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Pyrrolizidine Alkaloids
Published in Dongyou Liu, Handbook of Foodborne Diseases, 2018
Symphytum officinale (comfrey) is a perennial plant that has been consumed as herbal teas and used in folk medicine for over 2,000 years. PAs from comfrey are implicated in liver endothelial cell injury and abnormalities.
Examples That Present Public Health Risks
Published in Rowena K. Richter, Herbal Medicine, 2013
Comfrey (Symphytum officinale L.) is an example of an herbal product that has been restricted in Germany and Canada but remains on the market in the United States. Comfrey contains pyrrolizidine alkaloids that have been linked to veno-occlusive disease and liver tumors in humans.10 In Germany, the use of comfrey has been restricted to the external use of the root with a limit on the pyrrolizidine alkaloid content. In the United States, comfrey remains available in some health food stores and via mail order and the Internet, although it is sold less widely than in previous years. In July 1996, the American Herbal Products Association, a trade organization representing the dietary supplement industry, began recommending that manufacturers include the following warning on products containing comfrey: “For external use only. Do not apply to broken or abraded skin. Do not take while nursing.” Many manufacturers voluntarily include such warnings or have removed comfrey from their products. However, this warning is not required to be on the label and in the United States it is still quite possible for a consumer to obtain comfrey without being aware of the serious risks associated with it.
Antimicrobial activity of flavonoids glycosides and pyrrolizidine alkaloids from propolis of Scaptotrigona aff. postica
Published in Toxin Reviews, 2023
T. M. Cantero, P. I. Silva Junior, G. Negri, R. M. Nascimento, R. Z. Mendonça
Pyrrolizidine alkaloids are unknown in Apis mellifera propolis. Cyanogenic glycosides and alkaloids are often toxic to insects. Pyrrolizidine alkaloids are aliphatic bicyclic metabolites from several plant groups, including the genera Eupatorium, Heliotropium and Senecio (Asteraceae), Crotalaria (Leguminosae) and Symphytum (Boraginaceae). So far it is not possible to point out a likely plant origin of the pyrrolizidine alkaloids of the propolis analyzed. As mentioned in introduction, the preferential detection of the alkaloids in samples collected in months of October, November and December, suggests an herbaceous plant source (possibly with annual cycle). This is coherent with the phenology of Crotalaria and Senecio, two tropical genera widespread in Brazil. A higher likelihood is that a species of Crotalaria may be the resin source of this type of propolis. Symphytum officinale cannot be precluded as possible source. Although not of tropical origin, this medicinal herb is widely cultivated in many parts of the world and contains pyrrolizidine alkaloids structurally similar with found in this work (Negri et al. 2022). Despite the hepatotoxic, genotoxic, cytotoxic, tumorigenic, and neurotoxic activities of 1,2-unsaturated PAs, they can be used for the treatment of diseases and infections, due to their glycosidase inhibitory activity, that demonstrated antidiabetic effect, besides anticancer, fungicidal, and antiviral effects (Moreira et al. 2018, Tasca et al. 2018, Schramm et al. 2019, Mädge et al. 2020).
