Articles
15 April 1996

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

Publication: Annals of Internal Medicine
Volume 124, Number 8

Abstract

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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References

1.
Eisenberg DM, Kessler RC, Foster C, Norlock FE, Calkins DR, Delbanco TL. Unconventional medicine in the United States. Prevalence, costs, and patterns of use. N Engl J Med. 1993; 328:246-52.
2.
Huxtable RJ. The myth of beneficent nature: the risks of herbal preparations. Ann Intern Med. 1992; 117:165-6.
3.
Nelson SD, McClanahan RH, Knebel N, Thomassen D, Gordon WP, Oishi S. The metabolism of (R)-(+)-pulegone, a toxic monoterpene. In: Petroski RJ, McCormick SP, eds. Secondary-Metabolite Biosynthesis and Metabolism. New York: Plenum Pr; 1992:287-96.
4.
Gunby P. Plant known for centuries still causes problems today [News]. JAMA. 1979; 241:2246-7.
5.
Osol A. The Dispensatory of the United States of America. 25th ed. Philadelphia: JB Lippincott; 1955.
6.
Rose J. Herbs & Things. New York: Grosset & Dunlap; 1972.
7.
Lust J. The Herb Book. New York: Bantam Books; 1974.
8.
Vallance WB. Pennyroyal poisoning: a fatal case. Lancet. 1955; 850.
9.
Sullivan JB Jr, Rumack BH, Thomas H Jr, Peterson RG, Bryson P. Pennyroyal oil poisoning and hepatotoxicity. JAMA. 1979; 242:2873-4.
10.
Fatality and illness associated with consumption of pennyroyal oil—Colorado. MMWR Morb Mortal Wkly Rep. 1978; 27:511-3.
11.
Allen WT. Note on a case of supposed poisoning by pennyroyal. Lancet. 1897; 1022-3.
12.
Grieve M. A Modern Herbal. v 2. New York: Dover; 1981:624-6.
13.
Sudekum M, Poppenga RH, Raju N, Braselton WE Jr. Pennyroyal oil toxicosis in a dog. J Am Vet Med Assoc. 1992; 200:817-8.
14.
Gordon WP, Huitric AC, Seth CL, McClanahan RH, Nelson SD. The metabolism of the abortifacient terpene, (R)-(+)-pulegone, to a proximate toxin, menthofuran. Drug Metab Dispos. 1987; 15:589-94.
15.
McClanahan RH, Huitric AC, Pearson PG, Desper JC, Nelson SD. Evidence for a cytochrome P-450 catalyzed allylic rearrangement with double bond topomerization. Journal of the American Chemical Society. 1988; 110:1979-81.
16.
San Francisco Bay Area Regional Poison Control Center. Annual Report, 1993-1994.
17.
Wilcox WA. Uterine pathology. Boston Medical and Surgical Journal. 1869; 79:394.
18.
Smilkstein MJ, Knapp GL, Kulig KW, Rumack BH. Efficacy of oral N-acetylcysteine in the treatment of acetaminophen overdose. Analysis of the national multicenter study (1976 to 1985). N Engl J Med. 1988; 319:1557-62.
19.
Buechel DW, Haverlah VC, Gardner ME. Pennyroyal oil ingestion: report of a case. J Am Osteopath Assoc. 1983; 82:793-4.
20.
Jones CO. A case of poisoning by pennyroyal. Br Med J. 1913:745.
21.
Runnalls HB. Report of a case of acute poisoning by oil of pennyroyal. Medical Sentinel. 1904; XII:325.
22.
Flynn EF. Poisoning by essence of pennyroyal. Br Med J. 1893; 2:1270.
23.
Girling J. Poisoning by pennyroyal. Br Med J. 1887; 1:1214.
24.
Poisoning from an over-dose of oil of pennyroyal. Southern Medical Clinic. 1883; 6:323.
25.
Wingate UO. A case of poisoning by the oil of hedeoma (pennyroyal). Boston Medical and Surgical Journal. 1889; 120:536.
26.
Braithwaite PF. A case of poisoning by pennyroyal: recovery. Br Med J. 1906; 2:865.
27.
Holland GW. A case of poisoning from pennyroyal. Virginia Medical Semi-Monthly. 1902; 7:319.
28.
Early DF. Pennyroyal: a rare cause of epilepsy. Lancet. 1961:580-1.
29.
Kimball HW. A case of poisoning by oil of pennyroyal. Atlantic Medical Weekly. 1898:307-8.
30.
Stephen WH. Case of pennyroyal poisoning. Provincial Med Journal. 1894; 1:466.
31.
Black cohosh. The Lawrence Review of Natural Products. 1992; September:1-2.
32.
Der Marderosian AD, Liberti LE. Natural Product Medicine: A Scientific Guide to Foods, Drugs, Cosmetics. Philadelphia: G.F. Stickley; 1988.
33.
Spoerke DG Jr. Herbal Medications. Santa Barbara, CA: Woodbridge Pr; 1980.
34.
Rumack BH. Acetaminophen overdose in young children. Treatment and effects of alcohol and other additional ingestants in 417 cases. Am J Dis Child. 1984; 138:428-33.
35.
Lieh-Lai MW, Sarnaik AP, Newton JF, Miceli JN, Fleischmann LE, Hook JB, et al. Metabolism and pharmacokinetics of acetaminophen in a severely poisoned young child. J Pediatr. 1984; 105:125-8.
36.
Thomassen D, Slattery JT, Nelson SD. Menthofuran-dependent and independent aspects of pulegone hepatotoxicity: roles of glutathione. J Pharmacol Exp Ther 1990; 253:567-72.
37.
Gordon WP, Forte AJ, McMurtry RJ, Gal J, Nelson SD. Hepatotoxicity and pulmonary toxicity of pennyroyal oil and its constituent terpenes in the mouse. Toxicol Appl Pharmacol. 1982; 65:413-24.
38.
McEnvoy GK, Litvak K, Welsh OH Jr, Douglas PM, Kester LS, eds. American Hospital Formulary Service. Bethesda, MD: Drug Information; 1995.
39.
Moorthy B, Madyastha P, Madyastha KM. Hepatotoxicity of pulegone in rats: its effects on microsomal enzymes, in vivo. Toxicology. 1989; 55:327-37.
40.
Thomassen D, Knebel N, Slattery JT, McClanahan RH, Nelson SD. Reactive intermediates in the oxidation of menthofuran by cytochromes P-450. Chem Res Toxicol. 1992; 5:123-30.
41.
Madyastha KM, Raj CP. Biotransformations of R-(+)-pulegone and menthofuran in vitro: chemical basis for toxicity. Biochem Biophys Res Commun. 1990; 173:1086-92.
42.
Thomassen D, Slattery JT, Nelson SD. Contribution of menthofuran to the hepatotoxicity of pulegone: assessment based on matched area under the curve and on matched time course. J Pharmacol Exp Ther. 1988; 244:825-9.
43.
Nelson SD, Gordon WP. Mammalian drug metabolism. J Nat Prod. 1983; 46:71-8.
44.
Madyastha KM, Raj CP. Studies on the metabolism of a monoterpene ketone, R-(+)-pulegone—a hepatotoxin in rat: isolation and characterization of new metabolites. Xenobiotica. 1993; 23:509-18.
45.
Thomassen D, Pearson PG, Slattery JT, Nelson SD. Partial characterization of bilary metabolites of pulegone by tandem mass spectrometry. Detection of glucuronide, glutathione, and glutathionyl glucuronide conjugates. Drug Metab Dispos. 1991; 19:997-1003.
46.
McClanahan RH, Thomassen D, Slattery JT, Nelson SD. Metabolic activation of (R)-(+)-pulegone to a reactive enonal that covalently binds to mouse liver proteins. Chem Res Toxicol. 1989; 2:349-55.

