105880-23-7Relevant articles and documents
Influence of Na+ on DNA reactions with aromatic epoxides and diol epoxides: Evidence that DNA catalyzes the formation of benzo[a]pyrene and benz[a]anthracene adducts at intercalation sites
Fernando, Harshica,Huang, Chao-Ran,Milliman, Ann,Shu, Luchuan,LeBreton, Pierre R.
, p. 1391 - 1402 (2007/10/03)
Reactions of the benzo[a]pyrene (BP) and benz[a]anthracene (BA) metabolites, (±)-trans-7, 8-dihydroxy-anti-9, 10-epoxy-7, 8, 9, 10- tetrahydro-BP (BPDE), (±)-trans-3, 4-dihydroxy-anti-1, 2-epoxy-1, 2, 3, 4- tetrahydro-BA (BADE), (±)-BP-4, 5-oxide (BPO), and (±)-BA-5, 6-oxide (BAO), were examined under pseudo-first-order conditions at varying Na+ (2.0-100 mM) and native, calf thymus DNA (ctDNA) concentrations. In 0.2 mM ctDNA and 2.0 mM Na+, at a pH of 7.3, most BPDE, BADE, BPO, and BAO (87-95%) undergo DNA catalyzed hydrolysis or rearrangement. For BPDE and BPO, overall, pseudo- first-order rate constants, k, in 2.0 mM Na+ and 0.2 mM ctDNA are 21-72 times larger than values obtained without DNA. For BADE and BAO, the rate constants are less strongly influenced by DNA; k values in 0.2 mM ctDNA are only 9-12 times larger than values obtained without DNA. Kinetic data for BPDE, BPO, BADE, and BAO and DNA intercalation association constants (K(A)) for BP and BA diols which are model compounds indicate that K(A) values for BPDE and BPO in 2.0 mM Na+ are 6.6-59 times larger than those of BADE and BAO. The greater DNA enhancement of rate constants for BPDE and BPO, versus BADE and BAO, correlates with the larger K(A) values of the BP metabolites. DNA adducts, which account for less than 10% of the yields, also form. For BPDE in 0.20 mM ctDNA, k decreases 5.1 times as the Na+ concentration increases from 2.0 to 100 mM. Nevertheless, the DNA adduct level remains constant over the range of Na+ concentrations examined. These results provide evidence that, for BPDE in 0.20 mM DNA and 2.0 mM Na+, ctDNA adduct formation follows a mechanism which is similar to that for DNA catalyzed hydrolysis. The pseudo-first-order rate constant for adduct formation, k(Ad), given approximately by k(Ad) ? (k(cat, Ad)K(A)[DNA])/(1 + K(A)[DNA]), where k(cat, Ad) is a catalytic rate constant. For BADE, BPO, and BAO, the influence of varying DNA and Na+ concentrations on k values is similar to that for BPDE, and provides evidence that the formation of adducts follows the same rate law.
Detection of DNA and globin adducts of polynuclear aromatic hydrocarbon diol epoxides by gas chromatography - Mass spectrometry and [3H]CH3I postlabeling of released tetraols
Melikian, Assieh A.,Sun, Peng,Coleman, Stuart,Amin, Shantu,Hecht, Stephen S.
, p. 508 - 516 (2007/10/03)
Gas chromatography - negative ion chemical ionization mass spectrometry - selected ion monitoring (GC-NICI-MS-SIM) was employed to detect tetramethyl ether derivatives of tetraols formed upon hydrolysis of DNA and globin adducts derived from diol epoxides of benzo[α]-pyrene (BP) and other polynuclear aromatic hydrocarbons (PAH). The tetramethyl ether derivatives could also be detected by [3H]CH3I postlabeling. The methodology involves the following steps: (1) isolation of DNA or globin; (2) mild acid hydrolysis under vacuum; (3) isolation of the resulting tetraols and derivatization to the corresponding tetramethyl ethers using methyl sulfinyl carbanion and unlabeled or 3H-labeled CH3I; (4) analysis by GC-NICI-MS-SIM or HPLC with radioflow detection. The optimum conditions for hydrolysis of adducts and derivatization of the resulting tetraols as well as the feasibility of this approach for detecting PAH adducts in mice and humans were explored. Using the set of four BP-tetraols that can be formed upon hydrolysis of adducts formed from r-7,t-8-dihydroxy-t-9,10-epoxy-7,8,9,10-tetrahydrobenzo[α]pyrene (anti-BPDE) or r-7,t-8-dihydroxy-c-9,10-epoxy-7,8,9,10-tetrahydrobenzo-[α]pyrene (syn-BPDE) as models, the stability of the tetraols under the hydrolysis conditions was investigated. Adducts derived from anti-BPDE yield predominantly the stable r-7,t-8,9-c-10-tetrahydroxy-7,8,9,10-tetrahydrobenzo[α]pyrene (trans-anti-BP-tetraol), while adducts derived from syn-BPDE released cis-syn-BP-tetraol as a major hydrolysis product. Hydrolysis under vacuum significantly increased the recovery of tetraols. Conditions for derivatization of the BP-tetraols as well as tetraols derived from several other PAH anti-diol epoxides were investigated. Tetramethyl ethers proved to be superior derivatives that were stable, easy to prepare in high yields, and detectable with high sensitivity by GC-NICI-MS-SIM (1-50 fmol per injection). Alternatively, these derivatives could be detected by HPLC with radioflow detection if [3H]CH3I were employed for derivatization. The methodology was tested by comparing levels of DNA and globin adducts in mice treated with either unlabeled or 3H-labeled BP. Good agreement was obtained among the GC-NICI-MS-SIM, [3H]CH3I postlabeling, and conventional radiometric methods. Moreover, analysis of human hemoglobin by GC-NICI-MS-SIM resulted in detection of adducts derived from anti-BPDE and r-1,t-2-dihydroxy-t-3,4-epoxy-1,2,3,4-tetrahydrochrysene. The results of this study demonstrate that GC-NICI-MS-SIM of tetramethyl ethers of tetraols formed by hydrolysis of PAH diol epoxide DNA and globin adducts is a promising approach for detection and quantitation of adducts derived from a broad range of PAH.
