Relevant essential oil components: a minireview on increasing applications and potential toxicity.

Phenolic compounds carvacrol, thymol, eugenol, and vanillin are four of the most thoroughly investigated essential oil components given their relevant biological properties. These compounds are generally considered safe for consumption and have been used in a wide range of food and non-food applications. Significant biological properties, including antimicrobial, antioxidant, analgesic, anti-inflammatory, anti-mutagenic, or anti-carcinogenic activity, have been described for these components. They are versatile molecules with wide-ranging potential applications whose use may substantially increase in forthcoming years. However, some in vitro and in vivo studies, and several case reports, have indicated that carvacrol, thymol, and eugenol may have potential toxicological effects. Oxidative stress has been described as the main mechanism underlying their cytotoxic behavior, and mutagenic and genotoxic effects have been occasionally observed. In vivo studies show adverse effects after acute and prolonged carvacrol and thymol exposure in mice, rats, and rabbits, and eugenol has caused pulmonary and renal damage in exposed frogs. In humans, exposure to these three compounds may cause different adverse reactions, including skin irritation, inflammation, ulcer formation, dermatitis, or slow healing. Toxicological vanillin effects have been less reported, although reduced cell viability after exposure to high concentrations has been described. In this context, the possible risks deriving from increased exposure to these components for human health and the environment should be thoroughly revised.

Natural product incarvillateine aggravates epileptic seizures by inhibiting GABAA currents.

A natural monoterpene alkaloid incarvillateine isolated from the plant Incarvillea sinensis is known to relieve inflammatory and neuropathic pain. However, the molecular target for the action of incarvillateine remains elusive. Here, we report that incarvillateine exacerbates epileptic seizures by inhibiting subtypes of γ-Aminobutyric acid type A (GABAA) receptors. Two-electrode voltage clamp recordings of α1ß3γ2, α2ß3γ2, α3ß3γ2 and α5ß3γ2 subtypes expressed in Xenopus oocytes revealed that incarvillateine inhibited the GABAA currents with IC50 of 25.1 µM, 43.1 µM, 105.1 µM and 93.7 µM, respectively. Whole-cell patch clamp recordings of hippocampal slices confirmed that incarvillateine inhibited spontaneous inhibitory postsynaptic currents (IPSCs), and miniature IPSCs and tonic currents. Moreover, inhibition of GABAA currents and spontaneous IPSCs by incarvillateine persisted even in the presence of blockers of adenosine receptors. In addition, incarvillateine enhanced epileptic discharges induced by Mg2+-free artificial cerebrospinal fluid (ACSF) in hippocampal slices. Furthermore, intracerebral ventricular injections of incarvillateine increased the severity of seizures induced by kainic acid in a dose-dependent manner. Taken together, our data demonstrate that incarvillateine aggravates seizures by inhibition of GABAA currents and GABAergic synaptic transmissions.

RuII( p-cymene) Compounds as Effective and Selective Anticancer Candidates with No Toxicity in Vivo.

Ruthenium(II) complexes are currently considered a viable alternative to the widely used platinum complexes as efficient anticancer agents. We herein present the synthesis and characterization of half-sandwich ruthenium compounds with the general formula [Ru( p-cymene)(L-N,N)Cl][CF3SO3] (L = 3,6-di-2-pyridyl-1,2,4,5-tetrazine (1) 6,7-dimethyl-2,3-bis(pyridin-2-yl)quinoxaline (2)), which have been synthesized by substitution reactions from the precursor dimer [Ru( p-cymene)(Cl)(µ-Cl)]2 and were characterized by elemental analysis, mass spectrometry, 1H NMR, UV-vis, and IR spectroscopy, conductivity measurements, and cyclic voltammetry. The molecular structure for complex 2 was determined by single-crystal X-ray diffraction. The cytotoxic activity of these compounds was evaluated against human tumor cells, namely ovarian carcinoma A2780 and breast MCF7 and MDAMB231 adenocarcinoma cells, and against normal primary fibroblasts. Whereas the cytotoxic activity of 1 is moderate, IC50 values found for 2 are among the lowest previously reported for Ru( p-cymene) complexes. Both compounds present no cytotoxic effect in normal human primary fibroblasts when they are used at the IC50 concentration in A2780 and MCF7 cancer cells. Their antiproliferative capacity is associated with a combined mechanism of apoptosis and autophagy. A strong interaction with DNA was observed for both with a binding constant value of the same magnitude as that of the classical intercalator [Ru(phen)2(dppz)]2+. Both complexes bind to human serum albumin with moderate to strong affinity, with conditional binding constants (log Kb) of 4.88 for complex 2 and 5.18 for complex 1 in 2% DMSO/10 mM Hepes pH7.0 medium. The acute toxicity was evaluated in zebrafish embryo model using the fish embryo acute toxicity test (FET). Remarkably, our results show that compounds 1 and 2 are not toxic/lethal even at extremely high concentrations. The novel compounds reported herein are highly relevant antitumor metallodrug candidates, given their in vitro cytotoxicity toward cancer cells and the lack of in vivo toxicity.

