Phenolic carcinogens are ubiquitous in the environment, and are widely used as pesticides or fungicides. Pentachlorophenol (PCP, 1) and trichlorophenol are examples of chlorophenol toxins, which are listed by the U.S. Environmental Protection Agency (EPA) as priority pollutants. Phenols, such as PCP can be bioactivated by peroxidase enzyme leading to the formation of reactive phenoxyl radicals that covalently bind to biomolecules such as protein and DNA. In order to gain further insight into the possible toxicity of O-linked adducts, we characterized their influence on DNA duplex stability. The fungicide biphenyl is metabolized to 4-hydroxybiphenyl (4-phenylphenol) and is a possible human carcinogen.Thus, the 4-phenylphenol adduct (?2) was incorporated by a phosphoramadite approach, followed by a solid phase DNA synthesis into the 12mer NarI rectognition sequence (5'-CTCGGCXCCATC-3', X=4PhPhOdG). The modified strand was annealed to six different complementary strands. All duplexes were analyzed by UV-vis spectrophotometry to determine the thermal melting temperature (Tm), and circular dichroism (CD) to determine the conformation of the duplex DNA. Generally, duplexes with four bases opposite 4PhPhOdG were found to destabilize the duplex, compared to the unmodified natural duplex NarI(G):NarI'(C). The duplexes hybridized with the 10mer complement (NarI'(-2)) and the complement with an abasic site (NarI'(THF)) stabilized the duplex (?Tm=4.9�C and 6.6�C), compared to the respective unmodified duplex. Taken together, our data with known mutagenicity data, suggest that the adduct is in a stacked position in a B-form DNA duplex and may be positioned to induce a -2 frameshift.

Synthesis and properties of duplex DNA containing oxygen-linked deoxyguanosine adducts derived from phenolic carcinogens

248th National Meeting (2014)

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