J Pharm Pharm Sci (www.cspsCanada.org) 18(4) 825 - 843, 2015
Hepatotoxicity of Pyrrolizidine Alkaloids
Manuela G. Neuman1,2, Lawrence B. Cohen3,4, Mihai Opris1, Radu Nanau1, Hyunjin Jeong1,2
1.In Vitro Drug Safety and Biotechnology, 2. Department of Pharmacology and Toxicology, 3. University of Toronto, Division of Gastroenterology, Sunnybrook Health Sciences Centre, 4. Department of Internal Medicine, University of Toronto, Toronto, Canada.
Received, August 19, 2015; Revised, September 19, 2015; Accepted, November 21, 2015; Published, November 23, 2015.
ABSTRACT - PURPOSE: This article aimed 1) to review herbal medicine containing pyrrolizidine alkaloids (PA)-induced toxicities of the liver; 2) to encourage the recognition and prevention of common problems encountered when using complementary and alternative medicine and 3) to review the toxic effects of herbal remedies containing PAs. DESIGN AND METHODS: We performed a systematic literature search using the PubMed and Google Scholar engines. The search was not restricted to languages. We also provide an interpretation of the data. CONCLUSIONS: Herbal remedies containing PAs can induce liver damage, including hepato- sinusoidal obstruction syndrome or veno-occlusive disease. Preventing overdose and monitoring long-term use of such remedies may avoid glutathione depletion leading to mitochondrial injury, and therefore avoid liver cell damage. Moreover, immediately stopping the herbal medication prevents further harm to the liver. Chronic consumption of hepatotoxicants can lead to cancer formation and promotion. The role of active metabolites in PA-induced liver toxicity and their mechanism of action require further investigation.
This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page. ______
INTRODUCTION of parenchymal cell integrity. This is in contrast to direct hepatotoxins, which are agents that produce Therapies consisting of complementary and cholestasis, interfering mainly with biliary alternative medicine (CAM) span a diverse group secretion, and usually sparing the parenchyma. of substances that include herbal and dietary Indirect hepatotoxicants include agents that disturb supplements (1). The use of CAM therapies or competitively inhibit essential metabolites, increased dramatically in the last 20 years. alkylate or arylate key molecules, alter membranes, MacLennan et al. (2) described the escalating use or produce other selective metabolic blocks and of CAM in Australia. In the United States, 65% of physiologic lesions. Senecio extract, a natural the population reported the use of CAM therapies hepatotoxin, appears to fit this category in the (3-5). The out-of-pocket cost of purchasing non- experimental setting (15, 16). vitamin, non-mineral natural products amounted Traditional medicines composed of herbs often to $14.8 billion in 2007 in the United States (6). contain a complex mixture of both beneficial and Herbal supplements can be associated with toxic phytochemicals. These are directly prepared toxicities (7, 8). The frequency of hepatotoxicity from raw materials with little to no separation attributable to plant-derived products is under- procedures. Acute poisoning due to the use of reported, since not all patients inform their traditional medicines is a serious problem in South clinicians that they use such therapies (9). As a Africa. The inappropriate use of medicinal herbs has result, hepatotoxicity associated with herbal use resulted in numerous fatalities, especially in young may be missed (10-13). children (7, 17-23). Indirect hepatotoxicants, as defined by Zimmerman (14), are substances that cause hepatic injury by producing selective biochemical or Corresponding Author: M.G. Neuman M.Sc., Ph.D., FACB IN physiologic lesions which disrupt metabolic VITRO DRUG SAFETY & BIOTECHNOLOGY, Banting Institute, 100 College Street, lab 217 Toronto, Ontario, Canada, pathways or processes essential for the maintenance E-mail: [email protected]
825 J Pharm Pharm Sci (www.cspsCanada.org) 18(4) 825 - 843, 2015
It is currently estimated that 80% of the South Pyrrolizidine alkaloids African population consults with traditional healers PAs are a class of alkaloids based on the structure of and uses some form of traditional herbal medicine, pyrrolizidine which are present in distinct plant usually in combinations (24, 25). families that grow worldwide (15, 16, 27) (Table 1.). This review deals with phytochemicals of the PAs and PA N-oxides have been identified in plant cytotoxic group that are of special interest as species throughout the world (3% of the world's classical, experimental hepatotoxicants, or as agents flowering plants) (28). PA hepatotoxicity, which has of importance to clinical medicine. The natural been long recognized, is predominantly observed toxins discussed in this paper are excellent models after exposure to the following plant families: of indirect hepatotoxicity. They include a number of Boraginaceae (Heliotropium sp., Trichodesma sp., agents of practical importance to human and Symphytum sp. [Comfrey]), Compositae (Senecio sp. veterinary medicine such as the pyrrolizidine [Bush Teas], Eupatorium sp), Crotalaria sp. alkaloids (PA) (16). PAs are well-studied (Leguminosae), Greater Celandine (Chelidonium hepatotoxins that produce selective biochemical majus), and Ariaceae (Castilleja sp.) (28-48). Kava- lesions. kava (Piper methysticum) contains kava pyridone In figure 1 a (Senecio doronicum) and figure 1 b alkaloid, pipermethystine, which is abundant in (Senecio jacobea) we illustrate two of the species of leaves and stem peelings. This alkaloid induces Senecio. The experimental hepatocytoxicity mitochondrial toxicity. In addition, kavalactones induced by natural substances has been described such as 7,8- dihydromethysticin and by several authors (15, 26). desmethoxyangonin, abundant in the roots of the plant, may lead to different organ toxicities (46). While sporadic in Western countries, PA poisoning is nearly endemic in areas where traditional remedies are frequently used, such as China (40), Africa and India (49-52). The toxicity of Senecio plants and related species has been shown to cause disease in grazing domestic animals. A series of studies has been reviewed by McLean (53). The toxic principles (PAs) have been identified, their presence in some plants has been established, and the characteristics of the hepatic injury they produce has been defined (53). The hepatotoxic and carcinogenic species of plant pyrrolizidine alkaloids (e.g. echimidine and jacobine), are generated by hepatic CYP2B6 and CYP3A4. Figure 2a presents precursors of pyrrole metabolites The Figure 1a Senecio doronicum acute hepatic injury produced by PAs includes zone
3 hepatic necrosis, minor steatosis, and occlusive injury of the small branches of the efferent venules (10, 53, 54). Chronic expoxure leads to the development of very large cells ("megalocytes"), cirrhosis and hepatocellular carcinoma (53). The mechanism of injury appears to involve the injury of the hepatic vasculature and parenchyma by pyrrole derivatives that react with DNA (55-57). All PAs contain the core structure of pyrrolizidine, which consists of two fused penta- rings with a nitrogen atom at position four, one of the two points of fusion. The hepatotoxic derivatives are esters of 1-hydroxymethyl-1,2-dehydro-7-hydroxy- Figure 1b Senecio jacobea pyrrolizidine. Requirements for toxicity appear to include the 1-2 unsaturation and the esterification
826 J Pharm Pharm Sci (www.cspsCanada.org) 18(4) 825 - 843, 2015 with a branched-chain acid (53). These 1-2- levels of PAs on a commercial scale to be adopted unsaturated PAs are metabolized by CYP450 in the food regulation industry. However, enzymes in the liver to the corresponding "pyrrole commercial scale analytical methods are being type esters", responsible for PA-induced toxicity. explored as a way to sensitively detect toxic PAs Saturation of the double bond eliminates the toxicity; from complex mixtures. The lack of reference esterification does not play a major role in toxicity. standards for analysis is a great hindrance for Solubility of the alkaloids in aqueous solvents is low screening methods to be implemented (69). at a neutral pH, and is enhanced by acidification (53, Oplatowska et al. are in the process of developing 58). Pyrrolizidine alkaloids consist of a necine base a rapid enzyme-linked immunosorbent assay and necic acid. The necic acids are four to six carbon- (ELISA) capable of performing a multiplex containing mono- or di-carboxylic acids. The immunoassay for PAs with N-oxide (70). Griffin et structures of the four representative types are necine al. are also investigating a LC-ion trap MS method bases, platynecine, retronecine, heliotridine, and on a commercial scale to detect PAs in honey (71), otonecine. The platynecine type PAs, which do not whereas Martinello et al. are finding quantitative contain a double bond in the necine base, are methods to measure PA content by UPLC-MS to considered weakly toxic. However, the retronecine-, extrapolate on an industrial level (72). heliotridine-, and otonecine-type that have a double- bond at the C1 and C2 positions of the necine base Pyrrolizidine alkaloids toxicity exhibit high levels of hepatocytotoxicity (10). PAs are found in more than 6,000 plants within the Asteraceae, Boraginaceae, Compositae, and Laboratory measurements Fabaceae families (28, 73-75). In total, over 300 Both acute and chronic PA-induced toxicity have different PAs have been identified, and they are been reported in humans depending on the categorized according to their necine base and necic quantity and frequency of the exposure (59). Urine