Alkaloids in Diet PDF

Alkaloids in Diet Cheng Chen and Ligen Lin Contents 1 Introduction.................................................................................. 2 2 Pyrrolizidine Alkaloids...................................................................... 4 2.1 Borage (Borago ofﬁcinalis)........................................................... 5 2.2 Comfrey (Symphytum ofﬁcinale)..................................................... 7 2.3 Honey.................................................................................. 8 3 Tropane Alkaloids (TAs).................................................................... 8 3.1 Wolfberry (Lycium barbarum L.)..................................................... 10 3.2 Buckwheat (Fagopyrum esculentum)................................................. 11 3.3 Soybean and Flax..................................................................... 12 3.4 Cape Gooseberry (Physalis peruviana)............................................... 13 3.5 Coca................................................................................... 13 4 Quinolizidine Alkaloids (QAs)............................................................. 14 5 Isoquinoline Alkaloids...................................................................... 16 5.1 Opium Poppy (Papaver somniferum)................................................ 16 5.2 Lotus (Nelumbo nucifera)............................................................. 18 6 Quinoline Alkaloids......................................................................... 19 7 Glycoalkaloids (GAs)....................................................................... 21 7.1 Potatoes................................................................................ 21 7.2 Tomatoes.............................................................................. 22 7.3 Eggplants.............................................................................. 23 8 Purine Alkaloids............................................................................. 24 8.1 Coffee.................................................................................. 25 8.2 Tea..................................................................................... 26 8.3 Kola Nuts.............................................................................. 27 8.4 Cocoa Beans........................................................................... 27 9 Pyridine Alkaloids........................................................................... 27 9.1 Piper nigrum.......................................................................... 27 9.2 Areca Nuts............................................................................. 29 9.3 Nicotiana tabacum.................................................................... 29 C. Chen · L. Lin (*) State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, China e-mail: [email protected]; [email protected] © Springer Nature Singapore Pte Ltd. 2020 1 J. Xiao et al. (eds.), Handbook of Dietary Phytochemicals, https://doi.org/10.1007/978-981-13-1745-3_36-1 2 C. Chen and L. Lin 10 Amide Alkaloids............................................................................ 31 11 Conclusions.................................................................................. 33 References........................................................................................ 33 Abstract Food is one of the three basic requirements of mankind, supplying six kinds of nutrients including water, carbohydrate, protein, lipid, vitamins, and minerals. Alkaloid-containing foods are an intrinsic part of the human diet, such as tea, coffee, and tomato. These food-oriented alkaloid constituents possess diverse effects on the human body, either wanted or unwanted. A large variety of food-produced alkaloids exhibit potent bioactivities, such as caffeine, atropine, and cocaine, whereas, lots of other alkaloids are toxic to human, such as pyrrolizidine alkaloids. This chapter focuses on the alkaloids in human diet and their mode of action and possible toxic effects. To organize this chapter, the alkaloids were categorized into nine groups based on their structures: pyrrolizidine alkaloids, tropane alkaloids, quinolizidine alkaloids, isoquinoline alkaloids, quinoline alkaloids, glycoalkaloids, purine alkaloids, pyridine alka- loids, and amide alkaloids. The structures of food-derived alkaloids are described, and their pharmacological activities, bioavailability, metabolism, and toxicolog- ical effects are discussed. Moreover, the application of alkaloids in medicines and food supplement, patents, as well as a conclusion about their current impact on food safety are reviewed. The main purpose of this chapter is to provide a comprehensive and up-to-date state of knowledge from phytochemical, phar- macological, and toxicological studies performed on alkaloids in human food. Keywords Alkaloids · Bioactive constituents · Toxicity · Bioavailability · Safety 1 Introduction Alkaloids are a class of nitrogen-bearing organic compounds, which are produced by a large variety of organisms, including bacteria, fungi, plants, and animals. More than 13,000 alkaloids have been isolated and structurally elucidated. Plants are the major sources of alkaloids, especially certain families of ﬂowering plants, including Papaveraceae (poppy), Amaryllidaceae (amaryllis), Ranunculaceae (but- tercups), Solanaceae (nightshades), and Stemonaceae. Commonly, a given species contains only a few alkaloids with the same core structure, such as the opium poppy (Papaver somniferum) and the ergot fungus (Claviceps) each containing about 30 different morphine and ergoline alkaloids, respectively. Animal-produced alkaloids are seldom reported, such as the New World beaver (Castor canadensis) and poison- dart