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Research ArticleArticle

Synthesis and Reactivity of Coumarin 3,4-Epoxide

Stephanie L. Born, Pedro A. Rodriguez, Cynthia L. Eddy and Lois D. Lehman-McKeeman
Drug Metabolism and Disposition November 1997, 25 (11) 1318-1324;
Stephanie L. Born
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Pedro A. Rodriguez
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Cynthia L. Eddy
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Lois D. Lehman-McKeeman
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Abstract

Coumarin is used widely as a fragrance constituent and is administered clinically in the treatment of certain lymphedemas and malignancies. Although toxicity occurs only rarely in humans treated clinically with high-dose coumarin, it is well established that coumarin is hepatotoxic in the rat. This species difference in susceptibility to toxicity reflects the disparate metabolic processes occurring in humans and rodents. In humans, coumarin is converted extensively via cytochrome P450 2A6 to the nontoxic 7-hydroxycoumarin metabolite. In contrast, coumarin 3,4-epoxidation is thought to predominate in rodent species, resulting in the formation of several potentially toxic metabolites. Coumarin epoxide is thought to be highly unstable and has not been isolated synthetically or as a microsomal product. To address this issue, coumarin 3,4-epoxide was synthesized, and its stability and fate have been determined. Coumarin 3,4-epoxide was prepared by reacting coumarin with dimethyldioxirane. The epoxide was stable in organic solvents and survived conditions required for analysis by gas chromotography. Its structure was confirmed via1H-NMR and gas chromatography-mass spectrometry-infrared spectroscopy (GC-MS-IR). In contrast, coumarin 3,4-epoxide was unstable in aqueous solution, converting within 20 sec to a ring-opened compound. Using GC-MS-IR analysis, the single coumarin 3,4-epoxide product was identified aso-hydroxyphenylacetaldehyde (o-HPA). Although other investigators have suggested that 3-hydroxycoumarin is an intermediate in o-HPA formation from coumarin 3,4-epoxide, we have demonstrated that 3-hydroxycoumarin, incubated in an aqueous system or with liver microsomal proteins, does not formo-HPA. Thus, the results of the present work establish that coumarin 3,4-epoxide can be synthesized and that o-HPA, which has previously been shown to be a prominent coumarin metabolite in rat liver microsomal incubations, is formed directly from coumarin 3,4-epoxide. These results suggest that both coumarin 3,4-epoxide ando-HPA may contribute to the hepatotoxicity of coumarin.

Footnotes

  • Send reprint requests to: Dr. Stephanie L. Born, The Procter & Gamble Company, Miami Valley Laboratories, P.O. Box 538707, Cincinnati, OH 45253-8707.

  • Abbreviations used are::
    o-HPAA
    o-hydroxyphenylacetic acid
    DHC
    dihydrocoumarin
    DMD
    dimethyldioxirane
    GC-MS-IR
    gas chromatography-mass spectrometry-infrared spectroscopy
    o-HPA
    o-hydroxyphenylacetaldehyde
    o-HPE
    o-hydroxyphenylethanol
    o-HPLA
    o-hydroxyphenyllactic acid
    P450
    cytochrome P450
    TIC
    total ion chromatogram
    • Received May 19, 1997.
    • Accepted July 22, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition
Vol. 25, Issue 11
1 Nov 1997
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Research ArticleArticle

Synthesis and Reactivity of Coumarin 3,4-Epoxide

Stephanie L. Born, Pedro A. Rodriguez, Cynthia L. Eddy and Lois D. Lehman-McKeeman
Drug Metabolism and Disposition November 1, 1997, 25 (11) 1318-1324;

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Research ArticleArticle

Synthesis and Reactivity of Coumarin 3,4-Epoxide

Stephanie L. Born, Pedro A. Rodriguez, Cynthia L. Eddy and Lois D. Lehman-McKeeman
Drug Metabolism and Disposition November 1, 1997, 25 (11) 1318-1324;
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