Effect of DNA base sequence on the configuration of deoxyadenosine adducts formed by the Fjord region diol epoxide, (+)-(1R,2S,3R,4S)-3,4-dihydroxy-1,2-epoxy-1,2,3,4- tetrahydrobenzo[c]phenanthrene.
The carcinogen (+)-(1R,2S,3R,4S)-3,4-dihydroxy-1,2-epoxy-1,2,3,4- tetrahydrobenzo[c]phenanthrene (in which the 4-OH group and epoxide oxygen are cis) was reacted with duplexes formed from self-complementary oligodeoxyribonucleotides, producing 1S or 1R configured adducts through trans or cis epoxide ring opening, respectively, by the exocyclic amino group of a central target A. Sequences containing 5'-AT-3' generated much higher S vs R ratios than the average of 3.38 observed with calf thymus DNA samples, while sequences containing 5'-TA-3' generated much lower ratios. Sequences with G in the position immediately 5' to the central AT or TA, and C in the position immediately 3', generated moderately higher ratios than did sequences with adjacent 5'C and 3'G. When thymidine was replaced by deoxyuridine in several sequences, the ratios of S vs R configured dA adducts and dA adducts vs dG adducts were substantially and uniformly reduced, but otherwise varied with the choice of nearest neighbors in patterns similar to those observed with the T containing sequences. Two hypothetical mechanisms are proposed to explain the effect of nearest neighbors on the S vs R dA adduct ratio; in both, diol epoxide intercalation precedes covalent bonding. In one mechanism, intercalation to the 5' side of the target A yields an S adduct while intercalation to the 3' side yields an R adduct, and the extent of adduct formation follows the nearest neighbor series G > C > T.(ABSTRACT TRUNCATED AT 250 WORDS)
Cheh
A M
AM
Department of Chemistry, American University, Washington, D.C. 20016.
Yagi
H
H
Jerina
D M
DM
D000818:Animals; D001483:Base Sequence; D002273:Carcinogens / Q000737:chemistry*; D002417:Cattle; D004247:DNA / Q000737:chemistry*; D018736:DNA Adducts / Q000737:chemistry*; D003839:Deoxyadenosines / Q000737:chemistry*; D046911:Macromolecular Substances; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation; D009838:Oligodeoxyribonucleotides / Q000737:chemistry; D010616:Phenanthrenes / Q000737:chemistry*; D013329:Structure-Activity Relationship
D002273:Carcinogens; D018736:DNA Adducts; D003839:Deoxyadenosines; D046911:Macromolecular Substances; D009838:Oligodeoxyribonucleotides; D010616:Phenanthrenes; C090203:1,2-epoxy-3,4-dihydroxy-1,2,3,4-tetrahydrobenzo(c)phenanthrene; D004247:DNA