frogs (Phyllobates). Interestingly, alkaloids are widely existed in regular human diet, either intrinsic constituents of vegetables and drinks or food contaminants and ﬂavorings from food processing. Alkaloids in Diet 3 The function of alkaloids in plant is largely unknown. Alkaloids were originally considered as the by-products of plants’ metabolic processes, such as the biosyn- thesis of amino acids. More and more evidence has suggested that some alkaloids serve speciﬁc physiological function in plants, such as to protect some plants against certain microorganisms, insects, or animals, to mediate signaling transduction in plants, and to stimulate seed formation and ripeness. Alkaloids exist in plant tissues as water-soluble salts of organic acids and esters or combined with tannins or sugars rather than as free bases. In their pure form, most alkaloids are colorless, nonodorous, nonvolatile, and crystalline solids. The free bases of alkaloids are prone to dissolve in nonpolar organic solvents, such as chloroform and ether. On the contrary, the salts of alkaloids are soluble in water or dilute acids. The differences in the solubility of alkaloids, depending on their forms, are used in laboratory and industry for the extraction and production of pharmaceu- tically acceptable products. They also tend to have a bitter taste, such as quinine which is used as a bitter principle in tonic water. The structural diversity of alkaloids is extremely signiﬁcant. Most alkaloids have one or more of their nitrogen atoms as part of a ring structure. Biosynthetic pre- cursors of most alkaloids are amino acids, including ornithine, lysine, phenylalanine, tyrosine, tryptophan, histidine, aspartic acid, and anthranilic acid. The biosynthetic pathways of alkaloids are too numerous and mostly remained unknown at the current stage. Alkaloids possess diverse and signiﬁcant physiological effects on humans and other animals (both wanted and unwanted); thus they have been used for thousands of years as medicines, poisons, stimulants, insecticides, aphrodisiacs, and narcotics. Morphine is the ﬁrst alkaloid to be isolated and crystallized in 1804, as the active constituent of the opium poppy, which is a powerful narcotic used for the relief of pain. Codeine, the methyl ether derivative of morphine from the opium poppy, is an excellent analgesic. Ergonovine (from the fungus Claviceps purpurea) and ephedrine (from Ephedra species) function as blood vessel constrictors. Ergonovine is used to reduce uterine hemorrhage after childbirth, and ephedrine is used to relieve discomfort from common colds, sinusitis, hay fever, and bronchial asthma. Quinidine, widely distributed in plants of the genus Cinchona, has been used to treat arrhythmias and irregular rhythms of heartbeat; quinine (from Cinchona species) is used to treat malaria. The alkaloid curare (from Chondrodendron tomentosum) is used as a muscle relaxant in surgery. Two alkaloids, vincristine and vinblastine (from Vinca rosea), are widely used as chemotherapeutic agents in the treatment of many types of cancer. Alkaloids are often classiﬁed on the basis of their chemical structures. To organize this chapter, the common alkaloids in human diet were classiﬁed into nine groups based on their core structures: pyrrolizidine alkaloids (PA), tropane alkaloids (TA), quinolizidine alkaloids (QA), isoquinoline alkaloids, quinoline alkaloids, glycoalkaloids (GA), purine alkaloids, pyridine alkaloids, and amide alkaloids. The core structures of the nine types of alkaloids were shown in Fig. 1. For each type of alkaloids, the occurrence in food and their chemical structures are described, their pharmacological activities, bioavailability, metabolism, and the 4 C. Chen and L. Lin Fig. 1 The core structures of pyrrolizidine alkaloids, tropane alkaloids, quinolizidine alkaloids, isoquinoline alkaloids, quinoline alkaloids, glycoalkaloids, purine alkaloids, and pyridine alkaloids application in food (including correctly cooking foods rich in phytochemicals) are introduced, and the marketed products, toxicological effects, and existing safety assessments are discussed. 2 Pyrrolizidine Alkaloids PAs, also called as necine bases, are a group of naturally occurring alkaloids with a core structure of pyrrolizidine (Fig. 1). More than 660 PAs and their N-oxides have been identiﬁed in around 6,000 plants, and more than half of them exhibit hepatotoxicity. PAs are produced by plants as a defense mechanism against insect and herbivores. They are found frequently in plants from the families Boraginaceae, Asteraceae (Senecioneae and Eupatorieae), Orchidaceae, and Fabaceae (Crotalaria), less frequently in the families Convolvulaceae and Poaceae. Many kinds of foods have been reported to produce PAs, including borage (Borago ofﬁcinalis), comfrey (Symphytum ofﬁcinale), Gynura bicolor, and Emilia sonchifolia, to possess PA contamination, such as honey. Food-containing PAs are mostly esters of 1-hydroxymethyl-1,2-dehydro-pyrrolizidine, which always bear a hydroxyl group on carbon 7. Some examples of PAs in food were shown in Fig. 2. In grain commodities, the PAs are considered to originate from seeds or plant fragments of PA-containing weeds (ranging from 50 to 6,000 mg/kg). The consump- tion of PA-contaminated grains causes acute or chronic liver toxicity. Symptoms of acute PA poisoning include abdominal pain, ascites, nausea, vomiting, diarrhea, dropsy, and very rare, jaundice and fever. PA poisoning is associated with hepatic vein occlusive disease (HVOD) involving obstruction of the small veins with sudden hepatomegaly (enlarged liver) and ascites and may end with death (Dharmananda 2004). According to the World Health Organization (WHO), the lowest daily intake of PAs that causes adverse effects in a human is 0.015 mg/kg body