Synthesis and reactions of the highly mutagenic 7,8-diol 9,10-epoxides of the carcinogen benzo[a]pyrene

Yagi, Haruhiko; Thakker, Dhiren R.; Hernández, Oscar; Koreeda, Masato; Jerina, Donald M.

doi:10.1021/ja00447a053

Cited by 187 publications

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“…Of these four DE isomers, (ϩ)-(7R,8S,9S,10R)-DE-2 predominates on metabolism of the hydrocarbon in mammals (3) and is also by far the most tumorigenic isomer in animal models (4). Reaction of BaP DEs with nucleic acids in cells or in vitro occurs mainly by trans and to a lesser extent cis ring opening of their epoxide rings at C10 by the exocyclic 2-and 6-amino groups of the guanine and adenine bases, respectively, to give 16 possible covalent adducts (5-8), with the trans-(10S) deoxyguanosine (dG) adduct derived from the highly tumorigenic to each other, the preferred conformation of the glycosidic bond between the sugar and the purine base, and the conformation of the partially saturated tetrahydro benzo-ring can potentially influence the fit of these adducts in DNA into the active site of DNA processing enzymes.Crystal structures for both the racemic BaP DE-1 (9) and DE-2 (10) diastereomers have confirmed their relative stereochemistry as deduced by NMR (11,12). Absolute configurations of their optically active precursor trans-7,8-dihydrodiols were assigned by exciton chirality CD spectroscopy (13) of a derivative, and the configurations of the DEs were established by chemical synthesis from the assigned dihydrodiols (13).…”

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confidence: 85%

“…Crystal structures for both the racemic BaP DE-1 (9) and DE-2 (10) diastereomers have confirmed their relative stereochemistry as deduced by NMR (11,12). Absolute configurations of their optically active precursor trans-7,8-dihydrodiols were assigned by exciton chirality CD spectroscopy (13) of a derivative, and the configurations of the DEs were established by chemical synthesis from the assigned dihydrodiols (13).…”

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confidence: 85%

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Crystal and molecular structure of a benzo[ a ]pyrene 7,8-diol 9,10-epoxide N ² -deoxyguanosine adduct: Absolute configuration and conformation

Karle

Yagi

Sayer

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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Benzo[a]pyrene 7,8-diol 9,10-epoxide adducts in DNA are implicated in mutagenesis, and their formation from the diol epoxides and subsequent incorrect replication by human DNA polymerases provide an attractive mechanism for the induction of cancer by this highly carcinogenic hydrocarbon and its diol epoxide metabolites. Here, we describe the crystal structure of such an adduct at the exocyclic amino group of a purine nucleoside. The present adduct derives from trans opening at C10 of the (؊)-(7S,8R)-diol (9R,10S)-epoxide enantiomer by the exocyclic N 2 -amino group of deoxyguanosine. In the crystal, the pyrene rings of adjacent molecules stack with each other, but the guanine bases do not stack either intermolecularly with each other or intramolecularly with the pyrene. The most notable features of the molecular structure are (i) independent and unambiguous proof of the absolute configuration of the adduct based on the spatial relationship between the known chiral carbon atoms of the deoxyribose and the four asymmetric centers in the hydrocarbon moiety; (ii) visualization of the relative orientations of the pyrene and guanine ring systems as well as the conformation of the partially saturated hydrocarbon ring (comprising carbon atoms 7, 8, 9, and 10), both of which conformational features in the crystal are in good agreement with deductions from NMR and CD measurements in solution; and (iii) the presence in the crystal of a syn glycosidic torsion angle, a conformation that is unusual in B-DNA but that may be involved in error-prone replication of these benzo[a]pyrene 7,8-diol 9,10-epoxide deoxyguanosine adducts by DNA polymerases.T he polycyclic aromatic hydrocarbon benzo[a]pyrene (BaP), first isolated from coal tar and characterized by Cook et al. in 1933 (1), is one of the most prevalent environmental carcinogens to which humans are exposed (2). It is metabolized in mammals (3) by oxidation on the angular benzo-ring (carbon atoms 7, 8, 9, and 10; Fig. 1) to give two enantiomeric pairs of diastereomeric 7,8-diol 9,10-epoxides (DEs), designated as DE-1 (benzylic 7-hydroxyl group and epoxide oxygen cis; also referred to as the syn diastereomer) and DE-2 (benzylic 7-hydroxyl group and epoxide oxygen trans; also referred to as the anti diastereomer). Of these four DE isomers, (ϩ)-(7R,8S,9S,10R)-DE-2 predominates on metabolism of the hydrocarbon in mammals (3) and is also by far the most tumorigenic isomer in animal models (4). Reaction of BaP DEs with nucleic acids in cells or in vitro occurs mainly by trans and to a lesser extent cis ring opening of their epoxide rings at C10 by the exocyclic 2-and 6-amino groups of the guanine and adenine bases, respectively, to give 16 possible covalent adducts (5-8), with the trans-(10S) deoxyguanosine (dG) adduct derived from the highly tumorigenic to each other, the preferred conformation of the glycosidic bond between the sugar and the purine base, and the conformation of the partially saturated tetrahydro benzo-ring can potentially influence the fit of these adducts in DNA...

