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Research ArticleArticle

Metabolism of (R)-(+)-Pulegone in F344 Rats

Ling-Jen Chen, Edward H. Lebetkin and Leo T. Burka
Drug Metabolism and Disposition December 2001, 29 (12) 1567-1577;
Ling-Jen Chen
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Edward H. Lebetkin
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Leo T. Burka
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Abstract

(R)-(+)-Pulegone, a monoterpene ketone, is a major component of pennyroyal oil. Ingestion of high doses of pennyroyal oil has caused severe toxicity and occasionally death. Studies have shown that metabolites of pulegone were responsible for the toxicity. Previous metabolism studies have used high, near lethal doses and isolation and analysis techniques that may cause degradation of some metabolites. To clarify these issues and further explore the metabolic pathways, a study of 14C-labeled pulegone in F344 rats at doses from 0.8 to 80 mg/kg has been conducted. High-pressure liquid chromatography (HPLC) analysis of the collected urine showed the metabolism of pulegone to be extensive and complex. Fourteen metabolites were isolated by HPLC and characterized by NMR, UV, and mass spectroscopy. The results demonstrated that pulegone was metabolized by three major pathways: 1) hydroxylation to give monohydroxylated pulegones, followed by glucuronidation or further metabolism; 2) reduction of the carbon-carbon double bond to give diastereomeric menthone/isomenthone, followed by hydroxylation and glucuronidation; and 3) Michael addition of glutathione to pulegone, followed by further metabolism to give diastereomeric 8-(N-acetylcystein-S-yl)menthone/isomenthone. This 1,4-addition not only took place in vivo but also in vitro under catalysis of glutathione S-transferase or mild base. Several hydroxylated products of the two mercapturic acids were also observed. Contrary to the previous study, all but one of the major metabolites characterized in the present study are phase II metabolites, and most of the metabolites in free forms are structurally different from those previously identified phase I metabolites.

Footnotes

  • Abbreviations used are::
    TFA
    trifluoroacetic acid
    Gluc
    glucuronide
    GSH
    reduced glutathione
    GST
    glutathioneS-transferase
    ESI
    electrospray ionization
    MS/MS
    tandem mass spectrometry
    GC
    gas chromatography
    RT
    retention time
    • Received April 18, 2001.
    • Accepted September 14, 2001.
  • U.S. Government
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Drug Metabolism and Disposition: 29 (12)
Drug Metabolism and Disposition
Vol. 29, Issue 12
1 Dec 2001
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Research ArticleArticle

Metabolism of (R)-(+)-Pulegone in F344 Rats

Ling-Jen Chen, Edward H. Lebetkin and Leo T. Burka
Drug Metabolism and Disposition December 1, 2001, 29 (12) 1567-1577;

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Research ArticleArticle

Metabolism of (R)-(+)-Pulegone in F344 Rats

Ling-Jen Chen, Edward H. Lebetkin and Leo T. Burka
Drug Metabolism and Disposition December 1, 2001, 29 (12) 1567-1577;
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