Amygdalin

Amygdalin (vitamin B17) derived from the seeds of a variety of plants reduced atherosclerosis in Apo E−/− mice and increased regulatory T cells and expression of IL-10 and TGF-β (Jiagang et al., 2011).

From: The Autoimmune Diseases (Fifth Edition), 2014

A worldwide yearly survey of new data and trends in adverse drug reactions and interactions

M.H. Pittler, E. Ernst, in Side Effects of Drugs Annual, 2008

Drug–drug interactions

An interaction of amygdalin with vitamin C has been suggested.

A 68-year-old woman with cancer became comatose, with a reduced Glasgow Coma Score, seizures, and severe lactic acidosis, requiring intubation and ventilation shortly after taking amygdalin 3 g (46A). She also took vitamin C 4800 mg/day. She responded rapidly to hydroxocobalamin. The adverse drug reaction was rated probable on the Naranjo probability scale.

Vitamin C increases the in vitro conversion of amygdalin to cyanide and reduces body stores of cysteine, which detoxifies cyanide; the authors suggested that this was a plausible explanation for this adverse event.

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Toxic Neuropathies

Patrick M. Grogan, Jonathan S. Katz, in Clinical Neurotoxicology, 2009

Amygdalin Neuropathy

The cyanogenic glycoside, amygdalin, is found in several plant sources, particularly in the seeds of apples, pears, and members of the Prunus species (apricots, plums, peaches, etc.).97 Amygdalin is converted into hydrogen cyanide after ingestion and may induce cyanide toxicity. Reported neurological complications of cyanide toxicity include peripheral nerve demyelination, optic neuropathy, deafness, and parkinsonism.97 Because these fruit seeds are uncommon in Western diets, clinical cyanide toxicity is rarely seen. The increased popularity of herbal medicines, however, may change this.

Recently, two cases were reported of a subacute polyneuropathy in young, otherwise healthy individuals who took no medications other than daily herbal “supplements”—apricot kernels in one and “taoren,” or peach seeds, in the other.98,99 Both noted gradual, slowly progressive sensory loss and mild weakness involving the distal extremities symmetrically several weeks after seed ingestion began. Burning dysesthesias were reported by one.98 Deep tendon reflexes were diffusely reduced. Electrophysiological studies revealed a mixed sensorimotor polyneuropathy with diffusely reduced amplitudes. Conduction velocities were normal, but distal motor latencies were prolonged and the terminal latency index was reduced in one.98 Laboratory workup for other causes of peripheral neuropathy was normal except for reduced vitamin B12 levels in one.99 This latter finding was considered unrelated because no concomitant evidence of subacute combined degeneration or macrocytosis was present. Symptoms gradually improved after discontinuation of herbal supplements without residual neurological sequelae.

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Toxicology and Human Environments

Ernest Hodgson, in Progress in Molecular Biology and Translational Science, 2012

2.5.13 Prunus species

Members of the genus Prunus contain amygdalin, a cyanogenic diglucoside, d-mandelonitrile-beta-d-gentiobioside,9 usually in the kernels of the pits. Prunasin is the hydrolysis product of d-mandelonitrile-beta-d-glucoside. Prunus species include P. armeniaca (apricot), P. dulcis (bitter almond), P. persica (peach), P. serotina (black or wild cherry), and P. virginiana v. melanocarpa (choke cherry). Amygdalin becomes dangerous when hydrolyzed by emulsin in the crushed seed or by some human gut microorganisms to yield cyanide. Laetrile, a purported cancer cure, is largely amygdalin. Amygdalin [(6-O-β-d-glucopyranosyl-β-d-glucopyranosyl)oxy]benzenacetonitrile (Fig. 14.4)9 is a cyanogenic glycoside occurring in seeds, principally in bitter almonds and peach and apricot pits. It has been promoted as a treatment for cancer, but controlled clinical trials have repeatedly failed to confirm such claims. Its toxic actions are those that can be ascribed to cyanide as the cyanide released on hydrolysis inhibits cellular respiration by binding to the trivalent iron of cytochrome oxidase in mitochondria, blocking oxygen utilization and resulting in cytotoxic hypoxia.2

Figure 14.4. Less acutely toxic plant toxins: some representative examples.

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Herbal glycosides in healthcare

Benito Soto-Blanco, in Herbal Biomolecules in Healthcare Applications, 2022

12.5.2 Toxicity

The therapeutic use of amygdalin or laetrile may cause potentially fatal cyanide poisoning, mainly after oral administration [124,130,131]. Intravenous administration of amygdalin results in a minimal increase in plasma cyanide and thiocyanate levels [132–134]. The mean lethal dose (LD50) of amygdalin in mice and rats was estimated at 25 g/kg after intravenous injection, but only 0.8–0.9 g/kg after intragastric administration [125].