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mentioning

confidence: 85%

mentioning

confidence: 85%

Crystal and molecular structure of a benzo[ a ]pyrene 7,8-diol 9,10-epoxide N ² -deoxyguanosine adduct: Absolute configuration and conformation

Karle

Yagi

Sayer

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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“…The formation of water-soluble material exhibited a similar time-and (bi)sulfite-dependence, yielding about 50%o as much product as the epoxidation reaction. These water-soluble products have not been reported (13) and are possibly sulfited products.…”

Section: Resultsmentioning

confidence: 87%

“…Epoxidation of BP-7,8-diol by peroxyl radicals (7-10) and by peracids (11-13) is well documented. Though other routes of epoxidation have been used (13), the oxygen insertion from peroxyl radicals or peracid proceeds with a pronounced stereoselectivity, producing anti-BPDE as the predominant product (7)(8)(9)(10)(11)(12)(13). This same stereoselectivity is observed for BP-7,8-diol epoxidation occurring either during (bi)sulfite autoxidation or when treated with peroxomonosulfate.…”

Section: Discussionmentioning

confidence: 89%

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Epoxidation of (+/-)-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene during (bi)sulfite autoxidation: activation of a procarcinogen by a cocarcinogen.

Reed¹,

Curtis²,

Mottley³

et al. 1986

Proc. Natl. Acad. Sci. U.S.A.

