The polycyclic aromatic hydrocarbon carcinogens are formed in the inefficient combustion of organic matter and contaminate foods through direct deposition from the atmosphere or during cooking or smoking of foods. These potent carcinogens and mutagens require metabolism to dihydrodiol epoxide metabolites in order to express their biological activities. In vitro studies show that these reactive metabolites can react with the bases in DNA with different specificities depending upon the hydrocarbon from which they are derived. Thus, the more potent carcinogens react more extensively with adenine residues in DNA than do the less potent carcinogens, with the result that mutation at A . T base pairs is enhanced for the more potent carcinogens. In the past few years, considerable clarification of the mechanism of metabolic activation have been achieved and the focus for the immediate future is expected to be on how the reactive metabolites actually bring about biological responses.

Animals↗

PubMedDate not supplied

Characterization of 7,12-dimethylbenz[a]anthracene-adenine nucleoside adducts.

Chromatographic comparisons were made between radioactive adducts derived from the DNA of cells treated with [3H]7,12-dimethylbenz[a]anthracene and adducts derived from calf thymus DNA or nucleotides which had been treated in vitro with the synthetic syn 3,4-dihydrodiol 1,2-epoxide of this same carcinogen. This confirmed that three of the adducts formed in cells were derived from reaction of this particular dihydrodiol epoxide with deoxyadenosine while a fourth adduct was derived from its reaction with deoxyguanosine. After reaction of the dihydrodiol epoxide with polyadenylic acid, two ribonucleoside adducts were characterized by spectroscopic methods and were shown to have arisen from the cis opening of the epoxide ring at C1 by the amino group of adenine residues.

9,10-Dimethyl-1,2-benzanthracene↗

PubMedDate not supplied

Styrene oxide as a stereochemical probe for the mechanism of aralkylation at different sites on guanosine.

The stereochemistry at the alpha-carbon atom of the styrene moiety in styrene oxide-guanosine products was established, and the stereochemical consequences of reaction of optically active styrene oxide with guanosine were investigated. Inversion of stereochemistry in products at the alpha-carbon of styrene oxide decreased in the sequence 7- much greater than N2- greater than O6-substituted guanosines. These findings show that an extensively ionized substrate is needed for reaction at the exocyclic N2 and O6 sites on guanosine but that the reactive intermediate is not an ideal planar trigonal carbonium ion. This follows because inversion exceeds retention in both of the exocyclic substituted products.

Alkylation↗

PubMedDate not supplied

Sequence selectivity in the reaction of optically active hydrocarbon dihydrodiol epoxides with rat H-ras DNA.

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7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗

PubMedDate not supplied

DNA adducts from carcinogenic and noncarcinogenic enantiomers of benzo[a]pyrene dihydrodiol epoxide.

The characterization of eight benzo[a]pyrene-deoxyribonucleoside adducts derived from reaction of the anti-dihydrodiol epoxide and deoxyguanylic and deoxyadenylic acids is described. It is reported that the epoxide ring is opened by the purine amino groups to yield similar amounts of both cis and trans products. NMR data show that the 7- and 8-hydroxyl groups are pseudodiaxial in the cis products and pseudodiequatorial in the trans products, and we suggest that these products arise from reaction with the diaxial and diequatorial conformers of the dihydrodiol epoxides, respectively. The chiral nature of the interactions of these metabolites with DNA restricts the range of products formed with this macromolecule, and a trans product with deoxyguanosine is the major product formed with either enantiomer of the anti-dihydrodiol epoxide.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗

PubMedDate not supplied

Spectroscopic characterization of syn-5-methylchrysene 1,2-dihydrodiol 3,4-epoxide-deoxyribonucleoside adducts.

Eight deoxyribonucleoside adducts formed from reactions of syn-5-methylchrysene 1,2-dihydrodiol 3,4-epoxide with DNA or with nucleotides were characterized spectroscopically. The adducts arose from both cis and trans opening of the epoxide ring at C4 by the amino group of either deoxyadenosine or deoxyguanosine residues. NMR data indicated that the partially saturated 1,2,3,4-ring of the hydrocarbon residue adopted a boatlike conformation, with the purine residue being disposed pseudoaxially in all adducts. The cis and trans assignments for epoxide ring opening were readily made from coupling constants. Quantitatively, cis adducts predominated over trans adducts in both DNA and nucleotide reactions. Whereas deoxyadenylic acid appeared to trap this dihydrodiol epoxide more efficiently than deoxyguanylic acid, reaction with DNA led to more extensive reaction with deoxyguanosine than with deoxyadenosine residues.