weight, Alkaloids in Diet 5 Fig. 2 Some representative PAs in the plant-derived food corresponding to 0.9 mg/day for a 60 kg person, based on the use of comfrey over a period of 4–6 months (Dharmananda 2004). PAs exert fetotoxic and teratogenic effects at higher doses (Wiedenfeld et al. 2008). PAs are metabolically activated within the liver, and they can alkylate both proteins and DNA molecules; they are therefore hepatotoxic causing liver damage, as well as mutagenic and carcinogenic. The major metabolic pathways of PAs in human are described as follows: Ester hydrolysis and N-oxidation of PAs represent detoxiﬁcation processes (Prakash et al. 1999). Toxicity occurs via dehydrogenation of the pyrrolizidine nucleus to generate dehydro-pyrrolizidine moiety (pyrrolic derivatives), followed by acid-catalyzed cleavage of the C7-O bond, resulting in the formation of a carbocation. Then, carbocation may react with available nucleophiles like DNA, leading ultimately to liver necrosis and tumor formation (Prakash et al. 1999). 2.1 Borage (Borago officinalis) Borago ofﬁcinalis (Boraginaceae) is known as starﬂower, borage, burrage, bourrache, and bugloss. Borage is a plant being widely used in pharmaceutical, industrial, and forage ﬁelds and is also being used to make drinks and salads. Borage is native to Europe, North Africa, and Asia Minor and is now being cultivated worldwide. Historical documents showed that borage was ﬁrstly cultivated in North Africa and then spread to Spain and other regions. Borage is a common vegetable in Germany, the Spanish regions of Aragon and Navarre, the Greek island of Crete, and the northern Italian region of Liguria. The plant parts of borage are used in the following ways: leaves made into tea, washes, and poultices; ﬂowers eaten; seeds pressed for oil; and tinctures made from leaves and ﬂowering tops. One of the well-known German borage recipes is the green sauce 6 C. Chen and L. Lin (grüne soße) made in Frankfurt. In Italian Liguria, borage is commonly used as a ﬁlling of the traditional pasta ravioli and pansoti. The ﬂowers or petals of borage are edible and often used as a garnish on salads and soups and used to ﬂavor pickled gherkins in Poland. Borage leaves have been used in European herbal medicine since the Middle Ages and are mentioned by Pliny, Dioscorides, and Galen. The name “borage” derives from the Medieval Latin “burra,” meaning rough-coated, which refers to the hairs. An alternative explanation suggests it is a corruption of the Latin “corago” (courage). This is in line with its reputation as an herb to dispel melancholy. Borage leaves also have been used to treat rheumatism, cold, and bronchitis, as well as to increase lactation in women. Infusions of the leaves were used to induce sweating and diuresis. Before the invention of ice, borage was used in a cooling drink called a “cool tankard” or “claret cup” consisting of wine, water, lemon, sugar, and borage leaves and ﬂowers. Borage is still widely used in British herbalism, but its use has been waned in North America. Pliny the Elder believed borage to be antidepressant, and it has long been thought to give courage and comfort to the heart. One old wives’ tale states that if a woman slipped a bit of borage into a promising man’s drink, it would give him the courage to propose. In European traditional medicine, the heart was believed to store the vital spirit and circulate it around the body via the arteries. Thus “heart medicines” were usually medicines for the spirit – for depression and confusion. Lemon balm (Melissa ofﬁcinalis), lily of the valley (Convallaria majalis), motherwort (Leonurus cardiaca), and borage are speciﬁcs for matters of the heart. These remedies were used to protect the heart from excess heat in high fevers, and borage was much favored for this. Motherwort and borage are a useful combination in thyrotoxicosis, which is a modern version of “excess heat attacks the heart.” The leaves of borage were found to contain a high amount of PAs (10 mg/kg) (Dharmananda 2004). Thesinine (Fig. 2) is one of the few nontoxic PAs produced by plants and is responsible for the deep blue color of the ﬂowers of borage. It tastes sweet, honey-like, and is one of the few blue but edible compounds. Borage also produces small amounts of the poisonous PAs, including amabiline, supinine, intermedine and its enantiomorph lycopsamine, and their 7-acetyl derivatives (Fig. 2). Amabiline and supinine are structural analogues of indicine, a predominant PA in the seeds from plants of the Heliotropium species, which might contaminate cereals and grains intended for human and animal consumption. It is not recommended that borage leaves be taken long term internally because of the concentration of PAs that can damage the liver. Some recommend limiting its use to 4–6 weeks, others say 2–3 months at a time. Most sources specify low doses and limited use. Young leaves of borage have been shown to contain less PAs than older ones. Do not take borage if the persons are taking anticoagulants. Borage can cause nausea, cramping, bloating, and headache, although they are relatively mild. Currently, borage is not recommended during pregnancy or lactation, but it has been traditionally used as a galactagogue. Additionally, the hairs on the fresh leaves can irritate the skin. PAs are also present in borage seeds oil but may be removed by processing. Analysis of borage seed oil showed the possible existence of PAs to induce side Alkaloids in Diet 7 effects. Borage seed oil is used for chronic skin inﬂammatory disease, skin itch, and stimulation problems. 