Cyanide inhibits the action of cytochrome c oxidase, the terminal enzyme of the mitochondrial respiratory chain, reacting with the iron ion in the trivalent form (Fe3+) from cytochrome c oxidase, forming the complex cytochrome oxidase-CN. This complex maintains the iron in the trivalent form, impeding the electron transport system and the respiratory chain. The blockage of the mitochondrial respiratory chain results in cytotoxic hypoxia and anoxia. Furthermore, other metalloenzymes are inhibited by cyanide but demonstrate less toxicological importance [119,135].

The nutritional status of the patient influences the risk of cyanogenic glycoside poisoning. Dietary supplementation with vitamin C appears to augment the risk of poisoning. This vitamin improves cyanide release from cyanogenic glycoside and reduces cysteine levels in the body, resulting in the cyanide detoxification reaction [136–138]. Dietary vitamin B12 deficiency also increases the risk of cyanide poisoning [139]. Reportedly, hydroxocobalamin combines with cyanide-forming cyanocobalamin, both physiologically active chemical forms of vitamin B12 [140]. The insufficient consumption of sulfur-containing amino acids was found to be responsible for reducing the organism’s cyanide detoxification capacity. Moreover, some individuals might present a genetically determined low synthesis of cyanide-detoxifying enzymes [141].

Prolonged cyanide ingestion has been linked to hypothyroidism, nervous disorders, and reproductive disturbances. Thiocyanate, the principal product of cyanide detoxification, impairs thyroid function and causes hypothyroidism. This ion competes with iodine in the sodium iodide symporter, reducing iodine uptake by thyroid follicular cells. Consequently, thyroid hormone production is impaired [119]. Experimental studies in animals revealed that cyanogenic glycosides and cyanide caused mild degeneration of hepatocytes [128,142–146] and renal tubular epithelial cells [142,145].

Cyanide-induced nervous disorders may be attributed to the increased release of free radicals and inhibition of antioxidant enzymes, resulting in lipid peroxidation and cell damage [119,147]. Furthermore, this ion is known to activate the N-methyl-d-aspartate (NMDA) receptor [119,147,148]. Tropical ataxic neuropathy [149,150] and Konzo (spastic epidemic paraparesis) [150,151] are two nervous diseases associated with the prolonged consumption of poorly detoxified cassava as part of a low protein diet. The main clinical signs of tropical ataxic neuropathy include myelopathy, bilateral optic atrophy, polyneuropathy, and bilateral hearing impairment. Patients with Konzo are known to demonstrate a sudden onset of spastic paraparesis.

In addition, the reproductive toxic effects have been associated with exposure to cyanogenic glycosides. The testes of mice administered amygdalin (200 mg/kg) for four weeks presented inflammation, vacuolar degeneration of Sertoli and spermatogenic cells, and necrosis of Leydig cells [128]. Furthermore, laetrile was found to induce fetal malformations in experimental rodents [152]. A similar finding has been attributed to linamarin, a cyanogenic glycoside present in cassava [153]. Conversely, amygdalin showed no genotoxic effect on human peripheral blood lymphocytes [129]. Cyanide administration to pregnant animals did not induce any fetal malformation but promoted lesions in the liver, thyroid glands, and central nervous system of the offspring [154–156]. Furthermore, cyanide was found to induce vascular lesions in the goat placenta [156]. Cyanide [157] and its detoxification product thiocyanate [157,158] can be excreted into milk, representing a toxicological risk to infants.

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Cyanide Toxicity and its Treatment

Rahul Bhattacharya, Swaran J.S. Flora, in Handbook of Toxicology of Chemical Warfare Agents (Second Edition), 2015

Drugs

Cyanide is a metabolic product of amygdalin (Laetrile®) that was introduced as an anti-neoplastic agent in the 1950s and was responsible for several cyanide poisoning cases (Hall et al., 1986; Bromley et al., 2005). Intestinal beta-d-glucosidase digests the amygdalin, releasing HCN. Also, iatrogenic exposure to cyanide may result after the use of sodium nitroprusside, an anti-hypertensive agent (Vesey and Cole, 1985), and succinonitrile, an anti-depressant (Ryan, 1998). Sodium nitroprusside is used medicinally as Nipride®, and its intravenous infusion is used to lower blood pressure in hypertensive emergencies. This application of sodium nitroprusside occasionally causes classical cyanide toxicity (Kurt, 1983). Death caused by mercuric cyanide or mercuric oxycyanide poisoning was reported because of possible ingestion of an antiseptic or a hair lotion commercialized in France (Labat et al., 2004).

