Noncovalent binding of 7.beta.,8.alpha.-dihydroxy-9.alpha.,10.alpha.-epoxytetrahydrobenzo[a]pyrene to DNA and its catalytic effect on the hydrolysis of the diol epoxide to tetrol

Geacintov, Nicholas E.; Yoshida, Hiroko; Ibáñez, Víctor; Harvey, Ronald G.

doi:10.1021/bi00537a025

Cited by 59 publications

(62 citation statements)

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“…In these cases, the conformation and surface properties of nucleic acids likely contribute to the observed rate enhancements of reaction (18)(19)(20)(21)(22)(23)(24)(25). Probably the best studied example of this type of DNA-promoted process involves nucleobase reaction with cyclopropylpyrroloindole derivatives such as those found in natural products CC-1065 and the duocarmycins as well as a related synthetic analog bizelsin, currently undergoing clinical investigation (26)(27)(28)(29).…”

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confidence: 99%

A general strategy for target-promoted alkylation in biological systems

Zhou

Rokita²

2003

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

115

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confidence: 99%

A general strategy for target-promoted alkylation in biological systems

Zhou

Rokita²

2003

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

115

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“…The hydrolysis of BPDE has a spontaneous as well as an acidcatalyzed component that elevates the rate in acidic medium (18). The presence of either ds or ssDNA has been shown to clearly enhance the rate of hydrolysis of both the syn and anti isomers and is DNA-concentration-dependent (19)(20)(21).…”

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confidence: 99%

Reaction of aflatoxin B ₁ exo -8,9-epoxide with DNA: Kinetic analysis of covalent binding and DNA-induced hydrolysis

Johnson

Guengerich

1997

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

114

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The exo isomer of af latoxin B 1 (AFB 1 ) 8,9-epoxide appears to be the only product of AFB 1 involved in reaction with DNA and reacts with the N 7 atom of guanine via an S N 2 reaction from an intercalated state. Although the epoxide hydrolyzes rapidly in H 2 O (0.6 s ؊1 at 25°C), very high yields of DNA adduct result. Experimental binding data were fit to a model in which the epoxide forms a reversible complex with calf thymus DNA (K d ‫؍‬ 0.43 mg ml ؊1 , or 1.4 mM monomer equivalents) and reacts with guanine with a rate of 35 s ؊1 . Stopped-f low kinetic analysis revealed attenuation of f luorescence in the presence of DNA that was dependent on DNA concentration. Kinetic spectral analysis revealed that this process represents conjugation of epoxide with DNA, with an extrapolated rate maximum of 42 s ؊1 and half-maximal velocity at a DNA concentration of 1.8 mg ml ؊1 (5.8 mM monomer equivalents). The rate of hydrolysis of the epoxide was accelerated by calf thymus DNA in the range of pH 6-8, with a larger enhancement at the lower pH (increase of 0.23 s ؊1 at pH 6.2 with 0.17 mg DNA ml ؊1 ). The same rate enhancement effect was observed with poly[dA-dT]⅐poly[dAdT], in which the epoxide can intercalate but not form significant levels of N 7 purine adducts, and with singlestranded DNA. The increased rate of hydrolysis by DNA resembles that reported earlier for epoxides of polycyclic hydrocarbons and is postulated to involve a previously suggested localized proton field on the periphery of DNA. The epoxide preferentially intercalates between base pairs, and the proton field is postulated to provide acid catalysis to the conjugation reaction.Aflatoxin B 1 (AFB 1 ) exposure is a major factor in human liver cancer in some parts of the world. The compound is a natural product of the Aspergillus genus of molds, which grow on several foodstuffs stored in hot moist conditions, and is among the most potent hepatocarcinogens and genotoxins presently known. AFB 1 is enzymatically activated by cytochrome P450 3A4 to a very reactive epoxide (1, 2). AFB 1 exo-8,9-epoxide is the genotoxic isomer and reacts efficiently with DNA at the N 7 position of Gua, evidently after intercalation (Fig. 1) (3). We recently showed that AFB 1 exo-8,9-epoxide reacts spontaneously with H 2 O with a pseudo-first order rate of 0.6 s Ϫ1 at 25°C (4). Although DNA adduct yields have been determined (5), the instability of the AFB 1 exo-8,9-epoxide has precluded direct measurement of the reaction rate and the affinity for DNA.A proton-rich or low pH microenvironment at the surface of DNA molecules has recently been alleged, based on Poisson-Boltzmann distributions and Monte Carlo mathematical simulations (6, 7). We previously found the hydrolysis of AFB 1 exo-8,9-epoxide to be elevated by acid catalysis at pH Ͻ 5.4 but not base-catalyzed (4). Consequently, we considered this to be an excellent system for testing the theory of a proton-rich microenvironment around DNA, because such a field should enhance the hydrolysis rate. We show here that t...

