• DOI:10.7326/0003-4819-124-8-199604150-00004
• Corpus ID: 24375611

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

@article{Anderson1996PennyroyalTM,
  title={Pennyroyal Toxicity: Measurement of Toxic Metabolite Levels in Two Cases and Review of the Literature},
  author={Ilene B. Anderson and Walter Mullen and James E. Meeker and Siamak Cyrus Khojasteh-Bakht and Shimako Oishi and Sidney D. Nelson and Pauline Blanc},
  journal={Annals of Internal Medicine},
  year={1996},
  volume={124},
  pages={726-734}
}

• I. Anderson, W. Mullen, +4 authors P. Blanc
• Published 15 April 1996
• Medicine
• Annals of Internal Medicine

An increasing segment of the U.S. population is seeking alternatives to traditional Western allopathic medicine. In 1990, Americans made an estimated 425 million visits to providers of unconventional therapies [1]. One particularly popular alternative is herbal medication. Herbal medicines are promoted as more natural and therefore safer than conventional over-the-counter and prescription medicines, but many may be more dangerous than conventional pharmaceutical agents [2]. Both over-the-counter and prescription medicines in the United States must be extensively tested and certified before the Food and Drug Administration approves them for indicated uses. In contrast, herbal preparations are not subjected to such scrutiny before being promoted and sold. Pennyroyal is one widely available herbal medicine that can be life threatening after ingestion. Pennyroyal, an herb consisting of the leaves of either Mentha pulegium or Hedeoma pulegioides, primarily contains pulegone (Figure 1) plus smaller amounts of several other monoterpenes that are encountered in mint species [3]. Pennyroyal is commonly available in health food stores. Since Roman times, herbalists have recommended the herb as an abortifacient [4]. Although no evidence supports its efficacy in this regard [5], many herbal books continue to cite the use of pennyroyal for this purpose [6, 7], despite reports of centrilobular hepatic necrosis and death in connection with its use [8-11]. Pennyroyal is also advocated as a pesticide, primarily for controlling fleas on domestic pets and in the home [12]. Hepatotoxicity and other cellular damage have been reported in a household pet treated with pennyroyal oil [13]. Figure 1. Structures of the major monoterpene in pennyroyal, (R)-(+)-pulegone, and its major proximate toxic metabolite, menthofuran. Pennyroyal poisoning continues to occur regularly. Although pennyroyal ingestion can be fatal, cases of poisoning have only been sporadically documented in the modern medical literature, and none has involved the use of recent analytic techniques to measure pennyroyal metabolite levels. We report four recent cases of pennyroyal toxicity, two of which had laboratory confirmation of pulegone or its major toxic metabolite menthofuran [14]. We also review all of the published clinical case data from earlier reports and place our four cases in the context of reported signs and symptoms of toxicity. Methods Quantification of Pulegone and Menthofuran Plasma samples were acidified and extracted with diethylether after internal standards were added. To identify and quantify pulegone and menthofuran [14, 15], we compared their gas chromatographic retention times and mass spectra with those of known standards. Gas chromatographic analysis was done on a Hewlett-Packard (Palo Alto, California) Model 5980. Chromatography was done on a 30 m 0.320 mm Wall Coated Open Tubular DB-5 fused silica capillary column (J & W Scientific, Folsom, California). Electron-impact mass spectrometry was done using a VG-7070H double-focusing instrument (Manchester, United Kingdom) that was equipped with a Hewlett-Packard Model 5980 Series II gas chromatograph and was electronically linked to a Mass Spectrometry Service data system (Manchester, United Kingdom). Identification of Protein-Bound Pennyroyal Metabolites by Western Blot Analysis Liver microsomes were prepared from a liver sample obtained from patient 1 and from a human liver sample obtained from the University of Washington School of Pharmacy Liver Bank. To provide a positive control, a portion of the latter sample was incubated with menthofuran and an NADPH (reduced nicotinamide adenine dinucleotide phosphate)-regenerating system. Microsomal proteins were subjected to electrophoresis in sodium dodecyl sulfate-polyacrylamide gels, and the protein bands were transferred to nitrocellulose solid support. Protein adducts were detected using a primary antibody obtained from rabbits immunized with chemically synthesized oxidative metabolites of menthofuran coupled to metallothionein and with a secondary antibody of horseradish peroxidase-conjugated goat antirabbit IgG (Pierce Chemical Co., Rockford, Illinois). The membranes were developed using 0.004% nickel chloride, 0.0075% hydrogen peroxide, and 0.05% 3,3-diaminobenzidine tetrahydrochloride. Poison Center Reporting We selected patients by reviewing all cases involving pennyroyal ingestion for which the San Francisco Bay Area Regional Poison Control Center was primarily consulted during a 2-year period. We included all medically treated or symptomatic cases and excluded two other cases initially reported to a collaborating regional