Combination of carvacrol with simvastatin improves the lipid-lowering efficacy and alleviates simvastatin side effects.

The present investigation was designed to examine the possible additive hypolipidemic effect of carvacrol (CARV) in combination with simvastatin (SIM) on poloxamer 407 (P407)-induced hyperlipidemia. Rats were injected with P407, (500 mg/ kg; i.p.), twice a week, for 30 days. Treatment was carried out by administration of SIM (20 mg/kg/day; p.o.) or CARV (50 mg/kg/day; p.o.) or combination of them. Treatment with CARV significantly decreased total cholesterol, triglycerides, low-density lipoprotein, atherogenic index, leptin, and increased high-density lipoprotein and adiponectin. Moreover, CARV potentiated the hypolipidemic effect of SIM. Both SIM and CARV alleviated the oxidative stress induced by P407. Interestingly, CARV, when combined with SIM, significantly ameliorated SIM-induced liver and muscle injury by reducing the level of alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, creatine kinase, and myoglobin and restoring the normal histological picture of both liver and muscle as well as apoptosis.

Uses of hazardous medicinal plants: composition of the essential oil of Clinopodium gilliesii (Benth. ) Kuntze (Lamiaceae), collected in Chile / Uso de plantas medicinales peligrosas: composición del aceite esencial de Clinopodium gilliesii (Benth. ) Kuntze (Lamiaceae), recolectada en Chile

Clinopodium gilliesii (Benth.) Kuntze, harvested in the Chilean highlands, contains a surprising 93.87% of the toxic monoterpene pulegone in the essential oil. These results show remarkable differences with studies of the same species carried out in Argentina and Peru. These dissimilarities in the monoterpene composition of essential oils should be associated with differences in toxicity and biological activity of this medicinal plant used in ethnomedicine in different countries for the treatment of similar discomforts and diseases. These results are discussed considering the risk of consuming C. gilliesii, without clear recommendations and control of at least pulegone content in essential oils.

Clinopodium gilliesii (Benth.) Kuntze, recolectada en el altiplano chileno, contiene un sorprendente 93,87% del monoterpeno toxico pulegona, en el aceite esencial. Estos resultados muestran diferencias notables con estudios de la misma especie realizados en Argentina y Perú. Estas disimilitudes, en la composición de los aceites esenciales deben estar asociadas con diferencias en la toxicidad y actividad biológica de esta especie medicinal que se utiliza en etnomedicina en diferentes lugares para el tratamiento de molestias y enfermedades similares. Estos resultados se discuten considerando el riesgo de consumir C. gilliesii, sin recomendaciones claras y control de al menos el contenido de pulegona en los aceites esenciales.

Assessment of toxicity and biochemical mechanisms underlying the insecticidal activity of chemically characterized Boswellia carterii essential oil against insect pest of legume seeds.

