Effects of pH and salt concentration on the hydrolysis of a benzo[a]pyrene 7,8-diol-9,10-epoxide catalyzed by DNA and polyadenylic acid

Michaud, Dennis P.; Gupta, Satish C.; Whalen, Dale L.; Sayer, Jane M.; Jerina, Donald M.

doi:10.1016/0009-2797(83)90128-x

Cited by 47 publications

(29 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Similarly, the rate constant of B[ a ]PDE hydrolysis () was reduced 45 times in the presence of 0.1 M NaCl compared to native DNA containing no added salt . Our results on rate constants of hydrolysis in the presence of DNA are generally consistent with the pattern observed for anti -B[ a ]PDE ( , ) and anti -5-MeCDE (). However, the decreased rate constant values in denatured or Na + stabilized DNA in comparison with native DNA were not as dramatic as that observed for the anti -B[ a ]PDE or anti -5-MeCDE.…”

Section: Discussionsupporting

confidence: 89%

The Effect of Fluoro Substituents on Reactivity of 7-Methylbenz[a]anthracene Diol Epoxides

Baer‐Dubowska

Nair

Dubowski

et al. 1996

Chem. Res. Toxicol.

View full text Add to dashboard Cite

The present study has examined potential mechanisms for the influence of F-substituents on the biologic activity of methylbenz[a]anthracenes. DNA adducts derived from reaction of the racemic bay-region anti-diol epoxides of 7-methylbenz[a]anthracene, and its 9- and 10- fluoro derivatives, with calf thymus DNA in vitro were partially characterized. All three hydrocarbon diol epoxides produced similar DNA adduct profiles upon reaction with calf thymus DNA in vitro that were composed of two deoxyganosine and two deoxyadenosine adducts (tentatively identified as trans addition products). The extent of covalent binding to calf thymus DNA, as estimated by 32P-postlabeling, was similar for all three diol epoxides. The reactivity of the unsubstituted and 10-F-substituted diol epoxide was further assessed by measuring overall pseudo-first-order rate constants for hydrolysis in water or 0.1 M Tris-HCl buffer, pH 7.0, and in the presence or absence of native or denatured DNA. The rate constant for hydrolysis of 7-methylbenz[a]anthracene diol epoxide in the absence of DNA was similar to that of 10-F-7-methylbenz[a]anthracene diol epoxide (t1/2 = 138 min vs 115 min in water, respectively, and 93 vs 83 min in 0.1 M Tris-HCl buffer, respectively). In addition, the presence of DNA accelerated hydrolysis rates to similar extents for both diol expoxides. The skin tumor-initiating activities of the 9- and 10-F-substituted 3,4-diols of 7-methyl-, 12-methyl-, and 7,12-dimethylbenz[a]anthracene were determined in SENCAR mice. The presence of F-substituents in the 9- or 10- position did not enhance or in some cases reduced the tumor-initiating activity of the 3,4-diols of these hydrocarbons. Collectively, these results, as well as previous results from our laboratory, suggest that the influence of a F-substituent at position 10 of the benz[a]anthracene nucleus is not due to increased or altered reactivity of the bay-region diol epoxide but rather likely on the initial formation of the 3,4-diol.

show abstract

Section: Discussionsupporting

confidence: 89%

The Effect of Fluoro Substituents on Reactivity of 7-Methylbenz[a]anthracene Diol Epoxides

Baer‐Dubowska

Nair

Dubowski

et al. 1996

Chem. Res. Toxicol.

View full text Add to dashboard Cite

show abstract

“…Another finding was a progressively increasing frequency of oncogenic transformation and mutations as well as an increase in cytotoxicity with longer exposure of cells to BPDE I (Tables 111 and IV). This may indicate that, despite the general assumption, BPDE I remains active in the medium longer than has been generally accepted (usually on the order of minutes) [21,22]. Alternatively, BPDE I breakdown products may be cytotoxic and influence the occurrence of transformation and mutations.…”

Section: Discussionmentioning

confidence: 99%

“…This apparently very rapid transport of BPDE I molecules from the external medium into the cell is probably a passive one, related to the high affinity of this ultimate carcinogen for the cell membrane lipids. BPDE I sequestered within the lipid fraction of the cell has a much longer half-life [31] than in aqueous solutions [21,22] and, with time, is released to be bound with DNA. However, the kinetics of BPDE I release from the lipid fraction is unknown at the present time; further studies are needed to elucidate this mechanism.…”