poison control center for which our service provided a secondary consultation. All data were collected by telephone and were recorded on a standard American Association Poison Control Center Cooperative Poison Center report form at the time of the initial consultation. The poison information specialist obtained all pertinent information available. Follow-up contact by telephone was continued until the clinical outcome was determined. The San Francisco Poison Control Center receives an average of 60 000 consultations each year [16]. Literature Review We identified case reports by searching MEDLINE and Index Medicus and by reviewing the reference citations of all available publications. One reference citation was supposedly a case report of pennyroyal poisoning; however, we later reviewed the original report and discovered that the case did not involve poisoning and appears to have been cited in error [17]. Only 7 of the 18 cases are from the modern medical literature; the others were reported before 1905. The cases reported before 1905 are less well documented, but we did not exclude cases for this reason. Case Reports Case 1 A 24-year-old woman repeatedly ingested pennyroyal herbal extract (pennyroyal herb, 48% to 56% in an alcohol base) and black cohosh root (Cimicifuga racemosa) extract for 2 weeks in an attempt to induce an abortion. When this was unsuccessful, she ingested additional unknown amounts of pennyroyal herbal extract and black cohosh root extract over a short period. Soon after, abdominal cramps, chills, vomiting, and syncope developed, and the patient had difficulty walking. She was placed in a cold bath 7 hours after the acute ingestion and began to manifest rigors that her roommate interpreted as a seizure. Paramedics found the patient in cardiopulmonary arrest at a time estimated to be 7.5 hours after the acute ingestion. The patient was intubated, and then cardiopulmonary resuscitation was initiated and continued for 22 minutes until the patient arrived at the hospital. On arrival at the emergency department, the patient's heart rate was 120 beats/min and her blood pressure was 70/40 mm Hg while she received maximal dopamine. Her pupils were fixed and dilated. The physical examination showed coma and a rigid abdomen. A computed tomographic scan of the abdomen suggested a possible ruptured ectopic pregnancy. Initial laboratory values were the following: sodium level, 157 mmol/L; potassium level, 5.7 mmol/L; chlorine level, 107 mmol/L; bicarbonate level, 8 mmol/L; blood urea nitrogen level, 5.0 mmol/L; creatinine level, 221 mol/L; glucose level, 6.8 mmol/L; lactic acid level, 21.0 mmol/L; leukocyte count, 37.3 109/L; hemoglobin level, 89 g/L; hematocrit, 0.28; platelet count, 256 109/L; albumin level, 27 g/L; total bilirubin level, 5.1 mol/L; aspartate aminotransferase level, 0.82 kat/L; lactate dehydrogenase level, 3.54 kat/L; amylase level, 2.35 kat/L; prothrombin time, 23 seconds; partial prothrombin time, 68 seconds; and international normalized ratio, 4.1. A quantitative plasma human chorionic gonadotropin level indicated that the patient was 1 to 3 months pregnant. Arterial blood gas values (measured while the patient received 100% O2 by endotracheal tube) were the following: pH, 6.61; Pco 2, 23 mm Hg; and Po 2, 503 mm Hg. A toxicology screen was negative for alcohol, acetaminophen, and salicylates. Laboratory values 36 hours after the acute ingestion were notable for the aspartate aminotransferase level (44.53 kat/L), the alanine aminotransferase level (29.12 kat/L), and the lactate dehydrogenase level (68.18 kat/L). Throughout the initial 12 hours of hospitalization, the patient's course was marked by hemodynamic shock, decreasing hematocrit, and a clinical picture consistent with disseminated intravascular coagulation. During hospitalization, the patient received 10 units of packed red blood cells and multiple units of fresh frozen plasma. Exploratory laparotomy showed a hemorrhagic, right-sided ectopic pregnancy with indications of superinfection. A substantial amount of old blood, not otherwise quantified, was found. The pregnancy was not ruptured, but there was evidence of bleeding from the end of the tube. No active bleeding was seen during surgery. A computed tomographic scan of the head was consistent with anoxic encephalopathy. The patient remained unresponsive to all stimuli. Life support was withdrawn, and the patient died 46 hours after the acute pennyroyal ingestion. Other than the anticipated brain and uterine findings, the most notable abnormalities at autopsy were found in the liver. The substantial centrilobular degeneration and necrosis of the hepatic cells were consistent with a specific toxic insult. Diffuse degenerative changes involving the proximal tubules of the kidney were also noted. The pathologist concluded that the cause of death was multiorgan failure and anoxic encephalopathy secondary to ingestion of pennyroyal and black cohosh. Blood from the heart, collected at autopsy 26 hours after death, was tested for the presence of pulegone and menthofuran. The pennyroyal and black cohosh herbal extracts that the patient had ingested were also tested for the presence of pulegone and menthofuran (Table 1). Table 1. Laboratory Values of Pennyroyal Metabolites in Case 1* Po