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Drug Metabolism & Disposition

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KINETIC ISOTOPE EFFECTS IMPLICATE A SINGLE OXIDANT FOR CYTOCHROME P450-MEDIATED O-DEALKYLATION, N-OXYGENATION, AND AROMATIC HYDROXYLATION OF 6-METHOXYQUINOLINE

Tamara S. Dowers and Jeffrey P. Jones
Drug Metabolism and Disposition August 2006, 34 (8) 1288-1290; DOI: https://doi.org/10.1124/dmd.106.010280
Tamara S. Dowers
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Jeffrey P. Jones
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Abstract

One major point of controversy in the area of cytochrome P450 (P450)-mediated oxidation reactions is the nature of the active-oxygen species. A number of hypotheses have been advanced which implicate a second oxidant besides the iron-oxo species designated as compound I (Cpd 1). This oxygen is thought to be either an iron-hydroperoxy species (Cpd 0) or a second spin-state of Cpd 1. Very little information is available on what fraction of P450 oxidations is mediated by the two different oxidants. Herein, we report results on three cytochrome P450-mediated reactions: O-dealkylation, N-oxygenation, and aromatic hydroxylation, which occur by three distinct chemical mechanisms. We have used kinetic isotope effects to test for branching from O-demethylation to N-oxygenation and aromatic hydroxylation, using 6-methoxyquinoline and 2H3-6-methoxyquinoline as substrates for P4501A2. Identical large inverse isotope effects on Vmax/Km are obtained for the formation of both the N-oxide and the phenol. This indicates that all three reactions occur through the same enzyme-substrate complex and, thus, through a single iron-oxygen species. The nature of the iron-oxygen species is less certain but is more likely to be iron-oxo Cpd 1, given the energetics of these reactions.

Footnotes

  • This research was supported by National Institute of Environmental and Health Sciences Grant 09122.

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

  • doi:10.1124/dmd.106.010280.

  • ABBREVIATIONS: P450, cytochrome P450; Cpd, compound; LC/MS, liquid chromatography/mass spectroscopy.

  • ↵1 Current affiliation (T.S.D.): Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago.

    • Received March 23, 2006.
    • Accepted May 12, 2006.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 34 (8)
Drug Metabolism and Disposition
Vol. 34, Issue 8
1 Aug 2006
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KINETIC ISOTOPE EFFECTS IMPLICATE A SINGLE OXIDANT FOR CYTOCHROME P450-MEDIATED O-DEALKYLATION, N-OXYGENATION, AND AROMATIC HYDROXYLATION OF 6-METHOXYQUINOLINE
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OtherShort Communication

KINETIC ISOTOPE EFFECTS IMPLICATE A SINGLE OXIDANT FOR CYTOCHROME P450-MEDIATED O-DEALKYLATION, N-OXYGENATION, AND AROMATIC HYDROXYLATION OF 6-METHOXYQUINOLINE

Tamara S. Dowers and Jeffrey P. Jones
Drug Metabolism and Disposition August 1, 2006, 34 (8) 1288-1290; DOI: https://doi.org/10.1124/dmd.106.010280

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OtherShort Communication

KINETIC ISOTOPE EFFECTS IMPLICATE A SINGLE OXIDANT FOR CYTOCHROME P450-MEDIATED O-DEALKYLATION, N-OXYGENATION, AND AROMATIC HYDROXYLATION OF 6-METHOXYQUINOLINE

Tamara S. Dowers and Jeffrey P. Jones
Drug Metabolism and Disposition August 1, 2006, 34 (8) 1288-1290; DOI: https://doi.org/10.1124/dmd.106.010280
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