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PubMed1996

Pennyroyal toxicity: measurement of toxic metabolite levels in two cases and review of the literature.

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.

Acetylcysteine↗
PubMed1999

Metabolism of (R)-(+)-pulegone and (R)-(+)-menthofuran by human liver cytochrome P-450s: evidence for formation of a furan epoxide.

(R)-(+)-Pulegone, a monoterpene constituent of pennyroyal oil, is a hepatotoxin that has been used in folklore medicine as an abortifacient despite its potential lethal effects. Pulegone is metabolized by human liver cytochrome P-450s to menthofuran, a proximate hepatotoxic metabolite of pulegone. Expressed human liver cytochrome (CYP) P-450s (1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4) were tested for their ability to catalyze the oxidations of pulegone and menthofuran. Expressed CYP2E1, CYP1A2, and CYP2C19 oxidized pulegone to menthofuran, with respective Km and Vmax values of 29 microM and 8.4 nmol/min/nmol P-450 for CYP2E1, 94 microM and 2.4 nmol/min/nmol P-450 for CYP1A2, and 31 microM and 1.5 nmol/min/nmol P-450 for CYP2C19. The human liver P-450s involved in the metabolism of menthofuran are the same as pulegone except for the addition of CYP2A6. These P-450s were found to oxidize menthofuran to a newly identified metabolite, 2-hydroxymenthofuran, which is an intermediate in the formation of the known metabolites mintlactone and isomintlactone. Based on studies with 18O2 and H218O, 2-hydroxymenthofuran arises predominantly from a dihydrodiol formed from a furan epoxide. CYP2E1, CYP1A2, and CYP2C19 oxidized menthofuran with respective Km and Vmax values of 33 microM and 0.43 nmol/min/nmol P-450 for CYP2E1, 57 microM and 0.29 nmol/min/nmol P-450 for CYP1A2, and 62 microM and 0.26 nmol/min/nmol P-450 for CYP2C19.

Animals↗
PubMed2000

Fetal associative learning mediated through maternal alcohol intoxication.

BACKGROUND: The aim of the present study was to analyze whether alcohol as an unconditioned stimulus is capable of supporting associative learning in near-term fetuses. METHODS: In experiment 1, we determined pharmacokinetic profiles of alcohol and of an aromatic substance (cineole) in amniotic fluid and maternal blood during late gestation. The results obtained through gas chromatographic analysis allowed a second experiment in which we explicitly paired peak levels of cineole with peak levels of alcohol in amniotic fluid and blood, by intragastrically administering cineole and ethanol to the dams during gestational days 17 through 20 (paired condition). Control groups were dams given cineole 4 hr before commencement of an acute state of alcohol intoxication (long-delay group) or were only exposed to water administrations (water control group). The progeny were evaluated during postnatal day 16 in terms of behavioral responsiveness to intraorally infused solutions (cineole or alcohol presented in milk vehicle, or milk alone). RESULTS: Mouthing responsiveness to cineole was strongly affected by the nature of prenatal treatments. Pups in the paired prenatal condition mouthed significantly less than did long-delay and water controls. Physical and behavioral measures allowed us to reject the possibility that these effects were due to teratogenic effects of alcohol during late gestation. CONCLUSIONS: These results indicate that before birth, rat fetuses are capable of acquiring associative memories supported by the unconditioned properties of alcohol. This associative memory can be expressed during infancy through a significant reduction in mouth movements in the presence of the specific orosensory cue explicitly paired with alcohol interoceptive effects in utero.

Alcoholic Intoxication↗
PubMed2000

Role of C-5 chiral center in R-(+)-pulegone-mediated hepatotoxicity: metabolic disposition and toxicity of 5, 5-dimethyl-2-(1-Methylethylidene)-cyclohexanone in rats.

Metabolic disposition of 5, 5-dimethyl-2-(1-methylethylidene)-cyclohexanone (I) was examined in rats. Compound (I) was administered orally (250 mg/kg of body weight/day) to rats for 5 days. The following urinary metabolites were isolated and identified: 4,5,6,7-tetrahydro-3,6, 6-trimethylbenzofuran (III), 3,3-dimethylcyclohexanone (VI), 5, 5-dimethyl-3-hydroxy-2-(1-methylethylidene)-cyclohexanone (X), 5, 5-dimethyl-2-(1-hydroxymethylethyl)-cyclohexanone (IX), 3-hydroxy-5-hydroxymethyl-5-methyl-2-(1-methylethylidene)-cyclo hexano ne (XI), 5,6-dihydro-3,6,6-trimethyl-2(4H)-benzofuranone (VIII), and 5,5-dimethyl-3-hydroxy-2-(1-carboxy ethylidene)-cyclohexanone (XIII). Incubation of compound (I) with phenobarbital (PB)-induced rat liver microsomes in the presence of NADPH resulted in the formation of a metabolite, tentatively identified as a furanoterpene (III) based on proton magnetic resonance, gas chromatography, and gas chromatography-mass spectroscopy analyses. The formation of III was inhibited to a significant extent by carbon monoxide, metyrapone, SKF 525-A, and cytochrome c, suggesting the participation of PB-induced microsomal cytochrome P-450 system in the conversion of I to III. Compound I gave type I spectral change in the PB-induced liver microsomes and the dissociation constant (Ks) for I was 38.5 microM. Intraperitoneal administration of a single dose (250 mg/kg) of I to rats resulted in 26, 23, and 41% decreases in the levels of cytochrome P-450, glucose-6-phosphatase, and aminopyrine N-demethylase, respectively, at the end of 24 h. During this period, a 11-fold increase in serum glutamate pyruvate transaminase level was also observed. However, a decrease in the level of cytochrome P-450 and glucose-6-phosphatase, and an increase in serum glutamate pyruvate transaminase values were comparatively more pronounced when R-(+)-pulegone (250 mg/kg) or CCl(4) (0.6 ml/kg) was administered to rats. Pretreatment of rats with PB potentiated the hepatotoxicity caused by I, whereas pretreatment with 3-methylcholanthrene protected from it. This suggests that PB-induced cytochrome P-450-catalyzed reactive metabolites may be responsible for the toxic effects caused by I.