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Complementary and Alternative Medicine

Jeffrey D. White, in Abeloff's Clinical Oncology (Fifth Edition), 2014

Laetrile

Laetrile, also known as amygdalin, is a cyanogenic glucoside found in the pits of many fruits, in raw nuts, and in other plants such as lima beans, clover, and sorghum.28,29 Although it is frequently called vitamin B17 in the lay literature, amygdalin is not recognized as a vitamin by the Committee on Nomenclature of the American Institute of Nutrition. Laetrile has been given orally and intravenously with different pharmacokinetics and toxicity profiles. Laetrile became a popular alternative cancer therapy in the 1950s and remained so through the 1980s. Currently, its sale in the United States is banned by the FDA; however, products labeled as containing laetrile can easily be purchased via the Internet. When orally ingested, laetrile can be hydrolyzed by intestinal beta-glucosidase to produce hydrogen cyanide, benzaldehyde, and glucose. The enzymatic activity of beta-glucosidase, and thus the rate of production of cyanide, can be increased under various conditions, including the presence of vitamin C.30 Signs and symptoms of cyanide poisoning have been reported both from individual patients with cancer who ingested products containing laetrile31,32 and from patients enrolled in clinical trials of oral laetrile.33,34

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Subgingival Microbes

In Atlas of Oral Microbiology, 2015

4.2.2 Capnocytophaga

Capnocytophaga are gram-negative, facultative anaerobic bacteria. They were the earliest bacteria to be isolated and named from the human subgingival plaque. Common Capnocytophaga species are: Capnocytophaga ochracer, Capnocytophaga sputigena, Capnocytophaga gingivalis, Capnocytophaga granulose, and Capnocytophaga heamolytica.

Capnocytophaga cells are 0.42–0.6 μm × 2.5–2.7 μm in size and shaped like bent rods or filaments, usually with rounded or slightly pointed ends. The length of the cells varies. In liquid culture, cells are polymorphic or take on a long, filamentous morphology, and tight clumps can be observed. The bacteria produce no capsule and no sheath. They do not form spores, have no flagella, but have sliding motility.

Capnocytophaga are facultative anaerobes but do not grow under aerobic conditions. Cultures grow well in a CO2-added anaerobic environment. Primary cultures should be performed in an aerobic environment with CO2 added.

Species in this genus often form colonies of wet, thin, flat, diffuse growth with ragged edges on TS blood agar and BHI blood agar. After 24 h incubation at 35–37 °C, the size of colonies are like pinpricks. After incubation for 48–96 h, colonies become 2–4 mm in diameter and take on the appearance of bumps. Some colonies may become recessed into the agar. Aside from hemolytic Capnocytophaga (which produces β-hemolysis), other species are not hemolytic on blood agar. The concentration of agar in the medium affects the force of sliding motility. Capnocytophaga cultures can produce a special smell, similar to caramel or a bitter almond flavor.

Colonies on the agar surface can produce white to pink or orange-yellow pigmentation. Centrifuged cells appear to be an orange-yellow clump.

Capnocytophaga do not produce indole, can ferment glucose, lactose, maltose, mannose, and sucrose acid, and do not ferment mannitol and xylose. They can hydrolyze esculin and test negative for catalase and oxidase, while testing positive for ONPG and benzidine. Nitrate reduction, dextran hydrolysis, starch or gelatin hydrolysis and other biochemical tests can help identify this genus of bacteria.

A member of the normal microflora of humans and primates, this genus is mainly found to colonize the oral cavity. They are common oral bacteria and can be obtained from various parts of the oral cavity, including plaque, gingival sulcus, saliva and sputum, and throat specimens. These bacteria are often detected in mixed bacterial infections, such as juvenile periodontitis, infected root canal, dry socket after tooth extraction, oral ulcers, and other clinical specimens, and can also be isolated from bacteremia, soft tissue infections, injuries and abscesses at various locations, cerebrospinal fluid, vaginal, cervical, and amniotic fluid, trachea, and eyes.

The GC content of Capnocytophaga genomic DNA is 33–41% (by Tm method). The type species is yellowish Capnocytophaga.

4.2.2.1 Capnocytophaga gingivalis

This gram-negative bacterium is shown in Figure 4.7(A), (B), and (C). Characteristic colonies are shown in Figure 4.7(D) and (E).

Figure 4.7. (A) Cells of C. gingivalis (Gram stain). (B) Cells of C. gingivalis (SEM). (C) Cells of C. gingivalis (SEM). Cells of C. gingivalis are fusobacterium-shaped, and the ends are usually rounded. Cells are often arranged in an orderly manner and stain negative by Gram stain. (D) Colonies of C. gingivalis (BHI blood agar). (E) Colonies of C. gingivalis (stereomicroscope). Colonies of C. gingivalis on BHI blood agar are irregular, gray colonies, with ragged edges. Typical hair-like diffuse colonies can be seen under the stereomicroscope.

C. gingvalis does not ferment lactose, galactose, amygdalin, salicin, cellobiose, esculin, and glycogen. It also does not hydrolyze starch, dextran, and gelatin. Only 8% of the strains can reduce nitrate.

