Chemical research in toxicology

Cyclohexene ring and Fjord region twist inversion in stereoisomeric DNA adducts of enantiomeric benzo[c]phenanthrene diol epoxides.

PMID 11743746


The sterically hindered, nonplanar fjord region polycyclic aromatic hydrocarbons (PAHs) have been of great interest because of the exceptionally high mutagenic and tumorigenic activity of certain of their metabolically activated diol epoxides. Benzo[c]phenanthrene (B[c]Ph), a representative fjord region PAH, is metabolically activated to a pair of enantiomers, 1S,2R,3R,4S-3,4-dihydroxy-1,2-epoxy-1,2,3,4-tetrahydrobenzo[c]phenanthrene, (+)-anti-B[c]PhDE, and the corresponding 1R,2S,3S,4R enantiomer, (-)-anti-B[c]PhDE. Both of these can bind covalently to the amino group of purines in DNA via trans addition. In the present work we carry out an extensive computational investigation of the 1R(+) and 1S(-)-trans-anti-B[c]Ph adducts to the base guanine, with the goal of delineating the conformational possibilities for the fjord region and the adjacent cyclohexene-type benzylic ring and their relevance to DNA duplexes. We created 10 369 starting structures for each adduct and minimized the energy using AMBER 5.0. A limited set of conformational families is computed, in which the R isomer structures are near mirror images of the S isomer. The benzylic rings are essentially all half-chair-type. Cyclohexene-type ring inversion as well as fjord region twist inversion are possible for each isomer and are correlated. DNA duplexes modified by fjord region adducts select conformers from the allowed families that optimize stacking interactions, which contributes to the stability of the carcinogen-intercalated DNA duplex structures [Cosman et al. (1993) Biochemistry 32, 12488-12497; Cosman et al. (1995) Biochemistry 34, 1295-1307; Suri et al. (1999) J. Mol. Biol. 292, 289-307; Lin et al. (2001) J. Mol. Biol. 306, 1059-1080]. In turn, this stability could contribute to the resistance to repair by the human nucleotide excision system observed in fjord region adducts [Buterin et al. (2000) Cancer Res. 60, 1849-1856].

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Benzo[c]phenanthrene, BCR® certified Reference Material