2.2 Comfrey (Symphytum officinale) Comfrey (Symphytum ofﬁcinale) is commonly found throughout Europe and parts of Asia and North America, which has been used as a herbal medicine for the treatment of painful muscle and joint complaints for more than 2,000 years. Comfrey is commonly called knitbone because of its amazing ability to heal broken bones and “knit” them back together again. The botanical name, Symphytum, means “to unite.” Comfrey is used to treat upset stomach, ulcers, heavy menstrual periods, diarrhea, bloody urine, persistent cough, and chest pain as well as is applied to the skin for wounds, joint inﬂammation, bruises, and rheumatoid arthritis. The leaves and roots of comfrey are also used as herbal teas and vegetable (e.g., in salads). Several PAs, including echimidine and lasiocarpine (Fig. 2), have been isolated from comfrey. The PA content in comfrey leaves varies from 20 to 1,800 mg/kg. Comfrey root contains PAs with 1,2-unsaturated necine ring structures, almost entirely in the form of their N-oxides, the main ones being 7-acetylintermedine and 7-acetyllycopsamine together with smaller amounts of intermedine and symphytine (Fig. 2). The total amount of PAs given by different authors varies from 0.013% to 1.2% based on the analytical methods. The major hepatotoxic manifestation in humans ingesting comfrey is hepatic VOD, also called sinusoidal obstruction syndrome (SOS). Several cases of VOD/ SOS associated with comfrey ingestion were reported in humans, as well as in experimental animals. Comfrey-induced dose-dependent hepatic VOD was found in rats that were gavaged with a single dose of 200 mg/kg of the mixed PA or 50 and 100 mg/kg thrice a week for 3 weeks. The mechanisms underlying comfrey- induced genotoxicity and carcinogenicity are still not fully understood. The available evidence suggests that the active metabolites of PAs in comfrey interact with DNA in liver endothelial cells and hepatocytes, resulting in DNA damage, mutation induction, and cancer development. In 2001, the US Food and Drug Administration issued a ban on comfrey products marketed for internal use and a warning label for those intended for external use (FDA/CFSAN 2007). Nowadays, only pyrrolizidine-depleted or pyrrolizidine-free extracts are used in proprietary medicinal products. Comfrey should not be used during pregnancy and lactation, in infants, and in people having liver, kidney, or vascular diseases. To date, the activity-determining constituents and mechanisms of action of comfrey are only partly known. In accordance with the modern approach of evidence-based medicine, comfrey extract creams have been demonstrated their efﬁcacy and tolerability in a number of muscle and joint injuries, such as acute myalgia in the back area, and in blunt injuries. Comfrey herb has also been shown to be efﬁcacious in wound healing. Comfrey root has also been proven to be efﬁcacious in activated osteoarthritis and equivalent or more efﬁcacious in distortions compared with topical diclofenac. It could therefore be promising to investigate topical 8 C. Chen and L. Lin comfrey preparations in further indications related to muscle or joint pain, for instance, chronic forms of back pain. 2.3 Honey Honey is a sweet, viscous food substance produced by bees and some related insects. Bees produce honey from the sugary secretions of plants (ﬂoral nectar) or from secretions of other insects (such as honeydew). Honey production and use have a long history, depicted in Valencia, Spain, by a cave painting of humans foraging for honey at least 8,000 years ago. Over its history as a food, honey is used as a spread on bread; an addition to various beverages, such as tea; and a sweetener in some commercial beverages. Honey barbecue and honey mustard are other common ﬂavors used in sauces. Honey is also used to make mead beer, called “braggot.” Honey made by bees foraging on Senecio jacobaea (tansy ragwort) contain senecionine and jacobine, with the total PA content ranging from 0.3 to 3.9 mg/kg (Fig. 2). The highest level of PAs is 3.9 mg/kg in honey from Senecio jacobaea; because this value was not corrected for extraction efﬁciency, the amount of PAs might be higher. Plant genera-producing PAs are important contributors to honey production in many countries. Honey made by bees foraging mainly on Echium spp. contains echimidine as the major alkaloid (Fig. 2). Analysis of honey available on the German/European market revealed that 19 samples (9%) contained PAs within the 216 samples, in the range of 0.019–0.120 mg/kg, calculated as retronecine equiva- lents (Kempf et al. 2008). Levels of PAs present in honey from PA-containing plants are well above that considered by the German Federal Health Bureau. Long-term consumption of PA- containing honey is capable of causing progressive chronic toxicity, especially in infants and fetuses. Although no incidents of PA poisoning have been reported due to consumption of honey, a report issued by the International Programme on Chemical Safety (IPCS) concluded that the level of PAs in honey may contribute to chronic liver disease or liver tumors (Edgar et al. 2002). 3 Tropane Alkaloids (TAs) TAs are a class of bicyclic [3.2.1] alkaloids and secondary metabolites that contain a tropane ring in their chemical structure. TAs are found in plants of numerous families, especially Solanaceae, Erythroxylaceae, Convolvulaceae, Brassicaceae, and Euphorbiaceae, and they comprise mono-, di-, and tri-esters and carboxylated and benzoylated tropanes. More than 200 TAs have been isolated and identiﬁed. Several of these alkaloids occur as chiral structures due to the presence of a tropic acid residue attached to the ecgonine nucleus as an ester. The former occurs naturally in its R form; however, racemic mixtures may appear, especially during alkaline extraction (e.g., the formation of (+)-atropine from ()-hyoscyamine). Several acids Alkaloids in Diet 9 are distinguished as being present in the TAs, including tropic, tiglic, acetic, iso- valeric, isobutyric, benzoic, or