acid components (76, 77). Plants that are part of the and blood samples belonging to patients who have Senecio genus are reported to have high amounts been exposed to traditional medicine can be used of PAs in the form of senecionine, retrorsine, to identify the quantity of PA that is present, riddeliine, integerrimine, neosenkirkine, and which can help monitor chronic or acute PA florosenine (27, 78). Not all PAs are toxic. However, toxicity. Steenkamp et al. (60) and Neuman and the ones that are reported to be toxic all Steenkamp (51) showed an increased risk of veno- commonly have a double bond in the ring nucleus, occlusive disease in people who used herbal an esterified hydroxyl group, and a branched carbon remedies containing PAs, despite no previous in at least one of the ester side chains (76, 77, 79). medical history. In addition, no herb-therapeutic or Senecionine, retrorsine, and riddelliine are three of herb-herb interaction was noted, since the patients many PAs that meet these criteria. Despite their high did not take any barbituates, benzodiazepines, content in toxic PAs, plants of the Senecio spp. are tricylic antidepressants, paracetamol, or other herbal commonly used in traditional medicine for remedies. Moreover, there are several reports of numerous purposes. PA-induced toxicity manifests using the herbal material to livestock. Senecio its problematic nature in two dimensions: firstly, oxyriifolius DC is given to animals with swelling and grazing livestock experience irreversible and fatal Senecio tamoides DC is administered to animals with liver damage by feeding off plants that are rich in anthrax (61). PA or feeds that are contaminated with plants rich Analytical chemistry techniques such as high- in PA; and secondly, individuals treated with performance liquid chromatography (HPLC), gas traditional medicine or exposed to contaminated chromatography (GC), mass spectroscopy (MS), food, including both contaminated plants and and thin layer chromatography (TLC), in tandem products from infected animals, may experience with each other, have been conducted by past toxicity. researchers to provide chemical identification and Senecio-induced liver injury is a commonly quantitative data regarding the amount of PAs reported issue for livestock. Countries such as present in blood and urine (22, 62-68). Although Zimbabwe (80), South Africa (81), the United analytical techniques such as liquid chromatography Kingdom (82), Belgium (83), France (84), Australia (LC) and GC are currently available to detect traces (85), Spain (86), Brazil (87-91), Canada (92), and of PAs, there are no rapid screening assays to assess the United States (93, 94) have all reported PA-
827 J Pharm Pharm Sci (www.cspsCanada.org) 18(4) 825 - 843, 2015 induced livestock deaths after post-mortem products from the market (105). investigation. Senecio-induced liver poisoning in Special populations are more vulnerable to animals is preventable, and represents a high cost products containing PAs. Many of PA containing for farmers. Approximately 10% of cattle and 5% herbal teas are marketed for pregnant or lactating of small livestock are poisoned by PA-rich plants mothers; traces of PA may be exposed to infants, annually in South Africa, which is equivalent to harming the mother’s child (106). Another source approximately 8,107,521 South African rand in of exposure to PA is from food contamination. financial cost per year (81). Stuart et al. (95) Honey from nectar of PA-rich flowers is often reported Cocklerbur (Xanthium strumarium) contaminated with PAs according to LC-MS results, intoxication in swine, while Witte et al. (96) and the presence of PAs in honey is not uncommon describe the same phenomenon in cattle. Ninety per (107-113). Milk could also contain traces of PAs if cent of the complaints received by the United the cows eat Senecio-contaminated feed (114). An Kingdom Department for Environment, Fisheries outbreak of hepatic veno-occlusive disease (VOD) and Rural Affairs are from farmers regarding weed in Western Afghanistan occurred after people were catastrophes such as Senecio (97). The Australian exposed to PA-contaminated wheat flour (115). dairy industry loses $2,428,211 per year in milk A cohort study on Ugandan participants production and $434,327 per year in beef showed an increased risk of liver fibrosis when production because of Senecio jacobaea. Overall, an individual uses traditional medicine composed of more than $4.0 million is lost in the Australian herbs from the Asteraceae, Fabaceae, and agricultural industry solely due to Senecio jacobaea Lamiaceae families (116). This is problematic (98). The United States Department of Agriculture since many Ugandan patients with human have reported that cattle, deer, horses, and goats are immunodeficiency virus resort to traditional exposed to plant toxins by accidental exposure or medicine and neglect their antiretroviral therapy, dried as part of silage or hay (99, 100). It thus which may potentiate non-compliance to their provided suggested techniques to help mitigate prescribed treatment and by itself, or in combination the problem such as crop rotation techniques, with alcohol, may lead to hepatotoxicity (52, 117). proper forage harvesting, and control of weed Zimmerman (10) emphasized that the rules for invasion by pulling weeds mechanically or using "causality assessment" in attributing liver injury to broadleaf herbicide to mitigate the harm of PA- any toxin are similar to those for other therapeutics rich plants on livestock viability (100). (e.g. exposure must lead to the onset of liver injury Nevertheless, both developed and developing and other liver diseases should be excluded). The countries that face PA-induced livestock death lack severity of liver injury is enhanced by repeated detailed agricultural protocols that would assist exposure. The mainstay of therapy for herbal farmers from livestock attrition. Basic science hepatotoxicity is withdrawal of the offending toxin. research must be communicated coherently and Liver injury may improve after stopping the detailed protocols must be implemented for farmers ingestion of the toxin. However, in fulminant cases, and land managers in order to improve agricultural an abrupt decline in liver biochemical tests may conditions. indicate worsening of the liver status rather than Medicinal tea containing PA-rich herbs also improvement of its functional capacity. As a induced serious liver veno-occlusive disease in consequence, early recognition of toxicity is many parts of the world, with numerous people important to permit assessment of severity and ending up with severe liver damage and death (31, monitoring for acute liver failure (118). More 34, 101-103). Although analytical methods have extensive disease can lead to cirrhosis, hepatic confirmed that numerous herbal teas contain PAs, failure, and death (14). The acute form is rapidly which is detrimental to health, there are still licensed fatal in 20 to 40 percent of patients (with worse and registered commercial products that are prognosis in adults compared with children). available in the market for consumers to purchase Approximately 15% of patients with acute disease (104). For example, comfrey has been removed from will progress to subacute or chronic injury, the market in France following numerous reports of succumbing within several years to end stage liver liver damage. It remains widely available in the disease. Some of the patients develop cirrhosis and United States despite the US Food and Drug portal hypertension (14). Administration’s requests to remove comfrey Regardless of the intended use of traditional
828 J Pharm Pharm Sci (www.cspsCanada.org) 18(4) 825 - 843, 2015 remedy, clinical case reports have been published In vivo and in vitro models show concentration- regarding PA-induced hepatotoxicity; thus, the dependent PA-induced depletion of glutathione toxicology behind Senecio spp. and other PA-rich indicative of oxidative stress by PAs (122). One herbs should not be neglected or undermined. proposed mechanism implicates PAs in inhibiting Moreover, monitoring the levels of PA in blood hepatocyte proliferation and inducing cell death is by and/or urine will help in diagnosing and treating the decreasing the level of Bcl-x, an anti-apoptotic toxic reaction. protein, and increasing the level of Bax, a pro- apoptotic protein that enhances the release of Hepatic sinusoidal obstruction syndrome cytochrome c from the mitochondria for apoptosis Numerous case reports in human and veterinary (123). Another proposed mechanism to explain PA- medicine indicate that PAs at high doses induce induced apoptosis involves reduced p53expression, sinusoidal obstruction syndrome (HSOS) previously which is independent from Bcl expression (124). referred to as hepatic veno-occlusive disease (VOD). Zuckerman et al. have conducted an in vitro study Without medical intervention and discontinuation of and demonstrated that toxic PAs not only induce the toxicant exposure, HSOS can lead to more severe apoptosis, but also clump the tubulin cytoskeleton at complications such as liver fibrosis, cirrhosis, relatively low concentration, and lead to necrotic cell necrosis, and ultimately death (119). Willmot and bodies (125). The inflammatory response is also Robertson first clinically described the symptoms of suggested to be part of the pathogenesis of PA- HSOS by ascites, hyperbilirubinemia, induced HSOS (16). Cytokines such as tumor hepatomegaly, and abdominal pain (119-121). Non- necrosis factor (TNF)-α, interleukin (IL)-1β, and thrombotic luminal occlusion of the small endothelin-I (ET-1) are secreted by monocytes