Cyclohexene Ring and Fjord Region Twist Inversion in Stereoisomeric DNA Adducts of Enantiomeric Benzo[c]phenanthrene Diol Epoxides

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• 作者：Min Wu ; Shixiang Yan ; Dinshaw J. Patel ; Nicholas E. Geacintov ; and Suse Broyde
• 刊名：Chemical Research in Toxicology
• 出版年：2001
• 出版时间：December 2001
• 年：2001
• 卷：14
• 期：12
• 页码：1629 - 1642
• 全文大小：614K
• 年卷期：v.14,no.12(December 2001)
• ISSN：1520-5010

文摘

The sterically hindered, nonplanar fjord region polycyclic aromatic hydrocarbons (PAHs)have been of great interest because of the exceptionally high mutagenic and tumorigenic activityof certain of their metabolically activated diol epoxides. Benzo[c]phenanthrene (B[c]Ph), arepresentative 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 canbind covalently to the amino group of purines in DNA via trans addition. In the present workwe 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 possibilitiesfor the fjord region and the adjacent cyclohexene-type benzylic ring and their relevance toDNA duplexes. We created 10 369 starting structures for each adduct and minimized the energyusing AMBER 5.0. A limited set of conformational families is computed, in which the R isomerstructures 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 possiblefor each isomer and are correlated. DNA duplexes modified by fjord region adducts selectconformers from the allowed families that optimize stacking interactions, which contributesto 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 excisionsystem observed in fjord region adducts [Buterin et al. (2000) Cancer Res. 60, 1849-1856].