anisic acids. TA-containing plants have been used medicinally and for folkloric purposes in many countries. Atropine, hyoscyamine, and scopolamine are used therapeutically for different medical indications. TAs are commonly used as anti- colic and spas- molytic drugs (scopolamine) in both digestive and urinary tract spastic conditions. Especially, atropine is commonly used in ophthalmological eyedrops to enlarge pupils, paralyze the accommodation reﬂex, and enable the ophthalmic examination. The juice from Atropa belladonna was extensively used by women in the time of the Renaissance to enlarge the pupils of the eyes so as to improve their looks. The bioactivities of TAs are relied on the antagonistic action on muscarinic acetylcholine receptors (Brown and Taylor 2006). Several TAs are hallucinogenic agents and some are powerful anticholinergic drugs. Plants synthesize and store TAs as a protection against being eaten (e.g., by insects). Most TAs are toxic to humans. However, TAs are characterized by numerous contraindications and side effects. The effects of TA administration are characterized by dryness of the mucosa of the upper digestive and respiratory tract, constipation, pupil dilatation, disturbance of vision, photophobia, dose-dependent occurrence of hyper- or hypotension, bradycardia, tachycardia, arrhythmias, ner- vousness, restlessness, irritability, disorientation, ataxia, seizures, and respiratory depression (EFSA 2008b). Oral administration of atropine in single doses of 0.5–1 mg up to three times daily is used to treat smooth muscle spasms in the gastrointestinal tract, which causes side effects including slight cardiac slowing and dryness of mouth (Brown and Taylor 2006). A single oral dose of atropine in the range of 2–5 mg is associated with rapid heart rate, dilated pupils, blurring of vision, difﬁculties of speaking and swallowing, and dry and hot skin (Meletis and Wagner 2002). Oral doses of 10 mg or more atropine lead to rapid and weak pulse, ataxia, restlessness, excitement, hallucinations, delirium, and coma (Brown and Taylor 2006). Hyoscyamine is used in the treatment of visceral spasm in oral single doses of 0.15–0.3 mg up to four times daily, showing the same adverse effects as atropine (Martindale 2010). Scopolamine is administered orally in single doses of 0.15–0.3 mg up to four times daily in the prevention of postoperative dizziness and motion sickness. Typical adverse effects for anticholinergic drugs such as dryness of the mouth, changes in heart rate, and disturbance of vision are reported within the range of the therapeutically dosage (Martindale 2010). TAs should be avoided in patients with glaucoma, prostatic hypertrophy, and urinary tract diseases and also during pregnancy. TA intoxications for humans result mainly from abuse (because of the hallucino- genic effects), consumption with TA-containing plants, or accidental exposure (EFSA 2008b). Cocaine is a drug of abuse in many countries. It is the second most popular psychostimulant (after cannabis), temporarily improving mental and physical functions. Cocaine inhibits serotonin, norepinephrine, and dopamine reuptake. In higher doses, cocaine may evoke the blockage of sodium channels resulting in cardiac death. Chronic intake may cause serious transmitter level disorders leading to depressions, suicide attempts, insomnia, or psychomotor 10 C. Chen and L. Lin Fig. 3 Structures of some representative TAs in the plant-derived food retardation. Its abuse resulted in more than 4,000 deaths in 2013. It has local anesthetic properties which are largely forbidden nowadays. After absorption, hydrolysis of TAs inactivates their bioactivities and reduces their toxicity in certain animal species (EFSA 2008b). The TA-containing foods include wolfberry (Lycium barbarum L.), buckwheat (Fagopyrum esculentum), soybean (Glycine max), ﬂax (Linum usitatissimum), Cape gooseberry (Physalis peruviana), and coca (Erythroxylum coca). The structures of some food-producing TAs were shown in Fig. 3, such as ()- and (+)-hyoscyamine (a racemic mixture of these two alkaloids is known as atropine), ()-scopolamine (also known as ()-hyoscine), and cocaine. 3.1 Wolfberry (Lycium barbarum L.) Lycium barbarum L. and Lycium chinense Miller (wolfberry, belonging to Solanaceae family) are two closely related species with congruent uses as food and medicinal plants in East Asia. The berries of both species are a very popular ingredient in Chinese cuisine. They are consumed in soups and porridges and added to different meat and vegetable dishes. The young leaves of both species are a valued vegetable. Wolfberries are not only a vegetable but also a traditional Chinese herbal med- icine. Although only L. barbarum is ofﬁcinal in the China Pharmacopoeia, both Alkaloids in Diet 11 species, L. barbarum and L. chinense, have been used medically for more than 2,000 years. In traditional Chinese medicine, wolfberries are used as a mild Yin tonic, enriching Yin in the liver and kidney and moistening lung Yin. Wolfberries are prescribed to treat blurry vision and diminished visual acuity, infertility, abdominal pain, dry cough, fatigue, and headache. The berries are also praised in the folk medicine to increase longevity and against prematurely gray hair. In a representative study with 42 elderly participants, consumption of 50 mg of wolfberry extract twice a day over 2 months decreased dizziness, fatigue, chest distress, sleep problems, and anorexia. Besides China, wolfberry is also used as herbal drug in other Asian countries, including Vietnam, Korea, and Japan. Wolfberry is commonly designated as “Himalayan goji berry” or “Tibetan goji berry” on the global functional food market. The variety of commercialized products is considerable. Besides juices, beers, and wines, wolfberry