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Abstract

1. Development of the chemistry of polycyclic aromatic hydrocarbon (PAH) radical cations has provided evidence that these intermediates play a major role in the metabolism of PAHs by P450 and in their binding to DNA. 2. Fluoro substitution of benzo[a]pyrene (BP) represents a suitable probe for studying mechanisms of oxygen transfer in the P450-catalysed formation of quinones and phenols from BP. Formation of BP-1,6-, -3,6- and -6,12-dione from the metabolism of 6-fluoroBP (6-FBP) is mediated by the intermediate 6-FBP+. Similarly, metabolism of 1-FBP and 3-FBP by rat liver microsomes produces BP-1,6-dione and BP-3,6-dione respectively. These results demonstrate that formation of quinones and phenols occurs via an initial electron transfer from BP to P450 and subsequent transfer of oxygen from the iron-oxo complex of P450 to BP. 3. Radical cations also play a major role in the formation of DNA adducts by the potent carcinogens 7,12-dimethylbenz[a]anthracene (DMBA), BP and dibenzo[a, l]pyrene (DB[a, l]P). In the binding of BP both in vitro and in vivo, 80% of the adducts are formed by one-electron oxidation, namely, 8-(BP-6-yl)guanine (BP-6-C8Gua), BP-6-N7Gua and BP-6-N7adenine (Ade), and are lost from the DNA by depurination. For DB[a, l]P, depurinating adducts formed from the radical cation, DB[a, l]P-10-C8Gua, DB[a, l]P-10-N7Gua, DB[a, l]P-10-N7Ade, and DB[a, l]P-10-N3Ade comprise 50% of the total DNA adducts. For DMBA, 99% of the adducts are depurinating adducts formed from the radical cation, 7-CH3BA-12-CH2-N7Gua and 7-CH3BA-12-CH2-N7Ade. 4. In summary, radical cations of PAHs play a major role in both the metabolism and metabolic activation leading to formation of DNA adducts that are critical in the mechanism of tumour initiation.

Original languageEnglish (US)
Pages (from-to)677-688
Number of pages12
JournalXenobiotica
Volume25
Issue number7
DOIs
StatePublished - Jan 1 1995

Fingerprint

Polycyclic Aromatic Hydrocarbons
Cations
Metabolism
Chemical activation
DNA Adducts
Quinones
9,10-Dimethyl-1,2-benzanthracene
Phenols
Polycyclic aromatic hydrocarbons
Electrons
Oxygen
Benzo(a)pyrene
DNA
Guanine
Liver Microsomes
Carcinogens
Liver
Rats
Tumors
Substitution reactions

ASJC Scopus subject areas

  • Biochemistry
  • Toxicology
  • Pharmacology
  • Health, Toxicology and Mutagenesis

Cite this

Central role of radical cations in metabolic activation of polycyclic aromatic hydrocarbons. / Cavalieri, Ercole; Rogan, Eleanor G.

In: Xenobiotica, Vol. 25, No. 7, 01.01.1995, p. 677-688.

Research output: Contribution to journalArticle

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title = "Central role of radical cations in metabolic activation of polycyclic aromatic hydrocarbons",
abstract = "1. Development of the chemistry of polycyclic aromatic hydrocarbon (PAH) radical cations has provided evidence that these intermediates play a major role in the metabolism of PAHs by P450 and in their binding to DNA. 2. Fluoro substitution of benzo[a]pyrene (BP) represents a suitable probe for studying mechanisms of oxygen transfer in the P450-catalysed formation of quinones and phenols from BP. Formation of BP-1,6-, -3,6- and -6,12-dione from the metabolism of 6-fluoroBP (6-FBP) is mediated by the intermediate 6-FBP+. Similarly, metabolism of 1-FBP and 3-FBP by rat liver microsomes produces BP-1,6-dione and BP-3,6-dione respectively. These results demonstrate that formation of quinones and phenols occurs via an initial electron transfer from BP to P450 and subsequent transfer of oxygen from the iron-oxo complex of P450 to BP. 3. Radical cations also play a major role in the formation of DNA adducts by the potent carcinogens 7,12-dimethylbenz[a]anthracene (DMBA), BP and dibenzo[a, l]pyrene (DB[a, l]P). In the binding of BP both in vitro and in vivo, 80{\%} of the adducts are formed by one-electron oxidation, namely, 8-(BP-6-yl)guanine (BP-6-C8Gua), BP-6-N7Gua and BP-6-N7adenine (Ade), and are lost from the DNA by depurination. For DB[a, l]P, depurinating adducts formed from the radical cation, DB[a, l]P-10-C8Gua, DB[a, l]P-10-N7Gua, DB[a, l]P-10-N7Ade, and DB[a, l]P-10-N3Ade comprise 50{\%} of the total DNA adducts. For DMBA, 99{\%} of the adducts are depurinating adducts formed from the radical cation, 7-CH3BA-12-CH2-N7Gua and 7-CH3BA-12-CH2-N7Ade. 4. In summary, radical cations of PAHs play a major role in both the metabolism and metabolic activation leading to formation of DNA adducts that are critical in the mechanism of tumour initiation.",
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AU - Rogan, Eleanor G