in centrilobular veins leads to hepatic congestion and response to PAs (50, 126). TNF-α is a cytokine that subsequent hemorrhagic parenchymal necrosis (10). directly induces cell death in normal endothelial cells More extensive disease can lead to hepatic failure, (127). The pro-coagulant properties of TNF-α and and death (10). Regardless of the cause, HSOS IL-1β and the coagulation pathway remain active begins with injury to the hepatic venous areas of research in understanding HSOS (128, 129). endothelium. The preexisting liver disease increases As a result of liver injury, bile acid homeostasis the risk of developing HSOS. Preexisting liver is also compromised. Xiong et al. have investigated disease may impair metabolism of drugs and PA-induced hepatotoxicity and its change in phytochemicals, and thus predispose to cell injury. In metabolomics and genomic profiles in hepatocytes addition, patients with chronic viral or alcoholic (130). Genome microarray analysis and quantitative hepatitis may have abnormalities in hepatic polymerase chain reaction (qPCR) were used to endothelial cells that could make them more observe and verify the down-regulation of key susceptible to PAs (15). Endothelial cells in patients enzymes associated with bile acid homeostasis such with hepatitis may abnormally express adhesion as CYP7A1, bile acid CoA-amino acid N- molecules and procoagulant factors. The acute form acetyltransferase, sodium taurocholate is rapidly fatal in 20 to 40 percent of patients (with cotransporting polypeptide, and organic anion worse prognosis in adults compared with children). transporting polypeptide, and the up- regulation of Approximately 15 percent with acute disease will multidrug-resistance-associated protein 3. Patient progress to subacute or chronic injury, succumbing serum metabolomic analysis via ultraperformance within several years to end stage liver disease (10). liquid chromatography (UPLC) showed an Early pathologic changes include the deposition of elevated activity of alanine aminotransferase, fibrinogen and factor VIII within the venular walls aspartate aminotransferase, and increased and liver sinusoids (10). concentration of total bilirubin, all indicative HSOS is also a serious complication that is not biomarkers to hyperbilirubinemia associated with uncommon for hematopoietic stem cell transplant HSOS. A murine model conducted by Xiong et al. patients and exhibit similar pathological features showed similar results, with elevated level of (121). The pathogenesis of HSOS is elucidated alanine aminotransferase, aspartate employing in vivo and in vitro studies to understand aminotransferase, and total bilirubin concentration, its molecular basis. Studies suggest that endothelial all indicative biomarkers of hepatotoxicity (131). cell injury via oxidative stress and PA-induced PAs undergo three main metabolic pathways. apoptosis of hepatocytes is one contributing factor. PAs that are hydrolyzed to a carboxylic acid or N-
829 J Pharm Pharm Sci (www.cspsCanada.org) 18(4) 825 - 843, 2015 oxidized to a N-oxide metabolite are non-toxic and N-acetyl-cysteine, the precursor to glutathione, an soluble in water and thus excreted via urine (53). antioxidant compounds, lowered the susceptibility Although PAs in their native form are non-toxic, of PA-induced hepatotoxicity (122, 143), while a when they are biotransformed by CYP3A their glutathione synthesis inhibitor increased the metabolite reacts with nucleic acids and proteins susceptibility to PA-induced hepatotoxicity (143). (132-135). The initial oxidation by CYP3A, then the Primary mice hepatocytes have shown that spontaneous dehydrogenation of the necine ring senecionine and other PAs induce apoptotic DNA produces a dehydro-pyrrolizidine compound, a toxic laddering, caspase-3 activation, and a decreased pyrrolic ester that acts as an electrophile. Thus, level of Bcl-xL, an anti-apoptotic protein (144), CYP3A inducers could increase the susceptibility of thus concluding that PAs share a common PA-induced toxicity, while CYP3A inhibitors could hepatotoxic signaling pathway that involves the prevent toxic outcomes (136), since inhibitors yield degradation of Bcl-xL protein and activation of the less dehydropyrrolizidine alkaloids (137). Although intrinsic apoptotic pathway, mediated by the pyrrolizidine N- oxide metabolites are generally mitochondria. non-reactive and get excreted via urine, excess of Our previous research regarding Senecio- these metabolites can be further biotransformed into induced toxicity has showed that an aqueous toxic epoxides and necine bases, which is extract of Senecio induced cytotoxicity in a dose- detrimental to cellular function (138). At low time-dependent manner, as determined by ELISA concentrations, endogenous detoxification systems, and terminal dUTP nick-end labeling in HepG2 notably glutathione, would conjugate the cells. Furthermore, glutathione depletion was electrophilic metabolite, stabilizing it for excretion observed when cells were treated with Senecio via urine. In vivo and in vitro studies have shown extract and N-acetyl-cysteine was shown to that PA-induced HSOS has been linked to the potentially reduce cytotoxicity induced by Senecio. depletion of glutathione in sinusoidal endothelial Lastly, caspase-3 and caspase-9 inhibitors were cells, indicative of PA-induced oxidative stress demonstrated to prevent apoptosis associated with (122). Cattle with irreversible liver damage aqueous Senecio extract (145). A proposed induced by Senecio spp. showed higher activity of mechanism of toxicity is illustrated in Figure 2b. copper-zinc superoxide dismutase and thiobarbituric In hepatocytes, CYP - P450s convert dehydro- acid-reactive substances, and higher level of non- pyrrolizidine alkaloides (PA)s to 6,7-dehydro- protein sulfhydryl group, all indicative of lipid pyrrolizine esters which represent the toxic peroxidation and oxidative stress as contributing metabolites. Dehydro-retronecine and dehydro- pathological pathways (59). Glucuronidation of PA heliotridine are produced from the initial toxic has yet to be extensively investigated but the study metabolites via reactive oxygen species. Esterases by He et al. showed that senecionine and other can detoxify dehydro-PAs by hydrolyzing their ester PAs are conjugated by glucuronic acid in humans groups to produce non-toxic necic acids and necines. and animals (139). Dehydroretronecine and dehydroheliotridine react rapidly with nucleophiles such as SH, OH, NH PA toxicity is dose- and time-dependent groups on nucleotides, as well as with proteins to HepG2 cells have shown senecionine-induced dose- form adducts. Glutathione is responsible for and time-dependent cytotoxicity assessed by MTT, detoxification of the toxic metabolites in the liver. bromodeoxyuridine incorporation assay, neutral red Endothelial cells lining the sinusoids of the liver uptake assay, resazurine assay, lactate became damaged due to an accumulation of toxic dehydrogenase release assay, and sulforhodamine metabolites. This phenomenon causes the B assay (16, 140). Moreover, cell lines and obstruction of the sinusoids. injection bioassays show that PAs are cytotoxic in Over time, some tissue-bound adducts release a dose-dependent manner (141). L-02 cells show dehydroretronecine/heliotridine which are less in a dose- and time-dependent manner that reactive toxic metabolites than the senecionine and other PAs such as adonifoline, dehydroretronecine and dehydroheliotridine toxic senecionine, monocortaline, and isoline deplete metabolites. These metabolites form new adducts cellular glutathione levels and increase the level of leading to chronic diseases such as cancer, pulmonary oxidized glutathione, resulting in a decreased ratio hypertension, fibrosis of the liver and cirrhosis. of glutathione to oxidized glutathione (122, 141).
830 J Pharm Pharm Sci (www.cspsCanada.org) 18(4) 825 - 843, 2015
Figure 2a
Figure 2b. CYP – Cytochrome P450s, PA-pyrrolizidine alkaloids, RSO - reactive oxygen species, GSH-Gluthatione.
PAs and cancer Culvenor firstly reported the tumor-inhibiting
831 J Pharm Pharm Sci (www.cspsCanada.org) 18(4) 825 - 843, 2015 activity of PA isolated from Senecio mikanioides Indian medicine, Ayurveda, uses medicinal plants due to the compound’s ability to alkylate biological which contain toxic PAs which represent a severe molecules (146). Further investigation found mutagenic and cancerogenic risk (157). The indicine N-oxide as a lead compound for cancer carcinogenic species of PAs (e.g. echimidine and therapy since less severe hepatotoxicity in animal jacobine), namely pyrrole-type metabolites, are models was shown relative to other PAs (147). generated by hepatic CYP2B6 and CYP3A4 (158). Indicine N-oxide is a PA found in Heliotropium Roeder and his team described PA chemical structure indicium and has been produced semi-synthetically and the use of PA-containing remedies in the world for phase I and II clinical trials in patients with (159-161). In their recent review article, Roeder et al. advanced solid tumors and leukemia (148-151). (162) also mention that PAs are mutagenic, Kovach et al. noticed that administering daily carcinogenic, and teratogenic. In addition, the 2 authors recognized the need to identify and to doses of 3.0 g/m for five consecutive days to advanced cancer patients showed symptoms of regulate PA-containing medications. While the myelosuppression but no significant hepatic and mainstay of therapy for herbal hepatotoxicity is withdrawal of the offending toxin, early recognition renal impairment (152). Furthermore, three patients of toxicity is important to permit assessment of with advanced gastrointestinal