The present study was undertaken to investigate the insecticidal activity of chemically characterized Boswellia carterii essential oil (EO) and its mode of action against the pulse beetle Callosobruchus chinensis and C. maculatus. GC-MS analysis depicted α-thujene (69.16%), α-Pinene (7.20) and α-Phellandrene (6.78%) as the major components of test EO. EO exhibited absolute toxicity at 0.10µl/ml air against both C. chinensis and C. maculatus following 24h exposure. EO caused a significant reduction in oviposition and further reproductive development at LC50 doses (0.050µl/ml to 0.066µl/ml in air). Compared to control, a significant elevation in ROS level accompanied with impairment in enzymatic (SOD and CAT) and non-enzymatic (GSH/GSSH) antioxidant defense system has been observed in EO exposed insect pest. However, EO has no significant effect on in vivo AChE activity. An absolute protection of Vigna radiata seeds samples exposed to EO at LC90 doses was observed without affecting seed germination. The findings revealed that the B. carterii EO has strong insecticidal potential, hence, it could be recommended as a biorational alternative to synthetic insecticides.

Antimicrobial activity of coriander oil and its effectiveness as food preservative.

ABTRACT Foodborne illness represents a major economic burden worldwide and a serious public health threat, with around 48 million people affected and 3,000 death each year only in the USA. One of the possible strategies to reduce foodborne infections is the development of effective preservation strategies capable of eradicating microbial contamination of foods. Over the last years, new challenges for the food industry have arisen such as the increase of antimicrobial resistance of foodborne pathogens to common preservatives and consumers demand for naturally based products. In order to overcome this, new approaches using natural or bio-based products as food preservatives need to be investigated. Coriander (Coriandrum sativum L.) is a well-known herb widely used as spice, or in folk medicine, and in the pharmacy and food industries. Coriander seed oil is the world's second most relevant essential oil, exhibiting antimicrobial activity against Gram-positive and Gram-negative bacteria, some yeasts, dermatophytes and filamentous fungi. This review highlights coriander oil antimicrobial activity and possible mechanisms of action in microbial cells and discusses the ability of coriander oil usage as a food preservative, pointing out possible paths for the successful evolution for these strategies towards a successful development of a food preservation strategy using coriander oil.

Anti-inflammatory and healing action of oral gel containing borneol monoterpene in chemotherapy-induced mucositis in rats ( Rattus norvegicus )

ABSTRACT The aim of this study was to investigate the effect of gels containing the monoterpene borneol in induced oral mucositis using an animal model. Gels were prepared with borneol at 1.2% and 2.4% (w/w). Oral mucositis was induced by administration of three doses of 5-fluorouracil (30 mg/kg, i.p.) and injury with acetic acid (50%, v/v) soaked in filter paper applied to right cheek mucosa for 60s. Four subgroups comprising 12 animals each were formed. Six animals from each group were sacrificed at days seven and fourteen after oral mucositis induction. Mucous samples were processed and stained with hematoxylin-eosin and Masson's Trichrome. The semiquantitative evaluation involved observation of inflammatory parameters. ImageJ® software was used in the quantitative evaluation. For statistical analyses, Two-way ANOVA, followed by Tukey's post-test (p <0.05), were employed. Borneol 2.4% gel proved effective in the treatment of oral mucositis with statistically significant differences between groups for angiogenesis control, inflammatory cell count reduction and percentage neoformed collagen increase. The confirmation of anti-inflammatory and healing action of borneol in oral mucositis in rats renders it a good marker for predicting this activity for plant extracts rich in this substance

Effects of Rowachol on prevention of postcholecystectomy pain after laparoscopic cholecystectomy: prospective multicenter randomized controlled trial.

