Metabolism of 1- and 3-Fluorobenzo[a]pyrene by Cytochrome P450 and Horseradish Peroxidase

Ercole Cavalieri, Prabhakar Devanesan, Patrick Mulder, N. V S Ramakrishna, Eleanor G Rogan

Research output: Contribution to journalArticle

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Abstract

Benzo[a]pyrene (BP) is a good model for elucidating the mechanism of oxygen transfer for substrates that are considered good electron donors. Fluoro substitution of BP represents a suitable probe for studying mechanisms of oxygen transfer in the metabolic formation of BP quinones and BP phenols. By using this strategy with 6-fluoroBP (6-FBP), we have previously demonstrated that the BP quinones are formed metabolically via an initial one-electron oxidation of BP catalyzed by cytochrome P450. Now we have synthesized 1-FBP and 3-FBP with the purpose of elucidating the mechanism of phenol formation. If formation of 3-hydroxyBP (3-OHBP) (major metabolite of BP) and 1-OHBP (minor metabolite of BP) occurs via an initial electron transfer from BP to cytochrome P450, when we use 3-FBP and 1-FBP as substrates, one of the metabolites formed should be BP-3,6-dione and BP-1,6-dione, respectively, with displacement of fluorine. Metabolism of 1-FBP and 3-FBP by rat liver microsomes and by horseradish peroxidase (HRP) was conducted. With 1-FBP, BP-1,6-dione was obtained with cytochrome P450 or HRP. In addition, with cytochrome P450 the 4,5-, 7,8- and 9,10-dihydrodiol and a phenol of 1-FBP were obtained. With 3-FBP as substrate, HRP produced only BP-3,6-dione, whereas cytochrome P450 produced BP-3,6-dione, the 4,5-, 7,8- and 9,10-dihydrodiol, and a phenol of 3-FBP. The formation of BP quinones from 1-FBP and 3-FBP clearly demonstrates that 3-OHBP and 1-OHBP in the metabolism of BP are produced via an initial electron transfer from BP to the activated intermediate of cytochrome P450 or HRP.

Original languageEnglish (US)
Pages (from-to)129-136
Number of pages8
JournalPolycyclic Aromatic Compounds
Volume7
Issue number1-3
DOIs
StatePublished - Aug 1 1994

Fingerprint

Pyrene
Horseradish Peroxidase
Metabolism
Cytochrome P-450 Enzyme System
Quinones
Phenols
Metabolites
Phenol
Electrons
Substrates
Oxygen
Fluorine
Benzo(a)pyrene
Liver
3-fluorobenzo(a)pyrene
Rats
Substitution reactions
Oxidation

Keywords

  • Metabolism
  • catalytic mechanism
  • cytochrome P450
  • electron transfer
  • horseradish peroxidase
  • oxygen transfer

ASJC Scopus subject areas

  • Polymers and Plastics
  • Organic Chemistry
  • Materials Chemistry

Cite this

Metabolism of 1- and 3-Fluorobenzo[a]pyrene by Cytochrome P450 and Horseradish Peroxidase. / Cavalieri, Ercole; Devanesan, Prabhakar; Mulder, Patrick; Ramakrishna, N. V S; Rogan, Eleanor G.

In: Polycyclic Aromatic Compounds, Vol. 7, No. 1-3, 01.08.1994, p. 129-136.

Research output: Contribution to journalArticle

Cavalieri, Ercole ; Devanesan, Prabhakar ; Mulder, Patrick ; Ramakrishna, N. V S ; Rogan, Eleanor G. / Metabolism of 1- and 3-Fluorobenzo[a]pyrene by Cytochrome P450 and Horseradish Peroxidase. In: Polycyclic Aromatic Compounds. 1994 ; Vol. 7, No. 1-3. pp. 129-136.
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T1 - Metabolism of 1- and 3-Fluorobenzo[a]pyrene by Cytochrome P450 and Horseradish Peroxidase

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AU - Rogan, Eleanor G

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N2 - Benzo[a]pyrene (BP) is a good model for elucidating the mechanism of oxygen transfer for substrates that are considered good electron donors. Fluoro substitution of BP represents a suitable probe for studying mechanisms of oxygen transfer in the metabolic formation of BP quinones and BP phenols. By using this strategy with 6-fluoroBP (6-FBP), we have previously demonstrated that the BP quinones are formed metabolically via an initial one-electron oxidation of BP catalyzed by cytochrome P450. Now we have synthesized 1-FBP and 3-FBP with the purpose of elucidating the mechanism of phenol formation. If formation of 3-hydroxyBP (3-OHBP) (major metabolite of BP) and 1-OHBP (minor metabolite of BP) occurs via an initial electron transfer from BP to cytochrome P450, when we use 3-FBP and 1-FBP as substrates, one of the metabolites formed should be BP-3,6-dione and BP-1,6-dione, respectively, with displacement of fluorine. Metabolism of 1-FBP and 3-FBP by rat liver microsomes and by horseradish peroxidase (HRP) was conducted. With 1-FBP, BP-1,6-dione was obtained with cytochrome P450 or HRP. In addition, with cytochrome P450 the 4,5-, 7,8- and 9,10-dihydrodiol and a phenol of 1-FBP were obtained. With 3-FBP as substrate, HRP produced only BP-3,6-dione, whereas cytochrome P450 produced BP-3,6-dione, the 4,5-, 7,8- and 9,10-dihydrodiol, and a phenol of 3-FBP. The formation of BP quinones from 1-FBP and 3-FBP clearly demonstrates that 3-OHBP and 1-OHBP in the metabolism of BP are produced via an initial electron transfer from BP to the activated intermediate of cytochrome P450 or HRP.

AB - Benzo[a]pyrene (BP) is a good model for elucidating the mechanism of oxygen transfer for substrates that are considered good electron donors. Fluoro substitution of BP represents a suitable probe for studying mechanisms of oxygen transfer in the metabolic formation of BP quinones and BP phenols. By using this strategy with 6-fluoroBP (6-FBP), we have previously demonstrated that the BP quinones are formed metabolically via an initial one-electron oxidation of BP catalyzed by cytochrome P450. Now we have synthesized 1-FBP and 3-FBP with the purpose of elucidating the mechanism of phenol formation. If formation of 3-hydroxyBP (3-OHBP) (major metabolite of BP) and 1-OHBP (minor metabolite of BP) occurs via an initial electron transfer from BP to cytochrome P450, when we use 3-FBP and 1-FBP as substrates, one of the metabolites formed should be BP-3,6-dione and BP-1,6-dione, respectively, with displacement of fluorine. Metabolism of 1-FBP and 3-FBP by rat liver microsomes and by horseradish peroxidase (HRP) was conducted. With 1-FBP, BP-1,6-dione was obtained with cytochrome P450 or HRP. In addition, with cytochrome P450 the 4,5-, 7,8- and 9,10-dihydrodiol and a phenol of 1-FBP were obtained. With 3-FBP as substrate, HRP produced only BP-3,6-dione, whereas cytochrome P450 produced BP-3,6-dione, the 4,5-, 7,8- and 9,10-dihydrodiol, and a phenol of 3-FBP. The formation of BP quinones from 1-FBP and 3-FBP clearly demonstrates that 3-OHBP and 1-OHBP in the metabolism of BP are produced via an initial electron transfer from BP to the activated intermediate of cytochrome P450 or HRP.

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