Combined Actions and Interactions of Chemicals in Mixtures

nucleotide sequences and stereochemistry of DNA. The major forms of DNA
repair include direct reversal of DNA damage excision repair and post replication
repair.
In the simplest form of DNA-repair, direct reversal, one enzyme catalyzes a single
reaction, such as photo reactivation of pyrimidine dimers induced by UV
irradiation. Two different types of excision repair are considered. Base excision
repair removes smaller types of base damage such as lesions caused by
monofunctional alkylating agents e.g. 7-methylguanine and 3-methyladenine.
Nucleotide excision repair is a more versatile repair pathway, which operates in
cellular responses to a large number of various lesions (e.g. bulky DNA-adducts,
like DNA-PAH adducts, and ionizing radiation). Post replication repair: More
complex damage, such as DNA-DNA interstrand crosslinks and double-strand
breaks, may require repair of both DNA strands. It appears that interstrandcrosslinks
are repaired by a combination of nucleotide excision and
recombinational/post-replication repair. This repair pathway involves interchanges
between alleles and the mechanism is rather a mechanism for tolerance to DNA
damage than for repair of DNA damage, as this repair often results in misrepair of
the lesion.
Modulation of DNA repair
Numerous possibilities exists for chemicals to enhance or inhibit the genotoxic
effects of other substances through modulation of DNA repair processes, since
most DNA alterations can be repaired by different repair mechanisms, which can
be saturated, limited or subject to mistakes. The reparability of DNA lesions in
mammalian cells depends moreover upon the type of lesion, the localisation of the
lesion in the genome, and the functional state of the DNA in question (Hanawalt
1986).
Modulation of the genotoxic response of mammalian cells has in many cases been
shown to be mediated by influence on different repair systems. Brown et al. (1979)
have, for example, measured DNA excision repair in cultured human fibroblasts
after single or dual treatments with ultraviolet radiation, 4-nitroquinoline 1-oxide
(4NQO), or N-acetoxy-2-acetylaminofluorene (AAAF). Three approaches were
used to monitor repair: unscheduled DNA synthesis, measured by autoradiography;
repair replication, measured by the incorporation of a density-labelled DNA
precursor into repaired regions and excision of ultraviolet endonuclease-sensitive
sites. When a single repair-saturating dose of one of the three carcinogens was
administered, little stimulation of unscheduled DNA synthesis or repair replication
could be observed by additional treatment with one of the other carcinogens. In no
instance was total additivity of repair observed. These observations were confirmed
by showing that the excision of endonuclease-sensitive sites produced by
ultraviolet damage (i.e., pyrimidine dimers) was inhibited by exposure to 4nitroquinoline
1-oxide and N-acetoxy-2-acetylaminofluorene. The data indicate
that the repair of lesions induced by these substances may have common ratelimiting
steps, a conclusion previously indicated by the repair deficiency in
xeroderma pigmentosum cells in which a single mutation eliminates the repair of
damage caused by each of these agents. Ahmed & Setlow (1981) have later
measured the excision repair of DNA damage by the photolysis of bromodeoxyuridine
incorporated in the DNA during repair in normal human and xeroderma
pigmentosum fibroblasts treated with a combination of the AAAF and 4NQO.
Repair was additive in both types of cells treated with AAAF plus 4NQO, but the
results indicated that there are different rate limiting steps for removal of 4NQO
and AAAF lesions.
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