BACKGROUND: Postcholecystectomy pain (PCP) is characterized by abdominal pain after cholecystectomy. However, prevention of PCP is not well known yet. The purpose of this study was to determine whether Rowachol might be useful in preventing PCP. METHODS: Between May 2013 and January 2014, a total of 138 patients with gallbladder disease who were scheduled to undergo laparoscopic cholecystectomy were randomly assigned to orally receive 100 mg Rowachol or placebo three times daily for 3 months after surgery. Abdominal pain was assessed using the European Organization for Research and Treatment of Cancer QLQ-C30 questionnaire. RESULTS: Incidence of PCP in the placebo group (n = 9, 14.3%) was higher than that in the Rowachol group (n = 3, 4.7%) with statistically marginal significance (P = 0.08). Risk factor analysis implicated PCP with increased difficulty in performing LC, more frequent pathology with acute cholecystitis, and absence of postoperative Rowachol treatment. Multivariate analysis revealed that greater difficulty of laparoscopic cholecystectomy (HR = 5.78, 95% CI 1.36-24.40, P < 0.05), and absence of postoperative Rowachol treatment (HR = 2.54, 95% CI 1.10-10.39, P < 0.05) were independent risk factors for development of PCP. CONCLUSION: Rowachol might be beneficial for prevention of PCP after laparoscopic cholecystectomy.

Tea tree oil: contact allergy and chemical composition.

In this article, contact allergy to, and the chemical composition of, tea tree oil (TTO) are reviewed. This essential oil is a popular remedy for many skin diseases, and may be used as neat oil or be present in cosmetics, topical pharmaceuticals and household products. Of all essential oils, TTO has caused most (published) allergic reactions since the first cases were reported in 1991. In routine testing, prevalences of positive patch test reactions have ranged from 0.1% to 3.5%. Nearly 100 allergic patients have been described in case reports and case series. The major constituents of commercial TTO are terpinen-4-ol, γ-terpinene, 1,8-cineole, α-terpinene, α-terpineol, p-cymene, and α-pinene. Fresh TTO is a weak to moderate sensitizer, but oxidation increases its allergenic potency. The major sensitizers appear to be ascaridole, terpinolene, α-terpinene, 1,2,4-trihydroxymenthane, α-phellandrene, and limonene. The clinical picture of allergic contact dermatitis caused by TTO depends on the products used. Most reactions are caused by the application of pure oil; cosmetics are the culprits in a minority of cases. Patch testing may be performed with 5% oxidized TTO. Co-reactivity to turpentine oil is frequent, and there is an overrepresentation of reactions to fragrance mix I, Myroxylon pereirae, colophonium, and other essential oils.

Activation of the Endoperoxide Ascaridole Modulates Its Sensitizing Capacity.

The monoterpene ascaridole, a fairly stable endoperoxide found in essential oils such as tea tree oil can provoke allergic contact dermatitis which has been evidenced under patch test conditions. However, concomitantly we observed irritative skin reactions that demand further data underlining the sensitization potential of ascaridole. Here, we studied the effects of ascaridole on dendritic cell (DC) activation and protein reactivity, 2 key steps of chemical-induced skin sensitization. Treatment of human monocyte-derived DC with ascaridole found support for full DC maturation, a capability of sensitizers but not irritants. It induced significant upregulation of the expression of the costimulatory molecules CD86, CD80, CD40, and the adhesion molecule CD54 in a time-dependent manner. Maturation was accompanied by release of proinflammatory cytokines interleukin (IL)-1ß, tumor necrosis factor-α, IL-6, and IL-8. Similar to other chemical skin sensitizers including hydroperoxides, we observed a certain reactivity of ascaridole toward cysteine- but not lysine-containing peptides. During recent years, evidence accumulated for a radical mechanism as trigger for protein reactivity of peroxides. Treatment of the fairly stable endoperoxide ascaridole with iron as radical inducer ("activated ascaridole") resulted in cysteine peptide reactivity exceeding by far that of ascaridole itself. Furthermore, activated ascaridole showed increased potential for induction of the Nrf2 target gene heme oxygenase 1 and upregulation of CD86 and CD54 on THP-1 cells, an established DC surrogate. These results indicate that radical formation could be involved in the steps leading to skin sensitization induced by the endoperoxide ascaridole.

Essential Oil from Berries of Lebanese Juniperus excelsa M. Bieb Displays Similar Antibacterial Activity to Chlorhexidine but Higher Cytocompatibility with Human Oral Primary Cells.

