Revival: Biological Effects of Low Level Exposures to Chemical and Radiation (1992)

DNA REPAIR 55

Table 3.3. DNA Repair and Caloric Restriction

Damaging

Agent

Brown-Norway BNXF-344 B6C3F1
Ad Lib Restricted Ad Lib Restricted Ad Lib Restricted
MMS 1.16 1.18 1.40 1.61 a a
UV 1.38 1.41 2.07 2.75 a a
(MGAP) 0.38 0.65 a a 0.34 0.46
Source: Lipman et al.19
Note: MMS is at 0.5 mmM, UV is 20 J/m2. Skin cells from rat (Brown-Norway and cross with
F-344), and mouse (B6C3F1; 12 hours after lights on); restricted are fed 60% of ad lib.
Values are ratios of stimulated/unstimulated cells for damaging agents. MGAP is
activity of 0 6-methylguanine acceptor protein, an index of capacity for repair, in
pmols/mg DNA.
aNot done.

repair) are seen at different times of day. Different physiological states,

such as estrous, can also significantly alter DNA repair.16*17 This isozyme is
male specific, and is responsible for the metabolism of a number of agents,
such as doxylamine and aflatoxin B1 (AFB1).
It is instructive to look at AFB1 in a little more detail. As a result of
changes in agent metabolism, the urinary excretion of AFB1 increases 40%,
its plasma clearance increases by 70%, and its hydrophilic metabolites more
than double.18 This increased hydrophilicity results in increased excretion.
The net effect is to reduce the binding of an equivalent dose of AFB1 to the
liver genome to more than half (from 39.5 to 15.2 pmol AFBl/mg DNA, a
66 % decrease), with a 40% CR.
Directly measuring DNA repair in cells isolated from CR animals shows
that DNA repair increases in the rat and mouse with CR (Table 3.3). This is
true for both forms of excision repair, as illustrated by the effects on dam­
age induction by methylmethanesulfonate (MMS) and ultraviolet light. In
addition, 0 6-methylguanine acceptor protein, which is a repair system for a
particular damage, is also elevated.19
Finally, CR can protect the genome in a number of different ways. Inap­
propriate expression of oncogenes has been shown to be associated with
cancer.20 Lyn-Cook and Hass have shown that CR results in the hyper-
methylation of an HA-ras oncogene.21 Hypermethylation is usually associ­
ated with turning off of gene function,22 suggesting that potentially damag­
ing genes can be turned off by CR.
By approaching DNA repair as part of a larger process of protecting
genomic integrity, it can be seen that nutrition can affect almost every
aspect associated with genomic integrity, including DNA repair itself.

TOXICANTS

The best characterized system used to understand the effects of toxicants

in modulating DNA repair is the adaptive response, seen in E. coli and

mammalian cells.23 Recent advances in the area (the development of cDNA