is found in cookies, crispy bars, chocolate, muesli, sausages, and soaps. Wolfberry products are increas- ingly available in drugstores, “Reformhäuser,” and organic food shops. Wolfberries and its related products are legally sold as food or food supplements in USA and Europe. However, these products cannot be promoted as drugs, and therapeutic claims are prohibited. There have been some controversial reports about the atropine content in the fruits of L. barbarum. In 1989, a report showed around 0.95% atropine in the fruits of L. barbarum collected in India. In a systematic investigation of wolfberries from various provenances, only trace amount of atropine was detected with high-perfor- mance liquid chromatography-mass spectrometry (HPLC-MS) method, maximally 19 ppb (w/w) among the analyzed samples (Adams et al. 2006). The presence of atropine in the roots of wolfberry was reported, which is much higher than that in the fruits. In 2006, the US Food and Drug Administration sent warning letters to two wolfberry juice distributors in violation of marketing their product as a drug intended for the prevention or cure of disease, when wolfberry juice is not generally recog- nized as safe and effective for various health beneﬁts. The LD50 value of a water extract of wolfberries is 8.32 g/kg by subcutaneous application in mice (Potterat 2010), which conﬁrms the virtual absence of toxicity of wolfberry. Although there is no risk with cultivated plants, some caution is advised with samples of unknown origin. 3.2 Buckwheat (Fagopyrum esculentum) Buckwheat (Fagopyrum esculentum), also known as common buckwheat, Japanese buckwheat, and silver hull buckwheat, is a plant cultivated for its grain-like seeds and as a cover crop. The crop was originated from China, and nowadays, it is widely cultivated over the world. Buckwheat noodles have been consumed by people from Tibet and Northern China for centuries, as wheat cannot be grown in the mountain regions. Nowadays, buckwheat noodles are very popular in the cuisines of Japan (soba), Korea (naengmyeon, mak-guksu, and memil guksu), buckwheat fresh pasta (pasta di grano saraceno) are commonly consumed in Apulia region of Southern 12 C. Chen and L. Lin Italy and the Valtellina region of Northern Italy (pizzoccheri), and buckwheat groats are commonly used in Western Asia and Eastern Europe. Dehulled seeds (raw groats) are principally used for human consumption as breakfast cereals or as processed ﬂour for making different bakery products and buckwheat-enhanced nonbakery products (tea, honey, tarhana, and sprouts). Buckwheat is a gluten-free pseudocereal; these products may be included in gluten-free diets for patients suffering from gluten intolerance. Buckwheat is an important raw material used for functional food because it exhibits a broad range of bioactivities, such as antidiabetic, hypotension, hypocholesterolemic, and hypoglycemic effects. Buckwheat becomes a dietary source of bioactive compounds, such as nutritionally valuable protein, phenolic compounds, starch and dietary ﬁber, essential minerals, and trace elements. However, TAs are found in buckwheat and its related matrices at concentrations higher than 100 μg/kg. The major source of TA contamination in buckwheat is stramonium (Datura stramonium), which produces high concentration of TAs, including atropine and scopolamine. In most temperate climates, stramonium can easily thrive as weeds in buckwheat ﬁelds. Despite an adequate management, postharvest handling, and control, some seeds may go undetected to subsequent stages of the food chain making a certain degree of contamination by these TAs unavoidable. Both Datura and Fagopyrum species in fact produce, and maturate almost simultaneously, a dehiscent fruit-harboring seeds with similar size and weight. It may be particularly relevant for organic agriculture, as a less strict weed management may allow an increased in-ﬁeld presence of potentially dangerous plants alongside with crops. 3.3 Soybean and Flax Soybean is a species of legume native to East Asia. Soybean is a signiﬁcant and cheap source of protein for animal feeds and many packaged meals. Soybean products, such as textured vegetable protein (TVP), are ingredients in many meat and dairy substitutes. Approximately 85% of the world’s soybean crop is processed into soybean meal and soybean oil. Tofu, soy milk, and soy sauce are among the top edible commodities made from soybeans. Flax (Linum usitatissimum), also known as common ﬂax or linseed, is a species from the family Linaceae. It is a food and ﬁber crop cultivated in cooler regions of the world. Flax is grown for its seeds, which can be ground into a meal or linseed oil, a product used as a nutritional supplement. TA contamination has been found in soybean and ﬂax (animal feed). In surveys conducted in Germany, up to 31.1% of soybean and ﬂax products were contaminated with Datura seeds; and 65 of the 66 samples contained scopolamine at levels between 0.1 and 33 mg/kg (Bucher and Meszaros 1989). Alkaloids in Diet 13 3.4 Cape Gooseberry (Physalis peruviana) The genus Physalis, of the family Solanaceae, includes annual and perennial herbs bearing globular fruits, each enclosed in a bladderlike husk which becomes papery on maturity. Of the more than 70 species, only a very few are of economic value. A species which bears a superior fruit and has become widely known is the Cape gooseberry (Physalis peruviana L.), which is used for sauce, pies, and preserves in mild-temperate climates. Reportedly native to Peru and Chile, where the fruits are casually eaten and occasionally sold in markets but is still not an important crop, it has been widely introduced into cultivation in other tropical, subtropical, and even temperate areas. In addition to being canned whole and preserved