Chlorhexidine (CHX), one of the most effective drugs administered for periodontal treatment, presents collateral effects including toxicity when used for prolonged periods; here, we have evaluated the bactericidal potency and the cytocompatibility of Juniperus excelsa M. Bieb essential oil (EO) in comparison with 0.05% CHX. The EO was extracted from berries by hydrodistillation and components identified by gas chromatography and mass spectrometry. Bacterial inhibition halo analysis, quantitative cell viability 2,3-bis(2-methoxy-4-nitro-5-sulphophenyl)-5-[(phenyl amino) carbonyl]-2H-tetrazolium hydroxide assay (XTT), and colony forming unit (CFU) count were evaluated against the two biofilm formers Aggregatibacter actinomycetemcomitans and Streptococcus mutans. Finally, cytocompatibility was assessed with human primary gingival fibroblasts (HGF) and mucosal keratinocytes (HK). The resulting EO was mainly composed of monoterpene hydrocarbons and oxygenated monoterpenes. An inhibition halo test demonstrated that both bacteria were sensitive to the EO; XTT analysis and CFU counts confirmed that 10-fold-diluted EO determined a statistically significant (p < 0.05) reduction in bacteria count and viability towards both biofilm and planktonic forms in a comparable manner to those obtained with CHX. Moreover, EO displayed higher cytocompatibility than CHX (p < 0.05). In conclusion, EO exhibited bactericidal activity similar to CHX, but a superior cytocompatibility, making it a promising antiseptic alternative to CHX.

Syzygium cumini (L.) Skeels essential oil and its major constituent α-pinene exhibit anti-Leishmania activity through immunomodulation in vitro.

ETHNOPHARMACOLOGICAL RELEVANCE: Syzygium cumini (L.) Skeels (Myrtaceae), commonly known as "jambolão" in Brazil is widely used in folk medicine against leishmaniasis, inflammation, chronic diarrhea, and ulcers. It is one of the most commonly used plants for the treatment of diabetes worldwide. In previous studies, Syzygium cumini was shown to possess antihyperlipidemic and anti-allergic properties, and to exhibit good performance as an antimicrobial agent against bacteria, fungi, and protozoa parasites of the genus Leishmania and Trypanosoma. This study was aimed at evaluating the effects of S. cumini essential oil (ScEO) and its major component α-pinene on Leishmania (Leishmania) amazonensis, as well as their cytotoxicity and possible mechanisms of action. MATERIALS AND METHODS: To evaluate the anti-proliferative effect on Leishmania, effects on promastigote and axenic amastigote forms were assessed using tetrazolium salt (MTT) assay. The intramacrophagic amastigotes were exposed to ScEO and α-pinene to determine the survival index. To gain insight into the mechanism of action involved in the effect on the samples, we evaluated the modulation of macrophage activation state by observing structural (phagocytic and lysosomal activities) and cellular (nitric oxide increase) changes. To assess the safety profile of ScEO and α-pinene, murine macrophages and human red blood cells were treated with ScEO and α-pinene and the selectivity index was calculated for each treatment. RESULTS: α-Pinene was effective against Leishmania amazonensis promastigote forms, with a half-maximal inhibitory concentration (IC50) value of 19.7µg/mL. α-Pinene was more active (IC50 values of 16.1 and 15.6µg/mL against axenic and intracellular amastigotes, respectively) than ScEO (IC50 values of 43.9 and 38.1µg/mL against axenic and intracellular amastigotes, respectively). Our results showed that the anti-Leishmania effects were mediated by immunomodulatory activity, as evidenced by the observed increases in both phagocytic and lysosomal activity, and the elevated NO levels. ScEO and α-pinene exhibited low cytotoxicity against murine macrophages and human erythrocytes. The 50% cytotoxicity concentration (CC50) values for the macrophages in the MTT assay were 614.1 and 425.2µg/mL for ScEO and α-pinene, respectively, while the corresponding half-maximal hemolytic concentration (HC50) values were 874.3 and 233.3µg/mL. CONCLUSIONS: Taken together, the results demonstrate that ScEO and its major constituent α-pinene have significant anti-Leishmania activity, modulated by macrophage activation, with acceptable levels of cytotoxicity in murine macrophages and human erythrocytes. Further work is warranted, involving more in-depth mechanistic studies and in vivo investigations.