cancer had no severity and monitoring for liver damage. However definite therapeutic response to indicine N- oxide and its ability to treat solid tumors (152). of importance is prevention of the toxic event. The clinical trial of indicine N-oxide in acute leukemia patients conducted by Letendre et al. failed Regulation of herbal remedies Regulation of the safety, efficacy and quality of to show therapeutic improvement. Five out of herbal remedies is greater in the Europe (EU) than in eleven patients experienced severe hepatotoxicity the United States (US). Complementary and and four resulted in death due to liver failure (153). A five year-old boy with acute myelocytic Alternative Medicine in the United States receives 2 recommendation from the Institute of Medicine leukemia was given 7.5 g/m indicine N-oxide after Committee on the Use of Complementary and two complete remissions with standard Alternative Medicine regarding the possible use of chemotherapeutic agents. Three days later, the herbal remedies by the American Public (163). In patient showed signs of acute hepatic failure, and addition, FDA regulates the safety and efficacy of the died nine days later with hepatic necrosis (154). complementary and alternative medication as well as A phase I clinical trial was carried out by of the amount of PA in food and natural related Whitehead et al. using indicine N-oxide to treat products (164-169). EU requires manufacturers of all children with leukemia or solid tumors who failed to over-the-counter herbal products to register and show progress on standard chemotherapy. Myelo- license the product with the European Agency for the suppression and hepatotoxicity limited the dose of Evaluation of Medicinal Products. A premarket indicine N-oxide in pediatric patients with solid evaluation of quality and safety of the product is tumors and leukemia, respectively (150). Further, required. Companies have been asked to carry out no clinically significant objective responses were post- marketing surveillance and report serious noted in patients, thus disappointingly ceasing the adverse events. Instead of requiring new rigorous scientific investigation into indicine N-oxide. Miser efficacy studies to market a new product, et al. (155) carried out a phase II clinical trial in documentation from the medical literature of safety children with relapsed acute leukemia and although for the relevant condition and reasonable plausibility indicine N-oxide showed some anti-leukemic of efficacy is needed. The World Health activity, it was associated with severe and Organization (WHO) developed a Traditional irreversible hepatotoxicity. PA appears to be a Medicine Strategy to promote the safety of the compound of interest for anti-cancer therapy due to complementary and alternative medicine as well as its cytotoxic and angiogenesis inhibiting property. to regulate the poisonous substances of natural origin However, as a result of its severe hepatotoxicity, that may be found in food (164). As part of this clinical application is limited. effort, the WHO distributed a survey about national PAs found in several commonly consumed policies and regulations for herbal medicines to help plants are potential carcinogens or tumor promoters frame regulatory policies, enhance quality, safety and should be avoided (156). Also, the Traditional and efficacy. The potential PA contamination of
832 J Pharm Pharm Sci (www.cspsCanada.org) 18(4) 825 - 843, 2015 food, herbal medicine, herbal teas, dietary recommends dilution of contaminated product with supplements or food containing PA plant material uncontaminated product to achieve the representing potential threat to human health by PAs recommended level (FSANZ 2004), a practice not is studied. In pharmaceuticals, the use of these plants allowed in some other jurisdictions (European Food is regulated. Safety Authority (EFSA) 2007). In addition, Senecio Drying pollen granules during processing spp. is prohibited for therapeutic use in Australia. reduces the dehydroPA content of the granules (173). The safety of herbal medicinal products needed Nevertheless, 17 (31%) of 55 commercial bee-pollen to be evaluated on the basis of existing scientific products purchased at retail outlets in Europe have literature (data from clinical studies, case reports, been found to contain 1080– 16350 mg/kg1 of pre-clinical studies). Based upon the safety and dehydro-PAs mainly from Echium species (172). efficacy data, herbal medicinal products are Echium sp. pollen has a characteristic deep purple categorized as: (i) medicinal herbs with a recognized colour and bee-collected pollen granules from level of safety and efficacy; and (ii) traditional used Echium sp. have been observed, and in some cases medicinal herbs that do not have a recognized level confirmed by scanning electron microscopy, while of efficacy but are acceptably safe (175-183). Senecio pollen cannot be distinguish from the other DehydroPAs relative to consumption of honey plant's pollen. containing dehydroPAs tolerable daily intakes was Consideration of the PA concentrations observed determined by German (Bundesanzeiger 1992) and in honey from PA containing plants and pollen Dutch (Rijksinstituut voor Volksgezondheid en products led to an international regulation of PAs in Milieu (RIVM) 2007) to be 0.1 microgram/day. food. Safe doses for PA in dietary and herbal Australian and New Zealand (Food Standards remedies as well as in honey and pollen in different Australia-New Zealand (FSANZ) 2001) authorities EU countries (171-174). (175-183). Harmonization of the market for herbal Not all the countries regulate the type as quantity medicines is a fundamental requirement for of PA containing foods and remedies. Qianliguang is European industries and health professionals. Herbal traditional herbal medicine growing in different medicines can be also sold as food supplements, locations of China. Significant diversity of the PA which required a common regulatory status in the types and quantities were revealed among the various European countries. The European samples tested (184-185). The estimated total Parliament and by the Council of Europe established amounts of toxic PAs in some of the samples exceed that herbal medicines released in the market need the toxic limits of PA intake restricted by WHO, authorization by the national regulatory authorities demonstrating the timely and high demand for of each European country and that these products regulating both types and quantities of PAs present must have a recognized level of safety and efficacy. in Qianliguang as well as food containing PAs (184- In 1992, the Federal Health Department of Germany 185). Moreover, Qianliguang is used also as herbal has restricted “the manufacture and use of remedy in Europe. The United Kingdom Medicines pharmaceuticals containing pyrrolizidine alkaloids and Healthcare Product Regulatory Agency with a unsaturated necine skeleton”. The herbal restricted PAs in this herbal product to 1 mg/day (or plants “may be sold and used only if daily external 16.7 μg/kg/day for a 60-kg body weight) for 2 weeks exposure to no more than 100 μg pyrrolizidine and to 0.1 μg/day (1.67 μg/kg/day) for a longer alkaloids and internal exposure to no more than 1 μg period (186). Pharmacopoeia of P.R. China (2010 per day for no more than six weeks a year. edition) stated that adonifoline in Qianliguang In Europe, marketing of traditional herbal should not exceed 0.004% (40 μg/g of dried herb) medicinal products is regulated by an ad hoc (187). However, in addition to adonifoline there are Directive (i.e. Directive 2004/24/EC). Food other PAs (retronecine and the toxic otonecine-type Standards Australia New Zealand (FSANZ) has PAs)in the same herb (185). proposed a TDI for dehydro-PAs of 1 µg kg body weight/day. This is higher than those determined by CONCLUSION other authorities partly due to FSANZ considering the cancer risk to humans to be unproven and also to PA-induced toxicity demonstrates the lack of be unlikely due to a more efficient DNA-repair pharmacovigilance regarding traditional medicine system in humans (FSANZ 2001). FSANZ and herbal supplements. Therefore, a greater degree
833 J Pharm Pharm Sci (www.cspsCanada.org) 18(4) 825 - 843, 2015 of safety regulation is required to assess the Trends in use of complementary and alternative toxicological profiles of traditional medicine and medicine by US adults: 1997-2002. Altern Ther herbal supplements that are available to the public. Health Med, 2005;11:42-9. Moreover, stronger agricultural protocols to mitigate 2. MacLennan AH, Wilson DH, Taylor AW. Prevalence Senecio poisoning in livestock, as well as regulatory and cost of alternative medicine in Australia. Lancet, 1996;347:569-73. policies regarding safety of traditional medicine, is 3. Barnes PM, Bloom B, Nahin RL. Complementary and of utmost importance. In addition, individuals with alternative medicine use among adults and children: pre-existing liver injury or simultaneously taking United States, 2007. Natl Health Stat Report, drugs of use or misuse that induce certain 2008;12:1-23. cytochrome p450s may be more susceptible to PA- 4. Bailey RL, Gahche JJ, Lentino CV, Dwyer JT, Engel induced hepatotoxicity. Also should be taken into JS, Thomas PR, Betz JM, Sempos CT, Picciano MF. account the likelihood and significance of Dietary supplement use in the United States, 2003- intermittent level dietary exposure to PA as well as 2006. J Nutr, 2011;141:261-6. the potentiating effects of environmental copper and 5. Bailey RL, Gahche JJ, Miller PE, Thomas PR, Dwyer genetic factors. Another important factor is that the JT. Why US adults use