as jam, the Cape gooseberry is made into sauce; used in pies, puddings, chutneys, and ice cream; and eaten fresh in fruit salads and fruit cocktails. Because of the fruit’s decorative appearance in its showy husk, it is popular in restaurants as an exotic garnish for desserts. To enhance its food uses, hot air drying improved qualities of dietary ﬁber content, texture, and appearance. In Colombia, the fruits are stewed with honey and eaten as dessert. The British use the husk as a handle for dipping the fruit in icing. In Colombia, the leaf decoction is taken as a diuretic and an antiasthmatic. In South Africa, the heated leaves of Cape gooseberry are applied as poultices on inﬂammations, and the Zulus administer the leaf infusion as an enema to relieve abdominal ailments in children. The aerial parts and roots of Cape gooseberry have been shown to contain tigloidine and other secotropane alkaloids (Fig. 3). 3.5 Coca Coca is the leaves of the four cultivated plants in the family Erythroxylaceae, (Erythroxylum coca var. coca, Erythroxylum coca var. ipadu, Erythroxylum novogranatense var. novogranatense, and Erythroxylum novogranatense var. truxillense) native to western South America. Coca is grown as a cash crop in Argentina, Bolivia, Colombia, Ecuador, and Peru and even in areas where its cultivation is illegal. Coca is known for its psychoactive alkaloid, cocaine (Fig. 3). The alkaloid content of coca leaves is relatively low. The native people use it as a stimulant, like coffee, or an energy source. Although only the indigenous populations directly chew coca leaves, the consumption of coca tea (Mate de coca) is common among all sectors of society in the Andean countries and is considered to be beneﬁcial to health, mood, and energy. Coca leaf is packaged into tea bags and sold in most grocery stores in the region. Coca-Cola used coca leaf extract from 1885 to 1903. Extraction of cocaine from coca requires several solvents and a chemical process called acid-base extraction. Traditional medical uses of coca are foremost as a stimulant to overcome fatigue, hunger, and thirst. It is considered particularly effective against altitude sickness. Coca is also used as an anesthetic and analgesic to alleviate pain from headache, 14 C. Chen and L. Lin rheumatism, wounds, and sores. The high calcium content in coca explains why people used it for bone fractures. Because coca constricts blood vessels, it’s also used to stop bleeding. Indigenous use of coca has also been reported to treat malaria, ulcers, and asthma, to improve digestion, to guard against bowel laxity, and to extend life span. Modern studies have veriﬁed a number of these medical applications (Biondich and Joslin 2016). The major pharmacologically active ingredient of coca is cocaine, with the amount ranging from 0.3% to 1.5% in fresh leaves. Besides cocaine, the coca leaves contain a number of other alkaloids, including methylecgonine cinnamate, benzoylecgonine, truxilline, hydroxytropacocaine, tropacocaine, ecgonine, cuscohygrine, dihydrocuscohygrine, nicotine, and hygrine. When chewed, coca acts as a mild stimulant to suppress hunger, thirst, pain, and fatigue. Almost all of the coca alkaloids are absorbed within 20 min of nasal application, while it takes 2–12 h after ingestion of the raw coca leaves for alkaloid concentrations to peak. When the raw leaf is consumed in tea, around 59–90% of the coca alkaloids are absorbed. The direct consumption of coca leaves does not induce a physiological or psychological dependence or symptoms typical to substance addiction. Due to its alkaloid content and nonaddictive properties, coca has been suggested as a method to help recovering cocaine addicts to withdraw the drug. Coca is used in the cosmetics and food industries. A de-cocainized extract of coca leaves is one of the ﬂavoring ingredients in Coca-Cola. Coca tea is produced industrially from coca leaves in South America. Coca leaves are also found in a brand of herbal liqueur called “Agwa de Bolivia” (grown in Bolivia and de-cocain- ized in Amsterdam) and a natural ﬂavoring ingredient in Red Bull Cola. Coca-Cola is an energy drink which is produced in Bolivia from the coca extract. A health risk assessment of coca leaf extract-containing soft drink concluded that no health risk is to be expected from consumption of this product because of low cocaine content. The lowest dose of cocaine that can cause adverse effect is 4,800 mg per day for an adult. Assuming a high daily consumption of 1.7 L, the margin of safety (MOS) between the consumed amount of cocaine and the amount upward of which adverse effects may occur is a factor of approximately 7,000. The prohibition of the use of the coca leaf was established by the United Nations in 1961, except for medical or scientiﬁc purposes. The coca leaf is listed on Schedule I of the 1961 Single Convention together with cocaine and heroin. 4 Quinolizidine Alkaloids (QAs) QAs (norlupinane, octahydro-2H-quinolizine) are nitrogen-containing heterocyclic compounds. The most common QAs include sparteine and lupanine, α-isolupanine, 13α-hydroxylupanine, and anagyrine (Fig. 4). QAs exist in many species of the genus Lupinus, commonly known as lupin or lupine. Lupinus is a diverse genus; only four species have been domesticated and are agriculturally signiﬁcant: Lupinus angustifolius (NLL), Lupinus albus (white lupin), Lupinus luteus (yellow lupin), and Lupinus mutabilis. Plants from the genus Lupinus have been traditionally used as an Alkaloids in Diet 15 Fig. 4 Structures of some representative QAs in the plant-derived food animal feed and gained recognition as a healthy food. They contain high amount of protein and ﬁber and possesses certain beneﬁcial nutraceutical properties. QAs are nontoxic to the legumes that produce them but toxic and in some