Evaluation of linalool, a natural antimicrobial and insecticidal essential oil from basil: effects on poultry.

Linalool is a natural plant-product used in perfumes, cosmetics, and flavoring agents. Linalool has proven antimicrobial and insect-repellent properties, which indicate it might be useful for control of enteropathogens or insect pests in poultry production. However, there are no published reports that linalool may be safely administered to or tolerated by chickens. Linalool was added to the diets of day-of-hatch chicks, and they were fed linalool-supplemented diets for 3 wk. We studied the effects of linalool on serum chemistry, gross pathology, feed conversion, and relative liver weights. Linalool had a dramatic negative dose-dependent effect on feed conversion at concentrations in the feed exceeding 2% linalool, but not on gross pathology. Liver weights were significantly increased in the 5% linalool-treated birds. There was a statistical effect on blood glucose, but this parameter remained below the cut-offs for elevated serum glucose, and the result is likely of no biological significance. Linalool caused serum aspartate aminotransferase (AST) levels to increase, but it did not increase serum gamma-glutamyl transferase levels. The linalool effect on AST was dose-dependent, but in linalool doses between 0.1 and 2% of the feed, AST was not elevated beyond normal parameters. Linalool at 2% or less may be safely added to chicken feed. We suggest future studies to evaluate the addition of linalool to the litter, where it may be used as an antimicrobial or an insect repellent or to produce a calming effect.

Perillyl alcohol suppresses antigen-induced immune responses in the lung.

Perillyl alcohol (POH) is an isoprenoid which inhibits farnesyl transferase and geranylgeranyl transferase, key enzymes that induce conformational and functional changes in small G proteins to conduct signal production for cell proliferation. Thus, it has been tried for the treatment of cancers. However, although it affects the proliferation of immunocytes, its influence on immune responses has been examined in only a few studies. Notably, its effect on antigen-induced immune responses has not been studied. In this study, we examined whether POH suppresses Ag-induced immune responses with a mouse model of allergic airway inflammation. POH treatment of sensitized mice suppressed proliferation and cytokine production in Ag-stimulated spleen cells or CD4(+) T cells. Further, sensitized mice received aerosolized OVA to induce allergic airway inflammation, and some mice received POH treatment. POH significantly suppressed indicators of allergic airway inflammation such as airway eosinophilia. Cytokine production in thoracic lymph nodes was also significantly suppressed. These results demonstrate that POH suppresses antigen-induced immune responses in the lung. Considering that it exists naturally, POH could be a novel preventive or therapeutic option for immunologic lung disorders such as asthma with minimal side effects.

Intranasal administration of perillyl alcohol activates peripheral and bronchus-associated immune system in vivo.

Perillyl alcohol (POH) presents antitumoral activity but clinical application is hampered by adverse effects following oral administration. This work aimed to verify the cytotoxic effect of intranasal POH administration in the histology of lung, liver, brain; the cellularity and function of peripheral and bronchoalveolar-associated immune system. C57 adult mice received 1-min inhalation with POH, vehicle 70 % ethanol or saline buffer, once (84 µg/day) or twice (164 µg/day) during five consecutive days, and were killed 72 h after treatment. Spleen, cervical and mesenteric lymph nodes were removed for (3)H-thymidine proliferation assay, leukocyte cellularity and flow cytometry analysis. Peripheral blood and bronchoalveolar lavage cells were collected to assess cellularity and immunoglobulin (IgA, IgM) levels. Intranasal POH did not alter body weight or liver, brain and lung morphology, but increased splenocyte and cervical lymph node cell proliferation, and IgM production without altering peripheral lymphocyte subsets. Treatment also increased the percentage of alveolar macrophages (83 %) and IgA-producing lymphocytes (15 %), a pattern characteristic of activated bronchoalveolar innate immune system. Intranasal administration of POH activated peripheral immune system and innate immunity of bronchus-associated lymphoid tissue, thus suggesting a possible role for POH as a chemotherapeutic drug also in pathological processes affecting the lung.

