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Pennyroyal Toxicity: Measurement of Toxic Metabolite Levels in Two Cases and Review of the Literature

Ilene B. Anderson, PharmD; Walter H. Mullen, PharmD; James E. Meeker, PhD; Siamak C. Khojasteh-Bakht, MS; Shimako Oishi, PhD; Sidney D. Nelson, PhD; and Paul D. Blanc, MD
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From San Francisco Bay Area Regional Poison Control Center and University of California, San Francisco, San Francisco, California; Institute of Forensic Sciences Toxicology Laboratory, Oakland, California; and University of Washington School of Pharmacy, Seattle, Washington. Acknowledgments: The authors thank Koorosh Shariat, MD, for referring case 1. Grant Support: By National Institutes of Health Program Project grant GM32165 and, in part, by National Institutes of Health grant GM25418. Human liver microsomes were obtained from the University of Washington, School of Pharmacy, Human Liver Bank. Requests for Reprints: Ilene B. Anderson, PharmD, San Francisco Bay Area Regional Poison Control Center, San Francisco General Hospital, Room 1E86, 1001 Potrero Avenue, San Francisco, CA 94110. Current Author Addresses: Drs. Anderson and Mullen: San Francisco Bay Area Regional Poison Control Center, San Francisco General Hospital, Room 1E86, 1001 Potrero Avenue, San Francisco, CA 94110.

Ann Intern Med. 1996;124(8):726-734. doi:10.7326/0003-4819-124-8-199604150-00004
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Background: Pennyroyal is a widely available herb that has long been used as an abortifacient despite its potentially lethal hepatotoxic effects. However, quantitative data for pennyroyal constituents and their metabolites in humans have not been previously reported.

Objectives: To quantify pennyroyal metabolites in human overdose, to correlate these findings with clinical variables, and to place these findings in the context of previously reported cases of pennyroyal toxicity.

Design: Clinical case series of pennyroyal ingestions; quantification of pennyroyal metabolites by gas chromatography and mass spectrometry; qualitative detection of protein-bound adducts of the metabolites of pennyroyal constituents in human liver by Western blot assay; and review of the literature based on a search of MEDLINE, Index Medicus, and the reference citations of all available publications.

Results: We report four cases of pennyroyal ingestion. One patient died, one received N-acetylcysteine, and two ingested minimally toxic amounts of pennyroyal and were not treated with N-acetylcysteine. In the fatal case, postmortem examination of a serum sample, which had been obtained 72 hours after the acute ingestion, identified 18 ng of pulegone per mL and 1 ng of menthofuran per mL. In a serum sample from the patient treated with N-acetylcysteine, which had been obtained 10 hours after ingestion, the menthofuran level was 40 ng/mL. Review of 18 previous case reports of pennyroyal ingestion documented moderate to severe toxicity in patients who had been exposed to at least 10 mL of pennyroyal oil.

Conclusion: Pennyroyal continues to be an herbal toxin of public health importance. Data on human metabolites may provide new insights into the toxic mechanisms and treatment of pennyroyal poisoning, including the potential role of N-acetylcysteine. Better understanding of the toxicity of pennyroyal may also lead to stricter control of and more restricted access to the herb.


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Figure 1.
Structures of the major monoterpene in pennyroyal, (R)-(+)-pulegone, and its major proximate toxic metabolite, menthofuran.
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Figure 2.
Western blot of human liver samples obtained from the patient in case 1 to test for protein adducts of menthofuran metabolites.450

Lane 1: Molecular weight markers. Lane 2: Proteins from human liver microsomes after incubation with menthofuran and cofactors to support cytochrome P metabolism enzymes (positive control). Lane 3: Proteins from human liver microsomes that had not been exposed to menthofuran. Lane 4: Liver sample showing intense bands at several molecular weights that correspond to protein adducts of menthofuran metabolites.

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