Anticarcinogenic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on benzo(a)pyrene and 7,12-dimethylbenz(a)anthracene tumor initiation and its relationship to DNA binding

G. M. Cohen, W. M. Bracken, R. P. Iyer, D. L. Berry, J. K. Selkirk, Thomas J Slaga

Research output: Contribution to journalArticle

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Abstract

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) pretreatment inhibits the carcinogenicity of both benzo(a)pyrene [B(a)P] and dimethylbenz(a)anthracene when they are applied as skin tumor initiators in female Sencar mice. TCDD caused a marked decrease in the in vivo covalent binding of dimethylbenz(a)anthracene to DNA and RNA but caused a significant increase in the in vivo binding of B(a)P to DNA with relatively little change in RNA binding. The in vivo binding of B(a)P to DNA in the absence of TCDD pretreatment was accompanied by formation of a major hydrocarbon-deoxyribonucleoside adduct which cochromatographed with 7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene bound to the exocyclic amino group of guanine. The increased in vivo binding to DNA following pretreatment with TCDD did not result in the formation of detectable amounts of this adduct but in the formation of other, as yet unidentified adducts. It is suggested, partly on our observation, that the absence of the adduct of 7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene bound to guanine corresponded to the marked tumor-inhibitory properties of TCDD and that formation of this adduct may be a critical but by itself an inadequate step in B(a)P-induced mouse skin carcinogenesis. Thus, the inhibition by TCDD of B(a)P skin tumorigenesis correlated with the loss of known hydrocarbon-deoxyribonucleoside adducts but not with the total binding to DNA. This stresses the importance of the qualitative, not just the quantitative, nature of the hydrocarbon-DNA interactions and its subsequent relationship to carcinogenesis.

Original languageEnglish (US)
Pages (from-to)4027-4033
Number of pages7
JournalCancer Research
Volume39
Issue number10
StatePublished - 1979
Externally publishedYes

Fingerprint

Anticarcinogenic Agents
Benzo(a)pyrene
DNA
Hydrocarbons
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide
Deoxyribonucleosides
Neoplasms
Carcinogenesis
Guanine
Skin
RNA
Carcinogens
anthracene
Polychlorinated Dibenzodioxins
Observation

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Anticarcinogenic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on benzo(a)pyrene and 7,12-dimethylbenz(a)anthracene tumor initiation and its relationship to DNA binding. / Cohen, G. M.; Bracken, W. M.; Iyer, R. P.; Berry, D. L.; Selkirk, J. K.; Slaga, Thomas J.

In: Cancer Research, Vol. 39, No. 10, 1979, p. 4027-4033.

Research output: Contribution to journalArticle

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abstract = "2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) pretreatment inhibits the carcinogenicity of both benzo(a)pyrene [B(a)P] and dimethylbenz(a)anthracene when they are applied as skin tumor initiators in female Sencar mice. TCDD caused a marked decrease in the in vivo covalent binding of dimethylbenz(a)anthracene to DNA and RNA but caused a significant increase in the in vivo binding of B(a)P to DNA with relatively little change in RNA binding. The in vivo binding of B(a)P to DNA in the absence of TCDD pretreatment was accompanied by formation of a major hydrocarbon-deoxyribonucleoside adduct which cochromatographed with 7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene bound to the exocyclic amino group of guanine. The increased in vivo binding to DNA following pretreatment with TCDD did not result in the formation of detectable amounts of this adduct but in the formation of other, as yet unidentified adducts. It is suggested, partly on our observation, that the absence of the adduct of 7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene bound to guanine corresponded to the marked tumor-inhibitory properties of TCDD and that formation of this adduct may be a critical but by itself an inadequate step in B(a)P-induced mouse skin carcinogenesis. Thus, the inhibition by TCDD of B(a)P skin tumorigenesis correlated with the loss of known hydrocarbon-deoxyribonucleoside adducts but not with the total binding to DNA. This stresses the importance of the qualitative, not just the quantitative, nature of the hydrocarbon-DNA interactions and its subsequent relationship to carcinogenesis.",
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