Carcinogens↗

PubMedDate not supplied

Identification of individual benzo[c]phenanthrene dihydrodiol epoxide-DNA adducts by the 32P-postlabeling assay.

Purine deoxyribonucleoside 3'-phosphates were reacted separately with the four configurational isomers of benzo[c]phenanthrene 3,4-dihydrodiol 1,2-epoxide. Products resulting from the cis and trans opening of the epoxide ring by the exocyclic amino groups of deoxyadenosine and deoxyguanosine 3'-phosphates were separated by high-pressure liquid chromatography and identified by comparison of the observed circular dichroism spectra with the known spectra for the corresponding nucleoside adducts. The 16 structurally identified benzo[c]phenanthrene-purine deoxyribonucleoside 3'-phosphate adducts were then separately postlabeled according to the Randerath method, and the positions of the individual bisphosphates were mapped by thin-layer chromatography. Chromatographic conditions were developed that allowed separation of the four adducts for 3 of the 4 dihydrodiol epoxide isomers.

Chromatography, High Pressure Liquid↗

PubMedDate not supplied

Reaction with DNA and mutagenic specificity of syn-benzo[g]chrysene 11,12-dihydrodiol 13,14-epoxide.

The spectroscopic characterization of purine deoxyribonucleoside adducts derived from the fjord-region syn-benzo[g]chrysene 11,12-dihydrodiol 13,14-epoxide and the mutagenic specificity of the latter compound for the supF gene in the pSP189 shuttle vector are described. This dihydrodiol epoxide preferentially forms adducts with deoxyadenosine residues in DNA and is preferentially opened trans in reactions with DNA or with deoxyribonucleotides. In common with other fjord-region syn-dihydrodiol epoxides, the most frequently observed mutational changes were A-->T and G-->T changes. This hydrocarbon dihydrodiol epoxide is structurally similar to syn-benzo[c]phenanthrene 3,4-dihydrodiol 1,2-epoxide but has an additional benzene ring annelated distant from the reaction center. As anticipated, there were some common features in the chemistry and mutagenicities of these two compounds, but there were also substantive differences which indicate factors of importance in controlling reactions of these kinds of compounds with DNA.

Animals↗

PubMedDate not supplied

DNA sequence changes induced by two nitric oxide donor drugs in the supF assay.

To refine our understanding of the mutational spectra one might expect on exposure of human cells to nitric oxide (NO), we have treated the plasmid pSP189 at pH 7.4 with two compounds that generate NO spontaneously in solution, and then sequenced the mutations found when the treated plasmid was transfected into human Ad293 cells and allowed to replicate. G.C-->A.T transitions were the most abundant mutation observed with these NO donor drugs, whereas in previous work, A.T-->G.C transitions predominated when nitric oxide gas was bubbled through the plasmid solution under otherwise identical conditions. A difference in reactive intermediates formed in solution- versus gas-phase NO exposure was demonstrated by treating buffered 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonate) (ABTS) or ferrocyanide, in the presence or absence of azide, aerobically with preformed solutions of NO, with solutions of the two NO-releasing compounds, or with gaseous mixtures of equimolar NO/O2 in air; oxidation of these substrates was extensive with the gas-phase NO source whether azide was present or not, while azide almost completely quenched the oxidation pathway in the solution-phase reactions.

Azides↗

PubMedDate not supplied

Mutational spectra for 5,6-dimethylchrysene 1,2-dihydrodiol 3,4-epoxides in the supF gene of pSP189.

Dihydrodiol epoxides from 5,6-dimethylchrysene exhibit properties similar to those of fjord region-containing hydrocarbon derivatives in that they react extensively with deoxyadenosine residues in DNA and consequently generate substantial numbers of mutations at AT pairs as well as GC pairs. The syn-dihydrodiol epoxide favors reaction with deoxyadenosine (68% of adducts) to a greater extent than does the anti-dihydrodiol epoxide (52% of adducts), and point mutations at AT pairs (72% for syn- and 45% for anti-dihydrodiol epoxide) follow the same trend. A novel feature of the mutagenicity of the 5,6-dimethylchrysene derivatives is that they exhibit a higher fraction of AT-->GC transitions (28% and 26% for syn and anti, respectively) than has been seen for other hydrocarbon derivatives to date.

Base Sequence↗