cases very toxic to other organisms. The toxicity of alkaloids is considered to be connected with their bitter taste. The QAs are certainly bitter in taste to humans. The most toxic QAs are tetracyclic with a pyridone nucleus. One of these is anagyrine. One case mentions anagyrine being passed into the human body via milk from goats foraging on Lupinus latifolius. The anagyrine caused severe bilateral deformities of the distal thoracic limbs in a baby boy. Both sparteine and lupanine display moderate acute toxicity, the former being the more toxic one. The acute oral LD50 (lethal dose for 50% of the population) value in rats for the extract of Lupinus angustifolius L. is 2,279 mg/kg body weight and for lupanine is 1,464 mg/kg body weight. There are some cases of acute toxicity in humans. According to some results, the LD50 value for sparteine is 60 mg/kg, lupanine 159 mg/kg, 13-hydroxylupanine 189 mg/kg, 17- hydroxylupanine 177 mg/kg, and oxolupanine 190 mg/kg. When humans ate lupin beans, which had not been de-bittered, they suffered from blurry vision, dry mouth, facial ﬂushing, and confusion. A young man who drank 0.5 L of water that had been used for the de-bittering of lupin seeds suffered from sudden weakness, palpitations, extra systoles, and different anticholinergic symptoms. In another study, accidental ingestion of unripe lupin seeds resulted in nausea, migraine, abdominal pain, bradycardia, and respiratory depression. Sparteine is especially present in European Lupinus species, whereas lupanine is typical for Australian species. The Australian varieties developed by plant-breeding programs are called “sweet lupins” as they contain a strongly reduced amount of total alkaloids. The mean total alkaloid content of the marketed Australian sweet lupin (Lupinus angustifolius) seeds is on average 130–150 mg/kg, of which 70% is lupanine. European lupins, which are predominantly consumed in Southern Europe as seeds (beans), have a high alkaloid content of 10–20 g/kg. The alkaloid level can be reduced through a de-bittering process involving soaking and washing with water. Lupin ﬂour is used to replace a small percentage of wheat ﬂour and soybean ﬂour. 16 C. Chen and L. Lin It is further used in food formulations to replace soy ﬂour in food commodities and also in lupin-based meals, pastas, pastries, cakes, biscuits, snacks, tempe, bread, miso, soy sauce, dairy/tofu product, and coffee substitutes. For example, a coffee surrogate, made of roasted lupin beans, has an alkaloid content of 200 mg/kg of product. Lupins can be used to make a variety of foods, both sweet and savory. The European white lupin beans are commonly sold in a salty solution in jars (like olives and pickles) and can be eaten with or without the skin. QAs are potent antagonists on the nicotinic cholinergic receptor but weak antag- onists on the muscarinic cholinergic receptor. Neurological (weakness, dizziness, mydriasis, anxiety, confusion, malaise, loss of coordination, visual disturbances, and dry mouth), cardiovascular (dysrhythmias), and gastrointestinal (nausea, vomiting) symptoms are due to their anticholinergic effects. QAs act via inhibition of gangli- onic impulse transmissions of the sympathetic nervous system. It is evident that each QA has its own effect. On the other hand, some QAs are used as folk medicines. They probably have chronic toxicity. However, adequate knowledge about the chronic toxicity of these alkaloids and especially of chronic toxicity across genera- tions is not available. The premise that QAs have not produced hereditary symptoms has not been checked with total reliability. A risk of lupine allergy exists in patients allergic to peanuts. Indeed, most lupin reactions reported are in people with peanut allergy. Because of the cross-allerge- nicity of peanut and lupin, the European Commission has required that food labels indicate the presence of “lupin and products thereof” in food. 5 Isoquinoline Alkaloids Isoquinoline alkaloids constitute one of the largest groups of natural substances. These compounds are biogenetically derived from phenylalanine and tyrosine and include an isoquinoline or a tetrahydroisoquinoline ring as a basic structural feature in their skeleton. Isoquinoline alkaloids are widely distributed in plants of the families Papaveraceae, Berberidaceae, Ranunculaceae, Menispermaceae, Fumariaceae, Rutaceae, and Annonaceae. Poppy alkaloids, derived from Papaver somniferum, belong to the isoquinoline alkaloids. Isoquinoline alkaloids have a variety of biological activities, including antitumor, antibacterial, analgesic, immune regulation, antiplatelet aggregation, anti-arrhythmia, and antihypertensive effect. Foods containing isoquinoline alkaloids include opium poppy (Papaver somniferum) and lotus (Nelumbo nucifera). 5.1 Opium Poppy (Papaver somniferum) Papaver somniferum, commonly known as the opium poppy or bread seed poppy, is a species of ﬂowering plant in the family Papaveraceae. In 2016, the worldwide production of poppy seeds was 92,610 tons. The Czech Republic occupied 31% of the total, followed by Turkey and Spain. Alkaloids in Diet 17 Fig. 5 Structures of some representative isoquinoline alkaloids in the plant-derived food Isoquinoline alkaloids occur in the latex of opium poppy. The latex of immature capsules is called opium, which is released by incisions and dried on the capsule surface. Opium contains approximately 20–25% alkaloids. Till now, around 50 isoquinoline alkaloids have been isolated from opium. The main alkaloids of opium are morphine (depending on origin 7–20%), codeine (0.3–6%), and thebaine (0.2–1%) (Fig. 5). The seeds of opium poppy are the only part of the plant used as food. The alkaloid content in seeds varies greatly. Morphine (

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