Conformational Effects in the Hydrolyses of Benzo-Ring Diol Epoxides That Have Bay-Region Diol Groups
Sayer, J. M.,Whalen, D. L.,Friedman, S. L.,Paik, A.,Yagi, H.,et al.
, p. 226 - 233 (2007/10/02)
Kinetics of the hydronium ion catalyzed(KH) and pH-independent (k0) hydrolyses of several benzo-ring diol epoxides, derived from polycyclic aromatic hydrocarbons, that possess bay-region trans diol groups have been investigated in 1:9 dioxane-water at 25 deg C.These epoxides are 1,2,3,4-tetrahydrobenzanthracene-1,2-diol 3,4-epoxide, 1,2,3,4-tetrahydrotriphenylene-1,2-diol 3,4-epoxide, and 9,10,11,12-tetrahydrobenzopyrene-9,10-diol 11,12-epoxide.Both possible diastereomers of the diol epoxides in which the two hydroxyl groups are trans to each other were investigated: isomer 1, in which the benzylic hydroxyl group is cis to the epoxide oxigen, and isomer 2, in which this hydroxyl group and the epoxide oxygen are trans.The corresponding tetrahydro epoxides that lack a diol group were also investigated.For comparison, isomers 1 and 2 of 1,2,3,4-tetrahydrobenzanthracene-3,4-diol 1,2-epoxide, a bay-region epoxide with a non-bay-region trans diol group, and the corresponding benzanthracene tetrahydro epoxide were also studied.The most striking feature of the reactions of the diol epoxides that possess a bay-region diol group is a reversal of the relative reactivity of isomers 1 and 2 in the k0 reaction, when compared with diol epoxides whose diol group is not in a bay region.This reversal of reactivity, which causes k0 to be larger for isomer 2 than for isomer 1 when the diol is in a bay region, is explained by changes in conformational equilibria involving the cyclohexene ring due to steric crowding of the bay-region diol.Preference of this diol group for a pseudodiaxial conformation favors a conformation of isomer 2 which the benzylic C-O bond of the epoxide is more or less aligned with the ? orbitals of the aromatic system and strongly disfavors this aligned conformation of isomer 1.Reaction via the k0 process is faster for the aligned than for the nonaligned conformer; thus for epoxides with bay-region diol groups, k0 for isomer 2 is faster than k0 for isomer 1.The pH-independent reaction of isomer 2 of 1,2,3,4-tetrahydrobenzanthracene-1,2-diol 3,4-epoxide via the aligned conformer gives, in addition to cis and trans tetraol products, substantial quantitites of a keto diol, whereas no keto diol was detected from the corresponding isomer 1.This also represents a reversal of the pattern of product formation generally observed with diol epoxides that lack a bay region in the vicinity of the diol group.Rate constants for hydronium ion catalyzed hydrolysis (kH) are much less sensitive to conformational factors than k0.The distribution of cis and trans tetraol products from hydronium ion catalyzed hydrolysis of the 1,2,3,4-tetrahydrobenzanthracene-1,2-diol 3,4-epoxides and the 1,2,3,4-tetrahydrotriphenylene-1,2-diol 3,4-epoxides can be explained by preferential pseudoaxial attack of water upon the benzylic cations formed from these epoxides.On the basis of these observations and previous findings with non-bay-region diol, bay-region epoxides, rules for predicting the effects of conformation on rates...