Antitumor effect of 1, 8-cineole against colon cancer.

Several essential oils possess pharmacological effects. Among the various constituents of essential oils, 1, 8-cineole has been shown to possess pharmacological effects such as anti-bacterial and anti-inflammatory effects. The effect of 1, 8-cineole on human colorectal cancer cells, however, has not reported previously. In this study, we have investigated the anti-proliferative effect of 1, 8-cineole on human colon cancer cell lines HCT116 and RKO by WST-8 and BrdU assays. The cytotoxicity of 1, 8-cineole was investigated by LDH activity and TUNEL staining. The mechanism of apoptosis by 1, 8-cineole was determined by western blot analyses. In in vivo study, RKO cells were injected into the SCID mice and the effect of 1, 8-cineole was investigated. Specific induction of apoptosis, not necrosis, was observed in human colon cancer cell lines HCT116 and RKO by 1, 8-cineole. The treatment with 1, 8-cineole was associated with inactivation of survivin and Akt and activation of p38. These molecules induced cleaved PARP and caspase-3, finally causing apoptosis. In xenotransplanted SCID mice, the 1, 8-cineole group showed significantly inhibited tumor progression compared to the control group. These results indicated 1, 8-cineole suppressed human colorectal cancer proliferation by inducing apoptosis. Based on these studies 1, 8-cineole would be an effective strategy to treat colorectal cancer.

Assessment of the in vitro and in vivo genotoxicity of extracts and indole monoterpene alkaloid from the roots of Galianthe thalictroides (Rubiaceae).

Roots of Galianthe thalictroides K. Schum. (Rubiaceae) are used in folk medicine in the State of Mato Grosso do Sul, Brazil, for treating and preventing cancer. To gain information about the genotoxicity of extracts (aqueous and EtOH), the CHCl3 phase resulting from partition of the EtOH extract and the indole monoterpene alkaloid 1 obtained from this plant. The genotoxicity of 1 and extracts was evaluated in vivo through the Drosophila melanogaster wing Somatic Mutation and Recombination Test - SMART, while in vitro cytotoxic (MTT) and Comet assays were performed only with alkaloid 1. The results obtained with the SMART test indicated that the aqueous extract had no genotoxic activity. The EtOH extract was not genotoxic to ST descendants but genotoxic to HB ones. The CHCl3 phase was genotoxic and cytotoxic. Alkaloid 1 showed significant mutational events with SMART, in the cytotoxicity assay (MTT), it showed a high cytotoxicity for human hepatoma cells (HepG2), whereas for the Comet assay, not showing genotoxic activity. The ethanol extract was shown to be genotoxic to HB descendants in the SMART assay, while the results obtained in this test for the monoterpene indole alkaloid 1 isolated from this extract.

Thujone and thujone-containing herbal medicinal and botanical products: toxicological assessment.

Thujone, a major component of the notoriously famous absinthe drink, is neurotoxic, although the current view rather downgrades its risk to humans. In animal studies, thujone inhibits the gamma-aminobutyric acid A (GABA(A)) receptor causing excitation and convulsions in a dose-dependent manner, although there are uncertainties about the doses required in humans. Toxicity of thujone has been extensively studied. Neurotoxicity is the principal toxic outcome in acute and chronic studies. There is some equivocal evidence of carcinogenicity in rats. Metabolism of thujone has been elucidated both in vitro and in vivo in several species and in vitro in human liver preparations. CYP2A6 is the principal metabolic enzyme, followed by CYP3A4 and, to a lesser extent, CYP2B6. CYP-associated metabolism may give rise to some potential pharmacogenetic and metabolic interaction consequences. Although the data base for determining exposure limits is of variable usefulness, the best estimates for allowable daily intakes via herbal preparations and diet are of the order of 3-7 mg/day. There are still important gaps in the knowledge required to assess thujone toxicity, the most important ones being human dose-concentration-effect relationships including the elucidation of bioavailability, and the actual toxicological consequences of potential pharmacogenetic variations and environmental factors.