Aminopyrine N-Demethylase↗
PubMed2001

Oxidation of 1,8-cineole, the monoterpene cyclic ether originated from eucalyptus polybractea, by cytochrome P450 3A enzymes in rat and human liver microsomes.

1,8-Cineole, the monoterpene cyclic ether known as eucalyptol, is one of the components in essential oils from Eucalyptus polybractea. We investigated the metabolism of 1,8-cineole by liver microsomes of rats and humans and by recombinant cytochrome P450 (P450 or CYP) enzymes in insect cells in which human P450 and NADPH-P450 reductase cDNAs had been introduced. 1,8-Cineole was found to be oxidized at high rates to 2-exo-hydroxy-1,8-cineole by rat and human liver microsomal P450 enzymes. In rats, pregenolone-16alpha-carbonitrile (PCN) and phenobarbital induced the 1,8-cineole 2-hydroxylation activities by liver microsomes. Several lines of evidence suggested that CYP3A4 is a major enzyme involved in the oxidation of 1,8-cineole by human liver microsomes: (1), 1,8-cineole 2-hydroxylation activities by liver microsomes were inhibited very significantly by ketoconazole, a CYP3A inhibitor, and anti-CYP3A4 immunoglobulin G; (2), there was a good correlation between CYP3A4 contents and 1,8-cineole 2-hydroxylation activities in liver microsomes of eighteen human samples; and (3), of various recombinant human P450 enzymes examined, CYP3A4 had the highest activities for 1,8-cineole 2-hydroxylation; the rate catalyzed by CYP3A5 was about one-fourth of that catalyzed by CYP3A4. Kinetic analysis showed that K(m) and V(max) values for the oxidation of 1,8-cineole by liver microsomes of human sample HL-104 and rats treated with PCN were 50 microM and 91 nmol/min/nmol P450 and 20 microM and 12 nmol/min/nmol P450, respectively. The rates observed using human liver microsomes and recombinant CYP3A4 were very high among other CYP3A4 substrates reported so far. These results suggest that 1,8-cineole, a monoterpenoid present in nature, is one of the effective substrates for CYP3A enzymes in rat and human liver microsomes.

Animals↗
PubMed2001

Effect of ring size in R-(+)-pulegone-mediated hepatotoxicity: studies on the metabolism of R-(+)-4-methyl-2-(1-methylethylidene)-cyclopentanone and DL-camphorone in rats.

R-(+)-Pulegone, a monoterpene ketone, is a potent hepatotoxin. The present study was designed to evaluate whether the reduction of the ring size in R-(+)-pulegone would affect its mode of metabolism and its hepatotoxic potential. Metabolic fate of R-(+)-4-methyl-2-(1-methylethylidene)-cyclopentanone (I) and 5-methyl-2-(1-methylethylidene)-cyclopentanone (DL-camphorone; II) were examined in rats. Compounds I and II were administered orally (250 mg/kg of b.wt./day) to rats for 5 to 7 days. The following metabolites were isolated and identified from the urine of rats dosed with I: 3-methyl-5-(1-methylethylidene)-cyclopent-2-enone (Ie), Z-4-methyl-2-(1-hydroxymethylethylidene)-cyclopentanone (Ib), E-4-methyl-2-(1-hydroxymethylethylidene)-cyclopentanone (Ia), 3-hydroxy-4-methyl-2-(1-methylethylidene)-cyclopentanone (If), 4-hydroxy-4-methyl-2-(1-methylethylidene)-cyclopentanone (Ic), and E-4-methyl-2-(1-carboxyethylidene)-cyclopentanone (Id). Phenobarbital (PB)-induced rat liver microsomes in the presence of NADPH transformed compound I into metabolites, which were identified as Ia, Ib, Ic, Ie, and If. The following urinary metabolites were isolated and identified from compound II: 5-hydroxy-5-methyl-2-(1-methylethylidene)-cyclopentanone (IIc), 5-hydroxy-5-methyl-2-(1-methylethyl)-cyclopentanone (IIg), Z-5-methyl-2-(1-hydroxymethylethylidene)-cyclopentanone (IIb), 5-methyl-2-(1-hydroxymethylethyl)-cyclopentanone (IIf), E-5-methyl-2-(1-hydroxymethylethylidene)-cyclopentanone (IIa), E-5-methyl-2-(1-carboxyethylidene)-cyclopentanone (IId), and 5-methyl-2-(1-carboxyethyl)-cyclopentanone (IIe). PB-induced rat liver microsomes in the presence of NADPH were shown to transform compound II to IIa, IIb, and IIc. Studies carried out in vitro demonstrated that hydroxylation at the tertiary carbon atom or oxidation of the isopropylidene methyl groups in II can be specifically blocked through structural modifications as seen in compounds 2,2-dimethyl-5-(1-methylethylidene)-cyclopentanone (III) and 5-methyl-2-(1-ethyl-1-propylidene)-cyclopentanone (IV). Similar observation was also made when isopropylidene methyl groups in R-(+)-pulegone were replaced by ethyl groups. Intraperitoneal administration of a single dose (250 mg/kg) of I and II to rats did not elicit hepatotoxicity as judged by serum alanine aminotransaminase levels and liver microsomal drug metabolizing enzyme activities.