dietary supplements. JAMA Intern Med, 2013;173:355-61. methods of determining the quality and quantity of 6. Nahin RL, Barnes PM, Stussman BJ, Bloom B. Costs PAs in remedies and foods should be standardized. of complementary and alternative medicine (CAM) The work presented in this paper may contribute and frequency of visits to CAM practitioners: United to finding a rational approach to limit or prevent liver States, 2007. Natl Health Stat Report, 2009;18:1-14. damage due to herbal remedies. Based on our clinical 7. Bodenstein JW. Toxicity of traditional herbal cases of herbal remedy-induced liver damage, this remedies. S Afr Med J, 1977;52:790. subject deserves further investigation. From a social 8. Bateman J, Chapman RD, Simpson D. Possible point of view, the present investigation on the toxicity of herbal remedies. Scott Med J, 1998;43:7- mechanism of herbal remedy-induced HSOS may 15. assist in gaining a larger recognition of the problem, 9. Saydah SH, Eberhardt MS. Use of complementary and alternative medicine among adults with chronic which will be required for the development of diseases: United States 2002. J Altern Complement educational strategies aimed at informing physicians Med, 2006;12:805-12. and the public about the potential dangers of these 10. Zimmerman HJ. Hepatic Metabolism of Foreign commonly used remedies. A recommended strategy Compounds. In Hepatotoxicity. The adverse effects is to inform the consumers in articles which are of drugs and other chemicals on the Liver pp. 11-40. written in plain language, as well as, answering the 1999. Lippincott Williams & Wilkins: Philadelphia. key questions an individual might have about a given 11. Goldman P. Herbal medicines today and the roots of herbal product or condition. Another possible modern pharmacology. Ann Intern Med, strategy is to encourage physicians to ask their 2001;135:594-600. patients about the use of complementary and 12. Kennedy J. Herb and supplement use in the US adult population. Clin Ther, 2005;27:1847- 58. alternative medicine. 13. Navarro VJ. Herbal and dietary supplement The market of herbal remedies and dietary hepatotoxicity. Semin Liver Dis, 2009;29:373- 82. supplements has to ensure: (a) security in 14. Zimmerman HJ. Vulnerability of the Liver to Toxic composition, (b) definition of influence of metabolic Injury. In Hepatotoxicity. The adverse effects of aspects, including scientific validation and (c) drugs and other chemicals on the Liver pp. 41-60. regulatory aspects, e.g. the claims definition and 1999. Lippincott Williams & Wilkins: Philadelphia. relative influences. 15. Popat A, Shear NH, Malkiewicz I, Stewart MJ, Steenkamp V, Thomson S, Neuman MG. The toxicity ACKNOWLEDGEMENTS of Callilepis laureola, a South African traditional herbal medicine. Clin Biochem, 2001;34:229-36. 16. Popat A, Shear NH, Malkiewicz I, Thomson S, In Vitro Drug Safety and Biotechnology and Neuman MG. Mechanism of Impila (Callilepis Mahaffy Gastroenterology grant, Sunnybrook laureola)-induced cytotoxicity in Hep G2 cells. Clin Hospital, for the financial support. Biochem 35:57-64, 2002. 17. Wainwright J, Schonland MM, Candy HA. Toxicity REFERENCES of Callilepis laureola. S Afr Med J, 1977;52:313-5. 18. Watson AR, Coovadia HM, Bhoola KD. The clinical 1. Tindle HA, Davis RB, Phillips RS, Eisenberg DM. syndrome of Impila (Callilepis laureola) poisoning in
834 J Pharm Pharm Sci (www.cspsCanada.org) 18(4) 825 - 843, 2015
children. S Afr Med J, 1979;55:290-2. Mazzanti G, Menniti-Ippolito F, Raschetti R, 19. Joubert PH. Poisoning admissions of black South Santuccio C. Hepatitis from Greater celandine Africans. J Toxicol Clin Toxicol, 1990;28:85-94. (Chelidonium majus L.): review of literature and 20. Stewart MJ, Steenkamp V, Zuckerman M. The report of a new case. J Ethnopharmacol, toxicology of African herbal remedies. Ther Drug 2009;124:328-32. Monit, 1998;20:510-6. 37. Stickel F, Pöschl G, Seitz HK, Waldherr R, Hahn EG, 21. Venter CP, Joubert PH. Aspects of poisoning with Schuppan D. Acute hepatitis induced by Greater traditional medicines in southern Africa. Biomed Celandine (Chelidonium majus). Scand J Environ Sci, 1988;1:388-91. Gastroenterol, 2003;38:565-568. 22. Steenkamp V, Stewart MJ, Zuckerman M. Detection 38. Benninger J, Schneider HT, Schuppan D, Kirchner T, of poisoning by Impila (Callilepis laureola) in a Hahn EG. Acute hepatitis induced by greater mother and child. Hum Exp Toxicol, 1999;18:594-7. celandine (Chelidonium majus). Gastroenterology, 23. Stewart MJ, Moar JJ, Steenkamp P, Kokot M. 1999;117:1234-7. Findings in fatal cases of poisoning attributed to 39. Crijns AP, de Smet PA, van den Heuvel M, Schot traditional remedies in South Africa. Forensic Sci Int, BW, Haagsma EB. Acute hepatitis after use of a 1999;101:177-83. herbal preparation with greater celandine 24. van Wyk BE, Verdoorn GH, Schutte AL. Distribution (Chelidonium majus). Ned Tijdschr Geneeskd, and taxonomic significance of major alkaloids in the 2002;146:124-8. genus Podalyria. Biochem Syst Ecol, 1992;20:163- 40. Wang JY, Gao H: Tusanqi and hepatic sinusoidal 172. obstruction syndrome. J Dig Dis. 2014 25. Wainwright J, Schonland MM. Toxic hepatitis in Mar;15(3):105-7. doi: 10.1111/1751-2980.12112. black patients in Natal. S Afr Med J, 1977;51:571-3. 41. Greving I, Meister V, Monnerjahn C, Müller KM, 26. Pessayre D, Feldman G, Haouzi D, Fau A, Moreau A, May B. Chelidonium majus: a rare reason for severe Neuman MG: Hepatocyte apoptosis triggered by hepatotoxic reaction. Pharmacoepidemiol Drug Saf, natural substances (cytokines, other endogenous 1998;7 Suppl 1:S66- 9. molecules and foreign toxins). In Chapter 3, In: 42. Rifai K, Flemming P, Manns MP, Trautwein C. Cameron RG, Fauer G, eds. Handbook of Severe drug hepatitis caused by Chelidonium. Experimental Pharmacology: Apoptosis modulation Internist (Berl), 2006;47:749-51. by drugs. Vol. 142, Chapter 3. Heidelberg: Springer 43. Teschke R, Glass X, Schulze J, Eickhoff A. Verlag Publishers, 1999:69-109. Suspected Greater Celandine hepatotoxicity: liver- 27. Grue MR, Liddell JR. Pyrrolizidine alkaloids from specific causality evaluation of published case reports Senecio chrysocoma. Phytochem, 1993;33:1517- from Europe. Eur J Gastroenterol Hepatol, 1519. 2012;24:270-80. 28. Smith LW, Culvenor CC. Plant sources of 44. Teschke R, Glass X, Schulze J. Herbal hepatotoxicity hepatotoxic pyrrolizidine alkaloids. J Nat Prod, 1981; by Greater Celandine (Chelidonium majus): causality 44:129-52. assessment of 22 spontaneous reports. Regul Toxicol 29. Mattocks AR. Toxicity of pyrrolizidine alkaloids. Pharmacol, 2011;61:282-91. Nature, 1968;217:723-8. 45. Teschke R. Kava hepatotoxicity: pathogenetic aspects 30. Seeff LB. Herbal hepatotoxicity. Clin Liver Dis, and prospective considerations. Liver Int, 2007;11:577-96. 2010;30:1270-9. 31. Bach N, Thung SN, Schaffner F. Comfrey herb tea- 46. Lechtenberg M(1), Quandt B, Schmidt M, Nahrstedt induced hepatic veno-occlusive disease. Am J Med, A. Is the alkaloid pipermethystine connected with the 1989;87:97-9. claimed liver toxicity of Kava products? Pharmazie. 32. Ridker PM, McDermott WV. Comfrey herb tea and 2008;63(1):71-4. hepatic veno-occlusive disease. Lancet, 1989;1:657- 47. Bonkovsky HL. Hepatotoxicity associated with 8. supplements containing Chinese green tea (Camellia 33. Weston CF, Cooper BT, Davies JD, Levine DF. sinensis). Ann Intern Med, 2006;144:68-71. Veno-occlusive disease of the liver secondary to 48. Molinari M, Watt KD, Kruszyna T, Nelson R, Walsh ingestion of comfrey. Br Med J (Clin Res Ed), M, Huang WY, Nashan B, Peltekian Acute liver 1987;295:183. failure induced by green tea extracts: case report and 34. Yeong ML, Swinburn B, Kennedy M, Nicholson G. review of the literature. Liver Transpl, 2006;12:1892- Hepatic veno-occlusive disease associated with 5. comfrey ingestion. J Gastroenterol Hepatol, 49. Tandon HD, Tandon BN, Ramalingaswami V. 1990;5:211-4. Epidemic of toxic hepatitis in India of possible 35. Stickel F, Seitz HK. The efficacy and safety of mycotoxic origin. Arch Pathol Lab Med, comfrey. Public Health Nutr, 2000;3:501-8. 1978;102:372-6. 36. Moro PA, Cassetti F, Giugliano G, Falce MT, 50. Bras G, Brooks SEH, Watler DC. Cirrhosis of liver in
835 J Pharm Pharm Sci (www.cspsCanada.org) 18(4) 825 - 843, 2015
