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Research ArticleArticle

Substituent Elimination Fromp-Substituted Phenols by Cytochrome P450

ipso-Substitution by the Oxygen Atom of the Active Species

Tomoyuki Ohe, Tadahiko Mashino and Masaaki Hirobe
Drug Metabolism and Disposition January 1997, 25 (1) 116-122;
Tomoyuki Ohe
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Tadahiko Mashino
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Masaaki Hirobe
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ipso-Substitution by the Oxygen Atom of the Active Species

Abstract

When various p-substituted phenols (substituent = NO2, CN, CH2OH, COCH3, COPh, COOH, F, Cl, and Br) were incubated with rat liver microsomes, the substituent was eliminated to produce hydroquinone, and the reaction was inhibited by CO and a cytochrome P450-specific inhibitor. In the case of p-cresol (substituent = CH3),p-toluquinol was formed instead of hydroquinone. Experiments using 18O2 proved that the elimination is accompanied with ipso-substitution by the oxygen atom of the active species in cytochrome P450. These results are similar to those in a cytochrome P450 chemical model system (Ohe, T.,et al., Tetrahedron Lett. 42, 7681–7684, 1995), implying that the model is a good mimic of cytochrome P450. Substrates that lack a hydroxy group, namely p-substituted toluenes, did not undergo the reaction, thus indicating that a hydroxy group at the p-position to the eliminated substituent is necessary for this pathway. This is the same as the result obtained with the cytochrome P450 model. Finally, to elucidate how the substituent is eliminated, we attempted to detect the product derived from the eliminated group with several substrates. Results indicated that the mechanism of the substituent elimination can be divided into two types: the substituent is eliminated as an anion or as a cation.

Footnotes

  • Send reprint requests to: Dr. Tadahiko Mashino, Kyoritsu College of Pharmacy, 1-5-30 Shibakoen Minato-Ku, Tokyo 105, Japan.

  • ↵1 This work is Part XI in the series, “Application of Chemical Cytochrome P450 Model Systems to Studies on Drug Metabolism.”

  • ↵3 It was confirmed that benzaldehyde was converted into benzyl alcohol, as well as benzoic acid in the microsomes-NADPH/O2 system. However, benzyl alcohol was not obtained at all when p-benzoylphenol was used as a substrate. Therefore, we consider that benzaldehyde was not formed primarily.

  • Abbreviations used are::
    mCPBA
    m-chloroperoxybenzoic acid
    G-6-P
    glucose-6-phosphate
    G-6-P DHase
    glucose-6-phosphate dehydrogenase
    BSTFA
    N,O-bis(trimethylsilyl)trifluoroacetamide
    CO
    carbon monoxide
    • Received July 8, 1996.
    • Accepted September 27, 1996.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition
Vol. 25, Issue 1
1 Jan 1997
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Research ArticleArticle

Substituent Elimination Fromp-Substituted Phenols by Cytochrome P450

Tomoyuki Ohe, Tadahiko Mashino and Masaaki Hirobe
Drug Metabolism and Disposition January 1, 1997, 25 (1) 116-122;

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Research ArticleArticle

Substituent Elimination Fromp-Substituted Phenols by Cytochrome P450

Tomoyuki Ohe, Tadahiko Mashino and Masaaki Hirobe
Drug Metabolism and Disposition January 1, 1997, 25 (1) 116-122;
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