Risk assessment of herbal supplements containing ingredients that are genotoxic and carcinogenic
Published in Critical Reviews in Toxicology, 2019
Gerhard Prinsloo, Francois Steffens, Jacques Vervoort, Ivonne M.C.M. Rietjens
PAs are found in hundreds of plant species including various Symphytum spp, such as Comfrey (Symphytum officinale) (Hirono et al. 1978; Elvin-lewis 2001; Stewart and Steenkamp 2001), Senecio spp. such as Senecio longilobus, (containing riddelline) (Steenkamp et al. 2001; Zuckerman et al. 2002), grain contaminated with PA containing weeds (Elvin-lewis 2001; Knutsen et al. 2017) and various Crotoloria spp. (Prinsloo et al. 2018). PA exposure due to consumption of herbal remedies is associated with hepatotoxicity especially veno-occlusive disease (VOD) in humans (Stewart and Steenkamp 2001; Zuckerman et al. 2002; Robertson and Stevens 2017) with clinical symptoms that include vomiting, enlargement of the liver and bleeding diarrhea (Chen et al. 2010). Daily PA intake of 10 μg/kg bw may lead to VOD in humans and a dose of 1 μg/kg bw per day was suggested for this toxic effect to not occur (Dreger et al. 2009). The levels reported by EFSA for PAs at 2 mg/kg bw per day for short term exposure (Knutsen et al. 2017) might raise a concern becasue of induction of VOD and even death. In some case studies deaths resulting from PA intake were reported, probably linked to a high concentration intake for only a limited exposure duration as observed in traditional use of PA containing plants. When evaluating carcinogenicity as an endpoint, as done in the present study, it appears that an intake of 1.3 µg/kg bw per day for 2 weeks every year over a 70 year lifespan, which is in the range of the 1 μg/kg bw per day that was suggested to exclude occurence of VOD (Dreger et al. 2009), resulted in an MOE of 5450, indicating a concern because of the genotoxic and carcinogenic properties of the PAs. The 95th percentile exposure levels obtained in the probablistic intake estimates of the present study resulted in levels of 701 µg/kg bw per day which were remarkably higher than the level of 1 μg/kg bw per day considered to be safe for acute exposure preventing VOD. Thus, the results of the present study corroborate the fact also reported by EFSA that PA containing food supplements present a risk for acute adverse effects. Thus it is concluded that the chronic risks of exposure to PAs via food supplements with respect to their genotoxic carcinogenicity does not always raise a concern (MOEs >10,000), while potential acute toxicity resulting in VOD induced by even short time exposure to food supplements at the high range of the PA contamination level, may be a major concern.
How can we improve the safe use of herbal medicine and other natural products? A clinical pharmacologist mission
Published in Expert Review of Clinical Pharmacology, 2020
Elena Y. Enioutina, Kathleen M. Job, Lubov V. Krepkova, Michael D. Reed, Catherine M. Sherwin
Consumers generally consider marketed DSs as a safe alternative to conventional medications and often believe they can consume as much as they want. However, the use of DSs, especially in excessive amounts, can lead to multiple untoward effects, including severe adverse reactions and toxicity. The most common involve allergic reactions and hepatotoxicity [29–32]. Bunchorntavakul and Reddy reviewed nine studies conducted between 2000 and 2008 and identified that 2–73% of hepatotoxicity cases were associated with the use of medicinal herbs and DSs [31]. More recent studies from the Drug-Induced Liver Injury Network (DILIN) demonstrated that the percentage of NP/DS associated liver injuries has increased from 7% in 2004–2005 to 20% in 2013–2014 [33]. According to this study, many cases of hepatotoxicity were associated with the use of multicomponent DSs [33]. Teschke and Eickhoff report the mechanisms of hepatic injury that are primarily dose-independent idiosyncratic, unpredictable, dose-independent, immunologically or metabolically driven, or intrinsic, a predictable and dose-dependent injury [34]. Clinical presentations of herb-associated liver injury range from asymptomatic elevation of liver enzymes in the blood (i.e. alanine transaminase, aspartate transaminase, gamma-glutamyl transpeptidase) to cholestasis and even acute liver failure resulting in liver transplant. R-value is a significant factor in determining the degree and pattern of hepatic injury [30]. This value is defined as alanine aminotransferase (ALT)/upper limit of normal levels of ALT divided by alkaline phosphatase (APT)/upper limit of normal APT. R-value ≥5 suggests hepatocellular, < 2 cholestatic, and between 2 and 5 mixed patterns of liver injury. Stournaras and Tziomalos suggest that many herbal preparations induce hepatocellular liver injury [30]. The use of bodybuilding supplements has been associated with cholestasis, while the use of high doses of green tea extracts can result in hepatic injury [30,33]. Germanders (Teucrium chamaedrys L.), Greater celandine (Chelidonium majus L.), Babchi (Psoralea corylifolia L., Boh-Gol-Zhee) Comfrey (Symphytum officinale L.), Chaparral (Larrea tridentate (DC.) Coville), Black Cohosh (Cimicifuga racemose) are examples of medicinal herbs with known hepatotoxic properties [30–32]. Recent case reports suggest that concomitant use of excessive amounts of MHs (e.g. ginger and Eleuthero) may potentiate conventional drug hepatotoxicity [35,36].