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“…The observation made in several laboratories [4,5,7] that DNA catalyzes the hydrolysis of carcinogenic diol epoxides is of particular interest to this group in light of the recent calculation [8] indicating that the local environment of DNA has a high concentration of hydrogen ions. The significance of acidic domains around nucleic acids is primarily in the ability of the protons to catalyze reactions.…”

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Molecular orbital studies of the hydrolysis reactions of benzo[a]pyrene diol epoxides

Wong

Pack

1992

Int. J. Quantum Chem.

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Kinetic studies of the hydrolysis of benzo [a]pyrene diol epoxides have shown that hydrolysis proceeds through an acid-catalyzed SN1 mechanism and that the ratedetermining step is the formation of a benzylic carbocation. The formation of this carbocation indicates that the diol epoxide can react with nucleophilic sites on DNA as an alkylating agent. Previous work has indicated that the kinetic data could bc accurately fit to k,, = kH [H+] + b, in which kH [H+] is the pseudo first-order rate constant for acidcatalyzed hydrolysis and & is the rate constant for spontaneous hydrolysis. The observation made in several laboratories, that DNA catalyzes the hydrolysis of carcinogenic diol epoxides, is of direct interest in light of our recent calculation indicating that the local environment of DNA has a high concentration of hydrogen ions. The significance of acidic domains around nucleic acids is primarily in the ability of the protons to catalyze reactions. We have hypothesized that the high concentration of hydrogen ions at the DNA surface is responsible for the catalysis and that the generation of benzylic carbocations at the DNA surface can result in either nontoxic tetraols or in mutagenic nucleotide adducts, depending on the nucleophile with which the carbocation reacts. The calculations presented here are concerned with qualitatively understanding the rate constants in terms of the mechanisms of the acid-catalyzed and the spontaneous (HzO-catalyzed) hydrolysa. 0 1992 John Wiley & Sons, Inc.The environmental pollutant, benzo[a]pyrene, is the best characterized of the carcinogenic hydrocarbons. Two diastereomeric 7,8diol epoxides of benzo[a]-pyrene, BPDE-1, which has its oxirane ring syn with respect to the 7-hydroxy, and BPDE-2 in which the oxirane is anti with respect to the 7-hydroxy, are formed during metabolism. See Figure 1 for the structures and nomenclature. These diol epoxides (which each exist as enantiomeric pairs) may either react with the deoxyguanosine residue at the exocyclic amine site in the minor groove of DNA, leading to mutation of the genetic code, or they may be hydrolyzed to noncarcinogenic tetraols.The first kinetic studies of the hydrolysis of BPDE [ 1,2] showed that hydrolysis proceeds through an acid-catalyzed SN 1 mechanism. The rate-determining step was shown to be the formation of the benzylic carbocation. The formation of a carbocation precedes interaction with a nucleophile, which, in the case of the hydrolysis reactions, is a molecule of water. If formed in proximity to the surface of DNA, the carbocation might be expected to react with nucleophilic sites on DNA as an alkylating agent. Previous work [3] has indicated that the kinetic data can be accurately fit to

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Noncovalent binding of 7.beta.,8.alpha.-dihydroxy-9.alpha.,10.alpha.-epoxytetrahydrobenzo[a]pyrene to DNA and its catalytic effect on the hydrolysis of the diol epoxide to tetrol

Cited by 59 publications

References 31 publications

A general strategy for target-promoted alkylation in biological systems

A general strategy for target-promoted alkylation in biological systems

Reaction of aflatoxin B ₁ exo -8,9-epoxide with DNA: Kinetic analysis of covalent binding and DNA-induced hydrolysis

Molecular orbital studies of the hydrolysis reactions of benzo[a]pyrene diol epoxides

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Noncovalent binding of 7.beta.,8.alpha.-dihydroxy-9.alpha.,10.alpha.-epoxytetrahydrobenzo[a]pyrene to DNA and its catalytic effect on the hydrolysis of the diol epoxide to tetrol

Cited by 59 publications

References 31 publications

A general strategy for target-promoted alkylation in biological systems

A general strategy for target-promoted alkylation in biological systems

Reaction of aflatoxin B 1 exo -8,9-epoxide with DNA: Kinetic analysis of covalent binding and DNA-induced hydrolysis

Molecular orbital studies of the hydrolysis reactions of benzo[a]pyrene diol epoxides

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Reaction of aflatoxin B ₁ exo -8,9-epoxide with DNA: Kinetic analysis of covalent binding and DNA-induced hydrolysis