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N2 - 1. Development of the chemistry of polycyclic aromatic hydrocarbon (PAH) radical cations has provided evidence that these intermediates play a major role in the metabolism of PAHs by P450 and in their binding to DNA. 2. Fluoro substitution of benzo[a]pyrene (BP) represents a suitable probe for studying mechanisms of oxygen transfer in the P450-catalysed formation of quinones and phenols from BP. Formation of BP-1,6-, -3,6- and -6,12-dione from the metabolism of 6-fluoroBP (6-FBP) is mediated by the intermediate 6-FBP+. Similarly, metabolism of 1-FBP and 3-FBP by rat liver microsomes produces BP-1,6-dione and BP-3,6-dione respectively. These results demonstrate that formation of quinones and phenols occurs via an initial electron transfer from BP to P450 and subsequent transfer of oxygen from the iron-oxo complex of P450 to BP. 3. Radical cations also play a major role in the formation of DNA adducts by the potent carcinogens 7,12-dimethylbenz[a]anthracene (DMBA), BP and dibenzo[a, l]pyrene (DB[a, l]P). In the binding of BP both in vitro and in vivo, 80% of the adducts are formed by one-electron oxidation, namely, 8-(BP-6-yl)guanine (BP-6-C8Gua), BP-6-N7Gua and BP-6-N7adenine (Ade), and are lost from the DNA by depurination. For DB[a, l]P, depurinating adducts formed from the radical cation, DB[a, l]P-10-C8Gua, DB[a, l]P-10-N7Gua, DB[a, l]P-10-N7Ade, and DB[a, l]P-10-N3Ade comprise 50% of the total DNA adducts. For DMBA, 99% of the adducts are depurinating adducts formed from the radical cation, 7-CH3BA-12-CH2-N7Gua and 7-CH3BA-12-CH2-N7Ade. 4. In summary, radical cations of PAHs play a major role in both the metabolism and metabolic activation leading to formation of DNA adducts that are critical in the mechanism of tumour initiation.

AB - 1. Development of the chemistry of polycyclic aromatic hydrocarbon (PAH) radical cations has provided evidence that these intermediates play a major role in the metabolism of PAHs by P450 and in their binding to DNA. 2. Fluoro substitution of benzo[a]pyrene (BP) represents a suitable probe for studying mechanisms of oxygen transfer in the P450-catalysed formation of quinones and phenols from BP. Formation of BP-1,6-, -3,6- and -6,12-dione from the metabolism of 6-fluoroBP (6-FBP) is mediated by the intermediate 6-FBP+. Similarly, metabolism of 1-FBP and 3-FBP by rat liver microsomes produces BP-1,6-dione and BP-3,6-dione respectively. These results demonstrate that formation of quinones and phenols occurs via an initial electron transfer from BP to P450 and subsequent transfer of oxygen from the iron-oxo complex of P450 to BP. 3. Radical cations also play a major role in the formation of DNA adducts by the potent carcinogens 7,12-dimethylbenz[a]anthracene (DMBA), BP and dibenzo[a, l]pyrene (DB[a, l]P). In the binding of BP both in vitro and in vivo, 80% of the adducts are formed by one-electron oxidation, namely, 8-(BP-6-yl)guanine (BP-6-C8Gua), BP-6-N7Gua and BP-6-N7adenine (Ade), and are lost from the DNA by depurination. For DB[a, l]P, depurinating adducts formed from the radical cation, DB[a, l]P-10-C8Gua, DB[a, l]P-10-N7Gua, DB[a, l]P-10-N7Ade, and DB[a, l]P-10-N3Ade comprise 50% of the total DNA adducts. For DMBA, 99% of the adducts are depurinating adducts formed from the radical cation, 7-CH3BA-12-CH2-N7Gua and 7-CH3BA-12-CH2-N7Ade. 4. In summary, radical cations of PAHs play a major role in both the metabolism and metabolic activation leading to formation of DNA adducts that are critical in the mechanism of tumour initiation.

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