Jamaica. J Pathol Bacteriol. 1961, 82:503–512. 66. Laurens T, Bekker L, Steenkamp V, Stewart M. Gas 51. Neuman MG, Steenkamp V. Toxicity profile of chromatographic-mass spectrophotometric pyrrolizidine alkaloid-containing medicinal plants: confirmation of atractyloside in a patient poisoned Emphasis on Senecio species. Intl J Biomed Pharma with Callilepis laureola. J Chromatogr (B), Sci, 2009;3:104-8. 2001;765:127-33. 52. Neuman MG, Schneider M, Nanau RM, Parry C, 67. Crews C, Berthiller F, Krska R. Update on analytical Chersich M. The relationship between alcohol methods for toxic pyrrolizidine alkaloids. Anal consumption and human immunodeficiency virus Bioanal Chem, 2010;396:327-38. infection and risk behaviour: A systematic literature 68. Anderson IB, Mullen WH, Meeker JE, Khojasteh- review of high-risk groups, with a focus on South BakhtSC, Oishi S, Nelson SD, Blanc PD. Pennyroyal Africa; Chapter 13, In: Public Health - Social and toxicity: measurement of toxic metabolite levels in Behavioral Health, InTech Open Publication, pp. two cases and review of the literature. Ann Intern 243-92, 2012. Rijeka, Croatia. Med, 1996;124:726-34. 53. McLean E. The toxic actions of pyrrolizidine 69. Rosemann GM, Botha CJ, Eloff JN. Distinguishing (Senecio) alkaloids. Pharmacol Rev, 1970;22:429-83. between toxic and non-toxic pyrrolizine alkaloids and 54. Zimmerman HJ, Ishak KG. General aspects of drug- quantification by liquid chromatography-mass induced liver disease. Gastroenterol Clin North Am, spectrometry. Phytochem Lett, 2014;8:126-131. 1995;24:739-57. 70. Oplatowska M, Elliott CT, Huet AC, McCarthy M, 55. Valla D, Benhamou JP. Drug-induced vascular and Mulder PP, von Holst C, Delahaut P, Van Egmond sinusoidal lesions of the liver. Baillieres Clin HP, Campbell K. Development and validation of a Gastroenterol, 1988;2:481-500. rapid multiplex ELISA for pyrrolizidine alkaloids and 56. Bryant AT. Zulu medicine and medicine-men. their N-oxides in honey and feed. Anal Bioanal Annals of Natal Museum, 1909;2:1-103. Chem, 2014;406:757-70. 57. Bye SN, Dutton MF. The inappropriate use of 71. Griffin CT, Danaher M, Elliott CT, Glenn Kennedy traditional medicines in South Africa. J D, Furey A. Detection of pyrrolizidine alkaloids in Ethnopharmacol, 1991;34:253-9. commercial honey using liquid chromatography-ion 58. Teschke R, Genthner A, Wolff A. Kava trap mass spectrometry. Food Chem, 2013;136:1577- hepatotoxicity: comparison of aqueous, ethanolic, 83. acetonic kava extracts and kava-herbs mixtures. J 72. Martinello M, Cristofoli C, Gallina A, Mutinelli F. Ethnopharmacol, 2009;123:378-84. Easy and rapid method for the quantitative 59. Bondan C, Soares JC, Cecim M, Lopes ST, Graça DL, determination of pyrrolizidine alkaloids in honey by da Rocha RX. Oxidative stress in the erythrocytes of ultra performance liquid chromatography-mass cattle intoxicated with Senecio sp. Vet Clin Pathol, spectrometry: an evaluation in commercial honey. 2005;34:353-7. Food Control, 2014;37:146-152. 60. Steenkamp V, Stewart MJ, Zuckerman M. Clinical 73. Ridker PM, Ohkuma S, McDermott WV, Trey C, and analytical aspects of pyrrolizidine poisoning Huxtable RJ. Hepatic venocclusive disease associated caused by South African traditional medicines. Ther with the consumption of pyrrolizidine-containing Drug Monit, 2000;22:302- 306. dietary supplements. Gastroenterology, 61. McGaw LJ, Eloff JN. Ethnoveterinary use of southern 1985;88:1050-4. African plants and scientific evaluation of their 74. Schiano TD. Liver injury from herbs and other medicinal properties. J Ethnopharmacol, botanicals. Clin Liver Dis, 1998; 2:607-36. 2008;119:559-574. 75. International Programme on Chemical Safety. 62. Birecka H, Catalfamo J, Eisen R. A sensitive method Pyrrolizidine alkaloids. Environmental health for the detection and quantitative determination of criteria. World Health Organization, Geneva, 1988. pyrrolizidine alkaloids. Phytochemistry, 76. Lindigkeit R, Biller A, Buch M, Schiebel HM, 1981;20:343-4. Boppré M, Hartmann T. The two facies of 63. Mattocks A. Spectrophotometric determination of pyrrolizidine alkaloids: the role of the tertiary amine pyrrolizidine alkaloids- some improvements. Anal and its N-oxide in chemical defense of insects with Chem, 1968;40:1749-50. acquired plant alkaloids. Eur J Biochem, 64. Culvenor CCJ, Edgar JA, Smith LW, Tweedale HJ. 1997;245:626-36. Dihydropyrrolizines III. Preparation and reactions of 77. Hartmann T. Chemical ecology of pyrrolizidine derivatives related to pyrrolizidine alkaloids. Aust J alkaloids. Planta, 1999;207:483-95. Chem. 1970, 23:1853– 1867. 78. Habermehl GG, Martz W, Tokarnia CH, Döbereiner 65. Steenkamp V, von Arb M, Stewart M. Metal J, Mendez MC. Livestock poisoning in South concentrations in plants and urine from patients America by species of the Senecio plant. Toxicon, treated with South African traditional remedies. 1988;26:275-86. Forensic Sci Int, 2000;114:89-95. 79. Schoental R. Hepatotoxic action of pyrrolizidine
836 J Pharm Pharm Sci (www.cspsCanada.org) 18(4) 825 - 843, 2015
(Senecio) alkaloids in relation to their structure. strumarium, L. var. strumarium) intoxication in Nature, 1957;179:361-3. swine: review and redefinition of the toxic principle. 80. Cooper RG. Unusual case of Senecio sceleratus Vet Pathol, 1981;18:368-83. (Ragword) poisoning in an ostrich (Struthio camelus) 96. Witte ST, Osweiler GD, Stahr HM, Mobley G. in Zimbabwe. Turk J Vet Anim Sci, 2007;31:143-4. Cocklebur toxicosis in cattle associated with the 81. Kellerman TS, Naudé TW, Fourie N. The consumption of mature Xanthium strumarium. J Vet distribution, diagnoses and estimated economic Diagn Invest, 1990;2:263-7. impact of plant poisonings and mycotoxicoses in 97. Crews C, Driffield M, Berthiller F, Krska R. Loss of South Africa. Onderstepoort J Vet Res, 1996;63:65- pyrrolizidine alkaloids on decomposition of ragwort 90. (Senecio jacobaea) as measured by LC-TOF-MS. J 82. Giles CJ. Outbreak of ragword (Senecio jacobea) Agric Food Chem, 2009;57:3669-73. poisoning in horses. Equine Vet J, 1983;15:248-50. 98. Roberts PD, Pullin AS. The effectiveness of 83. Vandenbroucke V, Van Pelt H, De Backer P, management interventions used to control ragwort Croubels S. Animal poisonings in Belgium: a review species. Environ Manage, 2007;39:691-706. of the past decade. Vlaams Diergeneeskundig 99. Bolechová M, Cáslavský J, Pospíchalová M, Tijdschrift, 2010;79:259-68. Kosubová P. UPLC-MS/MS method for 84. Passemard B, Priymenko N. Equine poisoning by determination of selected pyrrolizidine alkaloids in Senecio in France. Revue Med Vet, 2007;158:425-30. feed. Food Chem, 2015;170:265-70. 85. McLaren DA, Ireson JE, Kwong RM. Biological 100. Jacobs J, Sing S. Ecology and management of tansy control of ragwort (Senecio jacobaea L.) in Australia. ragword (Senecio jacobaea L.). United States Proceedings of the X International Symposium on Department of Agriculture Natural Resources Biological Control of Weeds, 2000;67-79. Available Conservation Service Invasive Species Technical at http://www.invasive.org/proceedings/pdfs/10_67- Note, 2009;1-13. Available at 79.pdf. http://www.fs.fed.us/rm/pubs_other/rmrs_2009_jaco 86. Moyano MR, García A, Rueda A, Molina AM, bs_j001.pdf. Mendez A, Infante F. Echium vulgare and Senecio 101. McGee J, Patrick RS, Wood CB, Blumgart LH. A vulgaris poisoning in fighting bulls. J Vet Med A case of veno-occlusive disease of the liver in Britain Physiol Pathol Clin Med, 2006;53:24-5. associated with herbal tea consumption. J Clin Pathol, 87. de Barros CS, Driemeier D, Pilati C, Barros SS, 1976;29:788-94. Castilhos LM. Senecio spp poisoning in cattle in 102. Kumana CR, Ng M, Lin HJ, Ko W, Wu PC, Todd D. southern Brazil. Vet Hum Toxicol, 1992;34:241-6. Herbal tea induced hepatic veno-occlusive disease: 88. Gava A, Barros CS. Senecio spp. poisoning of horses quantification of toxic alkaloid exposure in adults. in southern Brazil. Preq Vet Bras, 1997;17:36-40. Gut, 1985;26:101-4. 89. Giaretta PR, Panziera W, Hammerschmitt ME, 103. Sperl W, Stuppner H, Gassner I, Judmaier W, Dietze Bianchi RM, Galiza G, Wiethan IS, Bazzi T, Barros O, Vogel W. Reversible hepatic veno-occlusive C. Clinical and pathological aspects of chronic disease in an infant after consumption of Senecio spp. poisoning in sheep. Pesq Vet Bras, pyrrolizidine-containing herbal tea. Eur J Pediatr, 2014;34:967-973. 1995;154:112-6. 90. Giaretta PR, Panziera W, Galiza GJ, Brum JS, 104. Schulz M, Meins J, Diemert S, Zagermann-Muncke Bianchi RM, Hammerschmitt ME, Bazzi T, Barros P, Goebel R, Schrenk D, Schubert-Zsilavecz M, CS. Senecio in cattle associated with Abdel-Tawab M. Detection of pyrrolizidine alkaloids pthosensitization. Pesq Vet Bras, 2014;34:427- 432. in German licensed herbal medicinal teas. 91. Tokarnia CH, Döbereiner J, Peixoto PV. Poisonous Phytomedicine, 2015;22:648-56. plants affecting livestock in Brazil. Toxicon, 105. U.S. Food and Drug Administration. FDA advises 2002;40:1635-60. dietary supplement manufacturers to remove comfrey 92. de Lanux-Van Gorder V. Tansy ragwort poisoning in products from the market, 2001. Accessed Aug 10 a horse in southern Ontario. Can Vet J, 2000;41:409- 2015. Available at 10. http://www.fd.gov/Food/DietarySupplements/Alerts/ 93. Stegelmeier BL. Pyrrolizidine alkaloid-containing ucm111219.htm. toxic plants (Senecio, Crotalaria, Cynoglossum, 106. Mädge I, Cramer L, Rahaus I, Jerz G, Winterhalter P, Amsinckia, Heliotropium, and Echium spp.). Vet Beuerle T. Pyrrolizidine alkaloids in herbal teas for Clin North Am Food Anim Pract, 2011;27:419-28. infants, pregnant or lactating women. Food Chem, 94. Varga A, Puschner B. Retrospective study of cattle 2015;187:491-8. poisonings in California: recognition, diagnosis, and 107. Deinzer ML, Thomson PA, Burgett DM, Isaacson treatment. Veterinary Medicine: Research and DL. Pyrrolizidine alkaloids: their occurrence in honey Reports, 2012;3:111-27. from tansy ragword (Senecio jacobaea L.). Science, 95. Stuart BP, Cole RJ, Gosser HS. Cocklebur (Xanthium 1977;195:494-9.
837 J Pharm Pharm Sci (www.cspsCanada.org) 18(4) 825 - 843, 2015