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Information & Authors

Information

Published In

cover image Annals of Internal Medicine
Annals of Internal Medicine
Volume 124Number 815 April 1996
Pages: 726 - 734

History

Published in issue: 15 April 1996
Published online: 15 August 2000

Keywords

Authors

Affiliations

Ilene B. Anderson, PharmD
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.
Walter H. Mullen, PharmD
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.
James E. Meeker, PhD
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.
Siamak C. Khojasteh-Bakht, MS
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.
Shimako Oishi, PhD
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.
Sidney D. Nelson, PhD
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.
Paul D. Blanc, MD
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.
Corresponding Author: 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.
Dr. Meeker: Institute of Forensic Sciences, Toxicology Laboratory, 2945 Webster Street, Oakland, CA 94609.
Mr. Khojateh-Bakht and Drs. Oishi and Nelson: University of Washington, Department of Medicinal Chemistry, Box 357610, Seattle, WA 98195-7610.
Dr. Blanc: Division of Occupational and Environmental Medicine, University of California, Box 0924, San Francisco, CA 94143.

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Ilene B. Anderson, Walter H. Mullen, James E. Meeker, et al. Pennyroyal Toxicity: Measurement of Toxic Metabolite Levels in Two Cases and Review of the Literature. Ann Intern Med.1996;124:726-734. doi:10.7326/0003-4819-124-8-199604150-00004

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