Halide-catalyzed cis product formation in the hydrolysis of anti-benzo[a]pyrene diol epoxide and its alkylation of poly(A).
The carcinogen 7-r,8-t-dihydroxy-9-t,10-t-epoxy-7,8,9,10- tetrahydrobenzo[a]pyrene (anti-BPDE) forms diastereomeric cis and trans products in its reactions with nucleic acids and water (adducts and tetrols, respectively). The effects of salts, buffers, and DNA on the hydrolysis product ratio were tested. Halide ions increase the cis-tetrol/trans-tetrol ratio, with the order of effectiveness being I > Br > Cl >> F. No cation effect was apparent. Non-halide salts of strong acids increase the ratio to a small degree. Buffers decrease the ratio, with phosphate being more effective than cacodylate. DNA also reduces the ratio, with denatured DNA being more potent than native DNA. Halide ions appear to catalyze cis-tetrol formation via trans halohydrin intermediates. At the lowest halide concentrations which significantly raise the product ratio, and at all levels of chloride ion, the rate of anti-BPDE hydrolysis is not greatly increased, indicating that the halide ions are reacting primarily with the BPDE carbocation formed in the rate-determining step. At higher concentrations, iodide ion and, to a lesser degree, bromide ion significantly accelerate hydrolysis, indicating that BPDE undergoes SN2 attack by these ions. Chloride ion was also found to increase the proportion of cis adducts formed between anti-BPDE and poly(A). The cis adduct/trans adduct ratio was quadrupled by 0.5 M NaCl. This suggests that chlorohydrins can be intermediates in the alkylation of nucleic acids by epoxides of polycyclic aromatic hydrocarbons.
Wolfe
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AR
Division of Toxicology, University of California, San Francisco 94143.
Meehan
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T
D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide / Q000737:chemistry / Q000378:metabolism*; D000478:Alkylation; D001965:Bromides / Q000737:chemistry / Q000378:metabolism*; D002712:Chlorides / Q000737:chemistry / Q000378:metabolism*; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D006868:Hydrolysis; D007454:Iodides / Q000737:chemistry / Q000378:metabolism*; D007700:Kinetics; D008956:Models, Chemical; D011061:Poly A / Q000378:metabolism*
D001965:Bromides; D002712:Chlorides; D007454:Iodides; D011061:Poly A; D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide; D004247:DNA