108. Edgar JA, Roeder E, Molyneux RJ. Honey from Lancet, 1920;196:848-849. plants containing pyrrolizidine alkaloids: a potential 120. Richardson P, Guinan E. The pathology, diagnosis, threat to health. J Agric Food Chem, 2002;50:2719- and treatment of hepatic veno- occlusive disease: 30. current status and novel approaches. Br J Haematol, 109. Dübecke A, Beckh G, Lüllmann C. Pyrrolizidine 1999;107:485-93. alkaloids in honey and bee pollen. Food Addit 121. Wadleigh M, Ho V, Momtaz P, Richardson P. Contam Part A Chem Anal Control Expo Risk Hepatic veno-occlusive disease: pathogenesis, Assess, 2011;28:348-58. diagnosis and treatment. Curr Opin Hematol, 110. Edgar JA, Colegate SM, Boppré M, Molyneux RJ. 2003;10:451-62. Pyrrolizidine alkaloids in food: a spectrum of 122. DeLeve LD, Shulman HM, McDonald GB. Toxic potential health consequences. Food Addit Contam injury to hepatic sinusoids: sinusoidal obstruction Part A Chem Anal Control Expo Risk Assess, syndrome (veno-occlusive disease). Semin Liver Dis, 2011;28:308-24. 2002;22:27- 42. 111. Kempf M, Wittig M, Reinhard A, von der Ohe K, 123. Chojkier M. Hepatic sinusoidal-obstruction Blacquière T, Raezke KP, Michel R, Schreier P, syndrome: toxicity of pyrrolizidine alkaloids. J Beuerle T. Pyrrolizidine alkaloids in honey: Hepatol, 2003;39:437-46. comparison of analytical methods. Food Addit 124. Ji LL, Zhang M, Sheng YC, Wang ZT. Pyrrolizidine Contam Part A Chem Anal Control Expo Risk alkaloid clivorine induces apoptosis in human normal Assess, 2011;28:332- 47. liver L-02 cells and reduces the expression of p53 112. Kempf M, Wittig M, Schönfeld K, Cramer L, protein. Toxicol In Vitro, 2005;19:41-6. Schreier P, Beuerle T. Pyrrolizidine alkaloids in food: 125. Zuckerman M, Steenkamp V, Stewart MJ. Hepatic downstream contamination in the food chain caused veno-occlusive disease as a result of a traditional by honey and pollen. Food Addit Contam Part A remedy: confirmation of toxic pyrrolizidine alkaloids Chem Anal Control Expo Risk Assess, 2011;28:325- as the cause, using an in vitro technique. J Clin Pathol, 31. 2002;55:676-9. 113. Griffin CT, O’Mahony J, Danaher M, Furey A. 126. Coppell JA, Brown SA, Perry DJ. Veno-occlusive Liquid chromatography tandem mass spectrometry disease: cytokines, genetics, and haemostasis. Blood detection of targeted pyrrolizidine alkaloids in honeys Rev, 2003;17:63-70. purchased within Ireland. Food Anal Methods, 127. Robaye B, Mosselmans R, Fiers W, Dumont JE, 2015;8:18-31. Galand P. Tumor necrosis factor induces apoptosis 114. Hoogenboom LA, Mulder PP, Zeilmaker MJ, van den (programmed cell death) in normal endothelial cells Top HJ, Remmelink GJ, Brandon EF, Klijnstra M, in vitro. Am J Pathol, 1991;138:447-53. Meijer GA, Schothorst R, Van Egmond HP. Carry- 128. DeLeve LD, Shulman HM, McDonald GB. Toxic over of pyrrolizidine alkaloids from feed to milk in injury to hepatic sinusoids: sinusoidal obstruction dairy cows. Food Addit Contam Part A Chem Anal syndrome (veno-occlusive disease). Semin Liver Dis, Control Expo Risk Assess, 2011;28:359-72. 2002;22:27- 42. 115. Kakar F, Akbarian Z, Leslie T, Mustafa ML, Watson 129. Katz GG, Shear NH, Malkiewicz IM, Valentino K, J, van Egmond HP, Omar MF, Mofleh J. An outbreak Neuman MG. Signaling for ethanol-induced of hepatic veno-occlusive disease in Western apoptosis and repair in vitro. Clin Biochem, afghanistan associated with exposure to wheat flour 2001;34:219-27. contaminated with pyrrolizidine alkaloids. J Toxicol, 130. Xiong A, Yang F, Fang L, Yang L, He Y, Wan YJ, 2010;2010:313280. Xu Y, Qi M, Wang X, Yu K, Tsim KW, Wang Z. 116. Auerbach BJ, Reynolds SJ, Lamorde M, Merry C, Metabolomic and genomic evidence for Kukunda-Byobona C, Ocama P, Semeere AS, compromised bile acid homeostasis by senecionine, a Ndyanabo A, Boaz I, Kiggundu V, Nalugoda F, Gray hepatotoxic pyrrolizidine alkaloid. Chem Res RH, Wawer MJ, Thomas DL, Kirk GD, Quinn TC, Toxicol, 2014;27:775-86. Stabinski L. Traditional herbal medicine use 131. Xiong A, Fang L, Yang X, Yang F, Qi M, Kang H, associated with liver fibrosis in rural Rakai, Uganda. Yang L, Tsim KW, Wang Z. An application of target PLoS One, 2012;7:e41737. profiling analyses in the hepatotoxicity assessment of 117. Kassler WJ, Blanc P, Greenblatt R. The use of herbal medicines: comparative characteristic medicinal herbs by human immunodeficiency virus- fingerprint and bile acid profiling of Senecio vulgaris infected patients. Arch Intern Med, 1991;151:2281-8. and Senecio scandens Buch.-Ham. Anal Bioanal 118. Ishak KG. Hepatic lesions caused by anabolic and Chem, 2014;406:7715-27. contraceptive steroids. Semin Liver Dis, 1981;1:116- 28. 132. Chou MW, Fu PP. Formation of DHP-derived DNA 119. Willmot FC, Robertson GW. Senecio disease, or adducts in vivo from dietary supplements and chinese cirrhosis of the liver due to Senecio poisoning. herbal plant extracts containing carcinogenic
838 J Pharm Pharm Sci (www.cspsCanada.org) 18(4) 825 - 843, 2015
pyrrolizidine alkaloids. Toxicol Ind Health, pyrrolizidine alkaloid. J. Pharmaceutical Sciences, 2006;22:321-7. 1968;57:1112-7. 133. Dai J, Zhang F, Zheng J. Retrorsine, but not 147. Kugelman M, Liu WC, Axelrod M, McBride TJ, Rao monocrotaline, is a mechanism-based inactivator of KV. Indicine-N-oxide: the antitumor principle of P450 3A4. Chem Biol Interact, 2010;183:49-56. Heliotropium indicum. Lloydia, 1976;39:125-8. 134. Li N, Xia Q, Ruan J, Fu PP, Lin G. Hepatotoxicity 148. Zalkow LH, Glinski JA, Gelbaum LT, Moore D, and tumorigenicity induced by metabolic activation Melder D, Powis G. Semisynthetic pyrrolizidine of pyrrolizidine alkaloids in herbs. Curr Drug Metab, alkaloid N-oxide antitumor agents. Esters of 2011;12:823-34. heliotridine. J Med Chem, 1988;31:1520-6. 135. Tu M, Li L, Lei H, Ma Z, Chen Z, Sun S, Xu S, Zhou 149. Niwa H, Ogawa T, Yamada K. An efficient H, Zeng S, Jiang H. Involvement of organic cation enantioselective synthesis of (+)- indicine N-oxide, transporter 1 and CYP3A4 in retrorsine-induced an antitumor pyrrolizidine alkaloid. Tetrahedron toxicity. Toxicology, 2014;322:34-42. Letters, 1989;30:4985- 6. 136. Fu PP, Xia Q, Lin G, Chou MW. Pyrrolizidine 150. Whitehead VM, Bernstein ML, Vega R, Vats T, alkaloids-genotoxicity, metabolism enzymes, Dyment P, Vietti TJ, Krischer J. Phase I trial of metabolic activation, and mechanisms. Drug Metab indicine-N-oxide in children with leukemia and solid Rev, 2004;36:1-55. tumors: a Pediatric Oncology Group study. Cancer 137. Wang YP, Yan J, Fu PP, Chou MW. Human liver Chemother Pharmacol, 1990;26:377-9. microsomal reduction of pyrrolizidine alkaloid N- 151. Miser JS, Smithson WA, Krivit W, Hughes C, Davis oxides to form the corresponding carcinogenic parent D, Krailo M, Hammond D. Phase II trial of indicine alkaloid. Toxicol Lett, 2005;155:411-20. N-oxide in relapsed pediatric solid tumors. A report 138. Yang Y, Yan J, Churchwell M, Beger R, Chan P, from the Childrens Cancer Study Group. Invest New Doerge DR, Fu PP, Chou MW. Development of a Drugs, 1991;9:339-42. (32)P-postlabeling/HPLC method for detection of 152. Kovach JS, Ames MM, Powis G, Moertel CG, Hahn dehydroretronecine- derived DNA adducts in vivo RG, Creagan ET. Toxicity and pharmacokinetics of a and in vitro. Chem Res Toxicol, 2001;14:91-100. pyrrolizidine alkaloid, indicine N-oxide, in humans. 139. He YQ, Yang L, Liu HX, Zhang JW, Liu Y, Fong A, Cancer Res, 1979;39:4540-4. Xiong AZ, Lu YL, Yang L, Wang CH, Wang ZT. 153. Letendre L, Ludwig J, Perrault J, Smithson WA, Glucuronidation, a new metabolic pathway for Kovach JS. Hepatocellular toxicity during the pyrrolizidine alkaloids. Chem Res Toxicol, treatment of refractory acute leukemia with indicine 2010;23:591-9. N-oxide. Cancer, 1984;54:1256-9. 140. Li YH, Kan WL, Li N, Lin G. Assessment of 154. Cook BA, Sinnhuber JR, Thomas PJ, Olson TA, pyrrolizidine alkaloid-induced toxicity in an in vitro Silverman TA, Jones R, Whitehead VM, Ruymann screening model. J Ethnopharmacol, 2013;150:560-7. FB. Hepatic failure secondary to indicine N-oxide 141. Nuringtyas TR, Verpoorte R, Klinkhamer PG, van toxicity. A Pediatric Oncology Group Study. Cancer, Oers MM, Leiss KA. Toxicity of pyrrolizidine 1983;52:61-3. alkaloids to Spodoptera exigua using insect cell lines 155. Miser JS, Smithson WA, Krivit W, Hughes CH, and injection bioassays. J Chem Ecol, 2014;40:609- Davis D, Krailo MD, Hammond GD. Phase II trial of 16. indicine N-oxide in relapsed acute leukemia of 142. Chen Y, Ji L, Xiong A, Yang L, Wang Z. Involvement childhood. A report from the Children's Cancer Study of intracellular glutathione in regulating isoline- Group. Am J Clin Oncol, 1992;15:135-40. induced cytotoxicity in human normal liver L-02 156. Bode AM, Dong Z: Toxic phytochemicals and their cells. Toxicol Ind Health, 2013;29:567-75. potential risks for human cancer. Cancer Prev Res 143. Ji L, Liu T, Chen Y, Wang Z. Protective mechanisms (Phila). 2015;8(1):1-8. doi: 10.1158/1940- of N-acetyl-cysteine against pyrrolizidine alkaloid 6207.CAPR-14-0160. clivorine-induced hepatotoxicity. J Cell Biochem, 157. Roeder E, Wiedenfeld H: Plants containing 2009;108:424-32. pyrrolizidine alkaloids used in the traditional Indian 144. Ji L, Chen Y, Liu T, Wang Z. Involvement of Bcl-xL medicine-including ayurveda. Pharmazie. 2013 degradation and mitochondrial-mediated apoptotic ;68(2):83-92. pathway in pyrrolizidine alkaloids-induced apoptosis 158. Zhou SF, Xue CC, Yu XQ, Wang G. Metabolic in hepatocytes. Toxicol Appl Pharmacol, activation of herbal and dietary constituents and its 2008;231:393-400. clinical and toxicological implications: an update. 145. Neuman MG, Jia AY, Steenkamp V. Senecio Curr Drug Metab. 2007;8(6):526-53. latifolius induces in vitro hepatocytotoxicity in a 159. Roeder E, Wiedenfeld H, Edgar JA. Pyrrolizidine human cell line. Can J Physiol Pharmacol, alkaloids in medicinal plants from North America. 2007;85:1063-75. Pharmazie. 2015;70(6):357-67. 146. Culvenor CC. Tumor-inhibitory activity of 160. Röder E, Medicinal plants in Europe containing
839 J Pharm Pharm Sci (www.cspsCanada.org) 18(4) 825 - 843, 2015
