-bound material markedly decreases with increasing dose,
that is when the integrity of the DNA is getting lost upon damage accumulation.
At one stage, O
2
•
−
seems to play a role, since the yield of total TBA-active mate-
rial is
G
= 0.3
×
10
−7
mol J
−1
in O
2
-sat-
urated solution (at 100 Gy). As compared to N
2
O/O
2
, the
•
OH yield is about half
in O
2
-saturated solutions, but the O
2
•
−
yield is markedly enhanced (Chap. 2.2).
This could point to hydroperoxides as precursors of the TBA-active material, but
details remain open. Yet, a
G
value of 0.2
10
−7
mol J
−1
in N
2
O/O
2
-saturated and 0.2
×
×
10
−7
mol J
−1
(O
2
-saturated) indicates
that this type of lesion is not an unimportant one, about 7% of
•
OH.
The formation of malonaldehyde induced by the Fenton reaction (Fe
2+
plus
H
2
O
2
in excess) has been studied using the
N
-methylhydrazine assay (Matsu-
fuji and Shibamoto 2004). Under such conditions, the yield of malonaldehyde
is much lower (2
×
10
−4
when Fe
2+
is complexed by
EDTA) than in the radiolytic system discussed above. The reasons for these dif-
ferences are not yet known.
The 3
10
−5
mol per mol Fe
2+
; 1
×
×
-phosphoglycolate end group whose formation has been discussed
above is a dominant DNA lesion formed upon
′
-radiolysis as well treatment with
NCS. The action of repair enzymes that might cope with this lesion has been
studied (Chaudry et al. 1999).
The
C
(1
γ
)-radical does not give rise to frank SSB as such, at least not in re-
markable yields (see above), but cationic polyamines and divalent metal cations
(Roginskaya et al. 2005) as well as transition metal ions such as 1,10-phenanth-
roline-copper ion are capable of catalyzing
′
-elimination processes from 2-dRL
that lead to an SSB and eventually to 5-MF. These reactions are discussed in
some detail below (Sect. 12.9.4). 5-MF is also produced by desferal-copper ion
(Joshi et al. 1994) or oxoruthenium(IV) (Neyhart et al. 1995; Cheng et al. 1995).
The final 5-MF yield obtained after heating in the presence of polylysine as
a catalyst is very high (
G
= 0.5
β
10
−7
mol J
−1
in oxygenated aqueous solution;
Roginskaya et al. 2005). This is difficult to reconcile on the basis of
•
OH-attack
at
C
(1
×
is quite hidden in the minor groove
(Sect. 12.2). Therefore, one is tempted to assume that a major part of the
C
(1
′
) as the only primary event, since H1
′
′
)
damage is due to base radical attack at
C
(1
), that is due to a damage amplifica-
tion reaction. Indeed, there is evidence for this type of reaction in model systems
(Chap. 10.3). Because of the importance of such reactions for our understanding
of free-radical-induced DNA damage this system should be investigated in more
detail, and the question as to the involvement of heat-labile hydroperoxides
(Chap. 11.2) should be addressed.
′
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