Section: Discussionmentioning

confidence: 99%

Effect of duration of exposure to benzo(a)pyrene diol‐epoxide on neoplastic transformation, mutagenesis, cytotoxicity, and total covalent binding to DNA of rodent cells

Krolewski

Little

Reynolds

1988

Teratog Carcinog Mutagen

View full text Add to dashboard Cite

We examined the effect of different durations of exposure (20 sec to 24 hr) to (+/-) 7-beta,8 alpha-dihydroxy-9 alpha, 10 alpha -epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene (BPDE I) on the induction of transformation in C3H/10T 1/2 cells and of mutations to 6-thioguanine resistance in Chinese hamster ovary cells (CHO), as well as on BPDE I-DNA binding in these two cell lines. A 20-sec exposure of the cells to BPDE I was sufficient to induce mutations and morphological transformation in vitro. However, the transformation frequency in CH3 mouse-embryo-derived 10T 1/2 cells increased twofold and the frequency of mutations in CHO cells sixfold when the exposure time to BPDE I was increased from 20 sec to 8 h. Cytotoxicity increased under similar conditions. A large number of BPDE I-DNA adducts were formed in both cell lines within the first 15-min of exposure of the cells to this ultimate carcinogen. The total covalent binding did not increase with longer than 15-min incubation times. These results suggest that in addition to its covalent binding to DNA, BPDE I may influence other cellular mechanism(s) that are responsible for the initiation of transformation and mutagenesis.

show abstract

“…Standard BPDE-BME derivative was prepared by a similar method as described earlier35. An alkaline solution of BME (2 M, 10 mL) was prepared using 0.4 M aq.…”

Section: Methodsmentioning

confidence: 99%

Interaction of benzo[a]pyrene diol epoxide isomers with human serum albumin: Site specific characterisation of adducts and associated kinetics

Motwani

Westberg

Törnqvist

2016

Sci Rep

View full text Add to dashboard Cite

Carcinogenicity of benzo[a]pyrene {B[a]P, a polycyclic aromatic hydrocarbon (PAH)} involves DNA-modification by B[a]P diol epoxide (BPDE) metabolites. Adducts to serum albumin (SA) are not repaired, unlike DNA adducts, and therefore considered advantageous in assessment of in vivo dose of BPDEs. In the present work, kinetic experiments were performed in relation to the dose (i.e. concentration over time) of different BPDE isomers, where human SA (hSA) was incubated with respective BPDEs under physiological conditions. A liquid chromatography (LC) tandem mass spectrometry methodology was employed for characterising respective BPDE-adducts at histidine and lysine. This strategy allowed to structurally distinguish between the adducts from racemic anti- and syn-BPDE and between (+)- and (−)-anti-BPDE, which has not been attained earlier. The adduct levels quantified by LC-UV and the estimated rate of disappearance of BPDEs in presence of hSA gave an insight into the reactivity of the diol epoxides towards the N-sites on SA. The structure specific method and dosimetry described in this work could be used for accurate estimation of in vivo dose of the BPDEs following exposure to B[a]P, primarily in dose response studies of genotoxicity, e.g. in mice, to aid in quantitative risk assessment of PAHs.

show abstract

Effects of pH and salt concentration on the hydrolysis of a benzo[a]pyrene 7,8-diol-9,10-epoxide catalyzed by DNA and polyadenylic acid

Cited by 47 publications

References 25 publications

The Effect of Fluoro Substituents on Reactivity of 7-Methylbenz[a]anthracene Diol Epoxides

The Effect of Fluoro Substituents on Reactivity of 7-Methylbenz[a]anthracene Diol Epoxides

Effect of duration of exposure to benzo(a)pyrene diol‐epoxide on neoplastic transformation, mutagenesis, cytotoxicity, and total covalent binding to DNA of rodent cells

Interaction of benzo[a]pyrene diol epoxide isomers with human serum albumin: Site specific characterisation of adducts and associated kinetics

Contact Info

Product

Resources

About