pyrrolizidine alkaloids, Pharmazie 1995; 50: 83-98. Assess. 2011;28(3):260-81. doi: 161. Röder E, Analysis of pyrrolizidine alkaloids, Current 10.1080/19440049.2011.555085. Organic Chemistry 1999; 3: 667-676. 174. Calixto JB: Efficacy, safety, quality control, 162. Röder E, Medicinal plants in China containing marketing and regulatory guidelines for herbal pyrrolizidine alkaloids, Pharmazie 2000; 55: 711- medicines (phytotherapeutic agents). Braz J Med Biol 726. Res. 2000;33(2):179-89. 163. Complementary and Alternative Medicine in the 175. Calapai G: European legislation on herbal medicines: United States. Institute of Medicine Committee on the a look into the future. Drug Saf. 2008;31(5):428-31. Use of Complementary and Alternative Medicine by 176. UK Committee on Toxicity, the American Public; National Academies Press http://cot.food.gov.uk/sites/default/files/cot/cotstate (US), Washington (DC), 2005. mentpa200806.pdf 164. US Food and Drug Administration. Information for 177. European Food Safety Authority, consumers: Dietary supplements. US Food and Drug http://www.efsa.europa.eu/sites/default/files/scientifi Administration. c_output/files/main_ documents/2406. pdf http://www.fda.gov/Food/DietarySupplements/Cons 178. Bundesamt für Risiokobewertung (BfR) umerInformation/default.htm (Accessed on July 10, http://www.bfr.bund.de/cm/349/chemical-analysis- 2012). and-toxicity-of-pyrrolizidine-alkaloids- and- 165. Federal Food, Drug, and Cosmetic Act (FD&C) Act assessment-of-the-health-risks-posed-by-their- http://www.fda.gov/RegulatoryInformation/Legislati occurence-in-honey.pdf on/FederalFoodDrugandCosmeticActF 179. Dutch authority on herbal preparation, DCAct/default.htm (Accessed on July 10, 2012). http://www.rivm.nl/dsresource?objectid=rivmp:2763 166. US Food and Drug Administration. Center for Food 09&type=org&disposition= inline&ns_ nc=1 Safety and Applied Nutrition. Dietary Supplements 180. Codex Alimentarius Commission Review, http://www.fda.gov/Food/DietarySupplements/defau ftp://ftp.fao.org/codex/meetings/cccf/cccf5/cf05_14e lt.htm (Accessed on July 10, 2012). .pdf 167. US Food and Drug Administration. Claims that can 181. Silano V, Coppens P, Larrañaga-Guetaria A, be made for conventional foods and dietary Minghetti P, Roth-Ehrang R. Regulations applicable supplements to plant food supplements and related products in the http://www.fda.gov/Food/LabelingNutrition/LabelCl European Union.Food Funct. 2011; 2(12):710-9. aims/ucm111447.htm (Accessed on July 10, 2012). 182. Nicoletti M: Nutraceuticals and botanicals: overview 168. US Food and Drug Administration. Guidance, and perspectives. Int J Food Sci Nutr. 2012;63 Suppl Compliance & Regulatory Information 1:2-6. doi: 10.3109/09637486.2011.628012. http://www.fda.gov/food/DietarySupplements/Guida 183. Edgar JA , Colegate SM , Boppré M, & Molyneux nceComplianceRegulatoryInformation (Accessed on RM Pyrrolizidine alkaloids in food: a spectrum of July 10, 2012). potential health consequences, Food Additives & 169. FDA advises dietary supplement manufacturers to Contaminants: 2011, 28:3, 308-324, DOI: remove comfrey products from the market 10.1080/19440049.2010.547520 http://www.fda.gov/Food/DietarySupplements/Alert 184. Fu PP, Yang YC , Xia Q, Chou MW, Cui YY, Lin G. s/ucm111219.htm (Accessed on December 14, 2011). Pyrrolizidine Alkaloids - Tumorigenic Components 170. National policy on traditional medicine and in Chinese Herbal Medicines and Dietary regulation of herbal medicines: report of a WHO Supplements Journal of Food and Drug Analysis, global survey. WHO. Geneva 2005. Available at: 2002,10,4, 198-211 http://apps.who.int/medicinedocs/en/d/Js7916e/ 185. Zhu L, Li N, Ruan , Fu PP, Zhao ZZ, Lin G. Chemical (Accessed on April 23, 2012) diversity investigation of hepatotoxic pyrrolizidine 171. Bundesgesundheitsamt, Bekanntmachung uber die alkaloids in Qianliguang (Senecio scandens) and Zulassung und Registrierung von Arzneimitteln, related species by UHPLC-QTOF-MS. World Bundesanzeiger 1992. 111: 4805; Journal of Traditional Chinese Medicine, 2015| Vol. 172. Kempf M, Reinhard A, Beuerle T. Pyrrolizidine 1| Issue 2, 1-11. alkaloids (PAs) in honey and pollen-legal regulation 186. Medicines and Healthcare Products Regulatory of PA levels in food and animal feed required. Mol Agency. MLX 296: proposals to prohibit the sale, Nutr Food Res. 2010;54(1):158-68. doi: supply or importation of unlicensed herbal medicinal 10.1002/mnfr.200900529. products for internal use which contain Senecio 173. Boppré M. The ecological context of pyrrolizidine species. Monograph on the Internet. Available at: alkaloids in food, feed and forage: an overview. Food http://www.mhra.gov.uk/Publications/Consultations/ Addit Contam Part A Chem Anal Control Expo Risk Medicinesconsultations/MLXs/CON.
840 J Pharm Pharm Sci (www.cspsCanada.org) 18(4) 825 - 843, 2015
Table 1. Species Use-Toxicity PA BORAGINACEAE FAMILY Alkanna tinctoria aka Triangularine Lithospermum Skin diseases, diarrhea. tinctorium Alkannet Amsinckia intermedia Horses and cows poisoned by it. Fiddleneck Anchusa officinalisL. Skin ulcers, expectorant and diuretic Alkannet, bugloss Borago officinalis L. Diuretic, inflammatory diseases and Intermedine, lycopsamine. Borage cough Cynoglossum officinale diarrhea; skin bruises. heliosupine, echinatine, lasiocarpine, hound's tongue, bugloss Causes liver cancer cynoglossophine. H. indicum: Ulcer, wounds, local Heliotrine, indicine Heliotropium arborescens L. inflammation lasiocarpine H indicum L . Da wei yao Livestock feed on heliotropium species H. popovii, H. lasiocarpum; H. -medicinal herb cause liver cancer; eichwaldii, H. bacciferum contaminated cereal crops cause human Heliotrope poisoning. -topically for sores and swellings. Intermedine Lappula intermedia M.Popov L. intermedia - Ascariasis, oxyuriasis, Stickseed infantile malnutition Lithospermum officinale Lithosenine Gromwell Contraceptive, antipyretic, gout, kidney
stones, diarrhea..
Lithospermum erythrorhizon skin diseases, antipyretic, Lithosenine, intermedine Zi cao antiphlogistic, . produces tumors Myosotis scorpioidesL. myoscorpine, scropioidine, Sedative, tonic; externally eye wash. forget-me-not. symphytine Symphytum officinale L,(comfrey) intermedine, lycopsamine, symphytine, S. asperum Lepech, S. caucasicum echimidine, symglandine. Bieb., S. peregrinum Causes liver damage in humans S. tuberosum, S. uplandicum Nyman (Russian comfrey) Trichodesma africana Contaminated cereal crops cause human also: T. incanum poisoning. ASTERACEA (COMPOSITAE) FAMILY Adenostyles alliariae Kern Lung disorders Lycopsamine, senecionine, seneciphylline, Arnebia euchroma (Ruan Zi Cao), Causes HSOS and spartioidine.
841 J Pharm Pharm Sci (www.cspsCanada.org) 18(4) 825 - 843, 2015
Chinese medicine A. conyzoides L. Chinese medicine - Ageratum conyzoides L. Sheng antipyretic, common colds, malaria hong ji Crops are used for feeding animals. In Senecionine Brachyglottis repens horses, causes paralysis of the limbs. Chromolaena odorata Fei ji cao Hemostatic; produces tumors Intermidine Crassocephalum crepidioides Jia C. crepidioides Cold, dysentery, urinary Jacobine tong hao infection Emilia sonchifolia DC senkirkine and doronine; Antipyretic influenza, cough, red tasselflower, Emilia's flower, hemoptysis and bronchitis Yang ti cao, Yi dian hong Eupatorium cannabinum L . Pei supinine, rinderine, echinatine, lan, intermidine and lycopsamine. E. cannabinum Influenza, cerebral E. purpreum - Joe Pye Weed stroke; Eupatorium japonicum Thunb. Hua E. japonicum: Measles, rheumatic pains zhe lan and colds
E. perforatum, boneset E. purpureum fever; diuretic, lowering E. rugosum cholesterol; E. cannabinum hemp agrimony symptoms of summer-heat syndrome. E. fortunei (Pai Lan)-Chinese medicine Farfugium japonicum Kitam Lian Petasitenine, senkirkine Colds and flu peng cao Gynura bicolor DC Guan yin xian, Dysmenorrhea, tuberculous hymoptysis Retrorsine Gynura segetum Merr. Ju shan qi, Hemoptysis, peripheral blood Senecionine,seneciphylline Tu san chii circulation disorder Ligularia hodgsonnii Hook otonecine-type PA, Anti-tussive traditional Chinese Lithospermum clivorine and ligularine, medicine produced in rural areas of erythrorhizon Zi Cao, Sichuan providence
Petasites hybridus PH Gaertn., B., senecionine, integerrimine, retrosine, Mey & Scherb. (Colts food), seneciphylline, jacobine, senkirkine Causes abdominal pain pestilence-wort or butterbur P. spurius. RCHB Senecio argunensis Turcz. Yu yie S.argunensis-Chinese medicine senecionine, riddelline, retrorsine, qian li guang Antienteritis; floridanine, monocrotaline, otosenine S. aureus- golden ragwort; S. aureus Diaphoretic and diuretic; high seneciphylline S. abrotarifolius, doses may induce abortion. S.alpestre, S. bicolor has been used in eye drops to S. bohemicus, treat cataracts and conjunctivitis. S. bicolor Tod. ssp. cineraria, S. chrysanthemoides Chinese medicine, Senecio chrysanthemoides DC Traumatic injury, breast abscesses Chien li kuang, Senecio sp.are used in Chinese S. douglasii medicine: febrile diseases, dysuria, S. doronicum, inflammation, diarrhea, and, cataracts. S. fluviatilis Livestock - antispasmodic. S. fuchsii S. longilobus - causes liver failure; S. Illiciformis S. nemorensis (Chinese medicine) S. jacobaea L., tansy (European) Enteritis, hepatitis, boils
842 J Pharm Pharm Sci (www.cspsCanada.org) 18(4) 825 - 843, 2015 ragwort Senecio is used in African herbal S. longilobus medicine causes liver cancer. S. nemorensis L, Huana wan Contaminated cereal crops- human S. scandens Qian Li Guang poisoning; causes infant death. S. sylvaticus, Qianliguang is traditional herbal S. tomentosus medicine growing in different locations S. vulgaris L. of China. It is registered and sold as herbal remedy in western countries. It may lead to toxic adverse reactions. Quian li guang or Chiu li ming Oral and pharyngeal infection
Tussilago farfara L. Senkirkine, senecionine Coltsfoot lung disorders (chronic bronchitis, Kuan Dong Hua (Chinese asthma), diarrhea medicine). FABACAEA FAMILY Crotalaria sp. rattlebox crotananine, monocrotaline cronaburmin, C. assamica Benth Zi xiao rong retrorsine (Nung gi li) Chinese remedy, Antipyretic and diuretic Contaminated C. mucronata Zhu zi tou Chinese cereal crops blamed for human medicine poisoning. C. juncea, C. nana, C. retusa, C. fulva; C. sessiliflora L
843