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The (bi)sulfite ion undergoes extensive autoxidation in neutral aqueous media with the formation of sulfur trioxide radical anion that is detected by ESR. The radical anion subsequently reacts with molecular oxygen to form a peroxyl radical. We find that when (±)-trans-7, 8-dihydroxy-7,8-dihydrobenzo[a]pyrene is included in this autoxidation system, BP-7,8-diol is converted to diolepoxides, ultimate carcinogenic derivatives of benzo [a]pyrene. This epoxidation occurs with a stereoselectivity consistent with either a peroxyl radical or a peracid as the epoxidizing agent. The epoxidation is dependent on the concentration of both (bi)sulfite and oxygen. In the presence of 10 IAM butylated hydroxyanisole, which abolishes (bi)sulflte autoxidation, no (bi)sulfite-dependent epoxidation occurs. These results are discussed in regard to the mechanism of (bi)sulfite autoxidation, and in relationship to the cocarcinogenicity of sulfur dioxide [anhydrous (bi)sulfite] for benzo [a]pyrene-induced pulmonary neoplasia.Sulfur dioxide, an environmental pollutant, exists primarily as the (bi)sulfite anion in aqueous solution at near neutral pH. The metal-catalyzed autoxidation of the (bi)sulfite anion, studied for decades, is an oxygen-consuming chain reaction (1-3). The initiating one-electron oxidation yields the sulfur trioxide radical anion ('SO-), a predominantly sulfur-centered radical (4) that reacts with molecular oxygen. Superoxide initiates (bi)sulfite oxidation by forming 'SO (1, 5) but is not a chain propagator (2, 5), implying superoxide is not formed by reactions of the '0j radical. Presumably the reaction product of SO with oxygen is a peroxyl free radical.S53 + 02 -03SOO. [1] Huie and Neta (6) presented a kinetic argument favoring this oxygen addition reaction. Since this pathway produces a peroxyl free radical, we sought to obtain chemical support for the formation of -03SOO during (bi)sulfite autoxidation based on products of a specific trapping reaction.The trapping agent employed was (±)-trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene . This compound is stereoselectively epoxidized to form (+)-7r,8t-dihydroxy-9t, 10t-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (anti-BPDE) by either peroxyl radicals (7-10) or peracids (11)(12)(13). The inclusion of BP-7,8-diol in an aqueous system for (bi)sulfite autoxidation did indeed lead to the production of anti-BPDE. In this paper we present a characterization of this epoxidation and consider the implications ofthis reaction in regard to the mechanism of (bi)sulfite autoxidation and the Butylated hydroxyanisole (BHA), 5,5-dimethyl-1-pyrroline N-oxide (DMPO), superoxide dismutase, and diethylenetriaminepentaacetic acid (DETAPAC) were from Sigma. Potassium peroxomonosulfate (OXONE, DuPont) was obtained from Aldrich. Polyoxyethylene sorbitan monolaurate (Tween 20) and all chromatography solvents were from Fisher.Reaction Conditions. Tritiated and unlabeled BP-7,8-diol, in ethanol, were added to the reaction vessel, and the solvent was evaporated under a stream of N2. The r...

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Heinrich Wieland hundert Jahre: Sein Werk und Vermächtnis heute

Witkop

1977

Angew. Chem.

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Synthesis and reactions of the highly mutagenic 7,8-diol 9,10-epoxides of the carcinogen benzo[a]pyrene

Cited by 187 publications

References 2 publications

Crystal and molecular structure of a benzo[ a ]pyrene 7,8-diol 9,10-epoxide N ² -deoxyguanosine adduct: Absolute configuration and conformation

Crystal and molecular structure of a benzo[ a ]pyrene 7,8-diol 9,10-epoxide N ² -deoxyguanosine adduct: Absolute configuration and conformation

Epoxidation of (+/-)-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene during (bi)sulfite autoxidation: activation of a procarcinogen by a cocarcinogen.

Heinrich Wieland hundert Jahre: Sein Werk und Vermächtnis heute

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Synthesis and reactions of the highly mutagenic 7,8-diol 9,10-epoxides of the carcinogen benzo[a]pyrene

Cited by 187 publications

References 2 publications

Crystal and molecular structure of a benzo[ a ]pyrene 7,8-diol 9,10-epoxide N 2 -deoxyguanosine adduct: Absolute configuration and conformation

Crystal and molecular structure of a benzo[ a ]pyrene 7,8-diol 9,10-epoxide N 2 -deoxyguanosine adduct: Absolute configuration and conformation

Epoxidation of (+/-)-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene during (bi)sulfite autoxidation: activation of a procarcinogen by a cocarcinogen.

Heinrich Wieland hundert Jahre: Sein Werk und Vermächtnis heute

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Crystal and molecular structure of a benzo[ a ]pyrene 7,8-diol 9,10-epoxide N ² -deoxyguanosine adduct: Absolute configuration and conformation

Crystal and molecular structure of a benzo[ a ]pyrene 7,8-diol 9,10-epoxide N ² -deoxyguanosine adduct: Absolute configuration and conformation