Animals↗
PubMed2001

Efficacy and safety of Ascoril in the management of cough--National Study Group report.

A total of 768 patients were recruited by 81 physicians and paediatricians all over the country in this National Study Group of 'Ascoril + Expectorant'. The results of this first large scale study of a cough formula indicates that 'Ascoril + Expectorant' is effective in controlling cough, breathlessness and decreasing the volume of sputum. No serious adverse events were noted. Ascoril was well accepted by the patients and its efficacy was rated very high by the physician. The National Study Group concludes that 'Ascoril + Expectorant' is highly effective in the management of cough associated with lower respiratory tract infection and COPDs.

Adolescent↗
PubMedDate not supplied

[Determination of the antibacterial and antiviral activity of the essential oil from Minthostachys verticillata (Griseb.) Epling].

The in vitro antiviral activity of the essential oil from Minthostachys verticillata was investigated against herpes simplex virus type 1 (HSV-1) and pseudorabies virus (PrV). The viral inhibition was assayed employing viral plaque reduction assay. The antiviral activity of the essential oil specifically affects PrV and HSV-1 multiplication, since it was found that non toxic effects on cells were observed at the concentrations assayed. The therapeutic index values were 10.0 and 9.5 for HSV-1 and PrV, respectively. The antibacterial activity was studied using a diffusion assay and the broth tube dilution method. Gram-positive bacteria were more sensitive to inhibition by plant essential oil than the gram-negative bacteria. The essential oil of M. verticillata was analyzed by gas chromatography (GC) technique. Of the six components identified in the volatile oil, pulegone (44.56%) and menthone (39.51%) were the major constituents. The antimicrobial activity can be explained to some extent by the presence of pulegone. Results suggest that further investigations concerning the isolation of the substance responsible for the antimicrobial activity and an effort to define the mechanisms of action are warranted.

Anti-Bacterial Agents↗
PubMed1998

[Gas chromatographic determination of camphora, mentholum, isoborneol and borneol in Guanxingao].

Guanxingao is a kind of traditional Chinese rubber electuary medicine which is able to either cure or guard against coronary heart disease and angina pectoris. The contents of camphora, mentholum, isoborneol and borneol in Guanxingao are determined by gas chromatography. The purpose of the study is to detect and control the loss of the four volatile components through production and standing and to guarantee the curative effect. Chromatographic analysis was performed on a GC-4004 gas chromatograph(FID). The column was a 3 mm i.d. x 2 m stainless steel tube packed with 7% PEG-1500 on 100-110 mesh 102 non-silanized white support. The column and the FID temperatures were 115 degrees C and 180 degrees C respectively. H2 was the carrier gas, 30 mL/min. Internal standard method was used for the quantitative estimation with naphthalene as the internal standard. The linear ranges were at least within 50-450 mg/L (r = 0.9999, n = 4). The correction factors against naphthalene were 1.262-1.286 and the RSDs were 0.32%-1.5%(n = 12). The recoveries were 98.44%-101.9%. In comparison with the theoretical contents, the average loss percentages are 71.72% (camphora), 65.60% (mentholum) and 66.31% (isoborneol + borneol). The samples were pretreated by means of isothermal (35 degrees C) water-bath extraction with acetone for 6 times with four hours each.

Camphanes↗
PubMed1998

[Analysis of constituents of essential oils from flos Magnoliae].

The constituents of essential oils from Magnolia biondii, M. denudata and M. sprengeri were analysed by GC-MS qualitatively and GC quantitatively. Ninety-one compounds of M. biondii, seventy-one compounds of M. denudata and eighty-eight compounds of M. sprengeri were identified at rates of 97.37%, 97.66% and 95.68% respectively.

Acyclic Monoterpenes↗
PubMed2001

Metabolism of (R)-(+)-pulegone in F344 rats.

(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 (14)C-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.

Animals↗