Reaction mechanisms of trans-1,2-dihydroxy-anti-3,4-epoxy-1,2,3,4-tetrahydro-5-methylchrysene with DNA in aqueous solutions

M. H. Kim, Nicholas Geacintov, M. Pope, J. Pataki, R. G. Harvey

Research output: Contribution to journalArticle

Abstract

Reactions of trans-1,2-dihydroxy-anti-3,4-epoxy-1,2,3,4-tetrahydro-5-methylchrysene (anti-5-MeCDE) with DNA and the effects of ionic strength on the reaction were studied in aqueous buffer solution (5 mM sodium phosphate, pH 7) by means of absorption and fluorescence spectroscopy. The results are compared with those obtained with the widely studied metabolite model compound trans-7,8-dihydroxy-anti-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BaPDE). The rate constant of hydrolysis of 5-MeCDE is k = 1.0 x 104/s, which is ~ 35 times smaller than the value of k for BaPDE under similar conditions. As in the case of BaPDE, the rate of reaction of 5-MeCDE is accelerated in the presence of DNA. This effect is attributed to the rapid formation of physical association complexes (binding constant K) and the subsequent slower formation (rate constant k3) of carbo-cations at DNA binding sites, which in turn decay rapidly via hydrolysis to tetraols (1,2,3,4-tetrahydroxytetrahydro-5-methylchrysene, 5-MeCT) and to covalent adducts. The values of K and k3 are 2800 ± 300/M and 8.7 x 10-3/s respectively, and are reduced to 450 ± 100/M and 1.8 x 10-3/s in the presence of 0.1 M NaCl. The fraction of 5-MeCDE molecules which bind covalently to DNA is, on the other hand, constant under these conditions and lies in the range of 5-8%. Similar values for the covalent binding are observed for BaPDE, even though the physical association constant K is ~ 10 times larger than for 5-MeCDE under similar conditions. This difference in the values of K are attributed to the larger aromatic ring system in BaPDE which allows for a higher interaction of this molecule with the bases of DNA. Finally, the tetraol derived from the hydrolysis of 5-MeCDE also binds non-covalently to DNA, but the value of K is ~ 3 times smaller than for the diol epoxide.

Original languageEnglish (US)
Pages (from-to)121-126
Number of pages6
JournalCarcinogenesis
Volume6
Issue number1
StatePublished - 1985

Fingerprint

Reaction Mechanism
Epoxy
DNA
Rate Constant
Molecules
Fluorescence Spectroscopy
Hydrolysis
Absorption Spectroscopy
Phosphate
Sodium
Buffer
Rate constants
Association reactions
Decay
Ring
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide
Pyrene
Fluorescence spectroscopy
Binding sites
Metabolites

ASJC Scopus subject areas

  • Cancer Research
  • Statistics, Probability and Uncertainty
  • Applied Mathematics
  • Physiology (medical)
  • Physiology
  • Behavioral Neuroscience

Cite this

Reaction mechanisms of trans-1,2-dihydroxy-anti-3,4-epoxy-1,2,3,4-tetrahydro-5-methylchrysene with DNA in aqueous solutions. / Kim, M. H.; Geacintov, Nicholas; Pope, M.; Pataki, J.; Harvey, R. G.

In: Carcinogenesis, Vol. 6, No. 1, 1985, p. 121-126.

Research output: Contribution to journalArticle

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title = "Reaction mechanisms of trans-1,2-dihydroxy-anti-3,4-epoxy-1,2,3,4-tetrahydro-5-methylchrysene with DNA in aqueous solutions",
abstract = "Reactions of trans-1,2-dihydroxy-anti-3,4-epoxy-1,2,3,4-tetrahydro-5-methylchrysene (anti-5-MeCDE) with DNA and the effects of ionic strength on the reaction were studied in aqueous buffer solution (5 mM sodium phosphate, pH 7) by means of absorption and fluorescence spectroscopy. The results are compared with those obtained with the widely studied metabolite model compound trans-7,8-dihydroxy-anti-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BaPDE). The rate constant of hydrolysis of 5-MeCDE is k = 1.0 x 104/s, which is ~ 35 times smaller than the value of k for BaPDE under similar conditions. As in the case of BaPDE, the rate of reaction of 5-MeCDE is accelerated in the presence of DNA. This effect is attributed to the rapid formation of physical association complexes (binding constant K) and the subsequent slower formation (rate constant k3) of carbo-cations at DNA binding sites, which in turn decay rapidly via hydrolysis to tetraols (1,2,3,4-tetrahydroxytetrahydro-5-methylchrysene, 5-MeCT) and to covalent adducts. The values of K and k3 are 2800 ± 300/M and 8.7 x 10-3/s respectively, and are reduced to 450 ± 100/M and 1.8 x 10-3/s in the presence of 0.1 M NaCl. The fraction of 5-MeCDE molecules which bind covalently to DNA is, on the other hand, constant under these conditions and lies in the range of 5-8{\%}. Similar values for the covalent binding are observed for BaPDE, even though the physical association constant K is ~ 10 times larger than for 5-MeCDE under similar conditions. This difference in the values of K are attributed to the larger aromatic ring system in BaPDE which allows for a higher interaction of this molecule with the bases of DNA. Finally, the tetraol derived from the hydrolysis of 5-MeCDE also binds non-covalently to DNA, but the value of K is ~ 3 times smaller than for the diol epoxide.",
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T1 - Reaction mechanisms of trans-1,2-dihydroxy-anti-3,4-epoxy-1,2,3,4-tetrahydro-5-methylchrysene with DNA in aqueous solutions

AU - Kim, M. H.

AU - Geacintov, Nicholas

AU - Pope, M.

AU - Pataki, J.

AU - Harvey, R. G.

PY - 1985

Y1 - 1985

N2 - Reactions of trans-1,2-dihydroxy-anti-3,4-epoxy-1,2,3,4-tetrahydro-5-methylchrysene (anti-5-MeCDE) with DNA and the effects of ionic strength on the reaction were studied in aqueous buffer solution (5 mM sodium phosphate, pH 7) by means of absorption and fluorescence spectroscopy. The results are compared with those obtained with the widely studied metabolite model compound trans-7,8-dihydroxy-anti-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BaPDE). The rate constant of hydrolysis of 5-MeCDE is k = 1.0 x 104/s, which is ~ 35 times smaller than the value of k for BaPDE under similar conditions. As in the case of BaPDE, the rate of reaction of 5-MeCDE is accelerated in the presence of DNA. This effect is attributed to the rapid formation of physical association complexes (binding constant K) and the subsequent slower formation (rate constant k3) of carbo-cations at DNA binding sites, which in turn decay rapidly via hydrolysis to tetraols (1,2,3,4-tetrahydroxytetrahydro-5-methylchrysene, 5-MeCT) and to covalent adducts. The values of K and k3 are 2800 ± 300/M and 8.7 x 10-3/s respectively, and are reduced to 450 ± 100/M and 1.8 x 10-3/s in the presence of 0.1 M NaCl. The fraction of 5-MeCDE molecules which bind covalently to DNA is, on the other hand, constant under these conditions and lies in the range of 5-8%. Similar values for the covalent binding are observed for BaPDE, even though the physical association constant K is ~ 10 times larger than for 5-MeCDE under similar conditions. This difference in the values of K are attributed to the larger aromatic ring system in BaPDE which allows for a higher interaction of this molecule with the bases of DNA. Finally, the tetraol derived from the hydrolysis of 5-MeCDE also binds non-covalently to DNA, but the value of K is ~ 3 times smaller than for the diol epoxide.

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