The GC content in C. gingivalis DNA is 40% (by method). The type strain is ATCC33624.

4.2.2.2 Capnocytophaga sputigena

This species is a gram-negative bacillus (Figure 4.8(A), (B), and (C)). Characteristic colonies are shown in Figure 4.8(D) and (E).

Figure 4.8. (A) Cells of C. sputigena (Gram stain). (B) Cells of C. sputigena (SEM). (C) Cells of C. sputigena (SEM). Cells of C. sputigena are bent bacilli, usually with rounded ends. They produce no spores and stain gram-negative. (D) Colonies of C. sputigena (BHI blood agar). (E) Mesh-like structure on the surface of colonies of C. sputigena (stereomicroscope). Colonies of C. sputigena on BHI blood agar surface are flat, spread orange colonies. Typical hair-like diffuse structure can be seen under the stereomicroscope.

The cells can ferment lactose, glucose, maltose, and sucrose but do not ferment mannitol, cellobiose, glycogen, and xylose. C. sputigena does not hydrolyze starch and dextran. The hydrolysis of gelatin and nitrate reduction are the most important features by which this species can be distinguished from other members of the genus. C. sputigena may be involved in juvenile periodontitis.

The GC content of C. sputigena DNA is 33–38% (Tm method). The type strain is ATCC33612.

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PLANT ANTINUTRITIONAL FACTORS | Characteristics

G.D. Hill, in Encyclopedia of Food Sciences and Nutrition (Second Edition), 2003

Compounds responsible

The compounds responsible vary with plant species. However, the major cyanogens are amygdalin and prunasin, which are found in fruit kernels. The latter also occurs in bracken fern (Pteridium aquilinum), dhurrin, found in members of the genus Sorghum and linamarin, found in clovers, linseed, cassava, and lima beans (Phaseolus lunatus). Cassava root contains relatively low levels at 53 mg of CN per 100 g of plant tissue. Sorghum forage contains 250 mg of CN per 100 g of plant tissue and lima beans up to 300 mg of CN per 100 g of plant tissue.

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Cyanide

S.A. Burr, Y.L. Leung, in Encyclopedia of Toxicology (Third Edition), 2014

Background

Cyanide is found naturally as cyanogenic glycosides as a defense against consumption in the seeds of several plants. Amygdalin in bitter almonds forms hydrogen cyanide (HCN) when in contact with emulsion in saliva. The bitter taste usually prevents a dangerous dose (10–20 bitter almonds could be fatal if eaten raw). Similarly, fruit of the Prunus genus in the rose family, such as apples, apricots, cherries, peaches, and plums, contain prunasin. Taxiphyllin is found in immature bamboo shoots. Linamarin and lotaustralin are particularly concentrated in the skin of both cassava and lima beans, while sorghum roots are rich in dhurrin, as a defense against insects such as rootworm. Other exposures are through industrial manufacturing and use of HCN and its salts. Cyanide poisoning can be treated with several antidotes, with differing mechanisms of action and diverse toxicological, clinical, and risk–benefit profiles. Depending on the type of exposure, Cyanokit (hydroxocobalmin) or the Cyanide Antidote Kit (amyl nitrite pearls administered by inhalation; sodium nitrite and sodium thiosulfate administered by infusion) can be used.

Historically, Zyklon B (40% HCN dissolved onto calcium sulfate) was devised by Fritz Haber 20 years prior to World War II and was initially used for parasite control in buildings. Zyklon B was eventually used by the Nazis as their preferred method for the extermination of over 5 million people sent to concentration camps. Thus cyanide has been used to assassinate more people than any other single toxin. Cyanide was also the method of death for the largest mass suicide in modern history: Jim Jones’ religious cult moved to Guyana and established the Peoples Temple of Jonestown. In 1978, 909 cult members (276 of whom were children) died on the same day by either swallowing or injecting a mixture of valium (anxiolytic), chloral hydrate (sedative), and cyanide.

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Plants, Poisonous (Humans)

M. Banasik, T. Stedeford, in Encyclopedia of Toxicology (Third Edition), 2014

Cellular Respiration Toxins

Scientific Name: Malus spp.

Common Name: Apple tree(s)

Toxins: The primary toxin is amygdalin, a cyanogenic glycoside, which is located in the seeds.

Chemical Abstracts Service Registry Number: 29883-15-6

Molecular Formula: C20H27NO11

Chemical Structure:

Mechanism of Action: Cyanide binds to the ferric form of cytochrome oxidase, which blocks cellular respiration.

Effects: The seeds must be chewed to release amygdalin, which is hydrolyzed in the gastrointestinal tract to release cyanide. Consumption of a large number of chewed seeds may cause abdominal pain, sweating, convulsions, and cardiovascular collapse.

Scientific Name: Manihot esculenta

Common Names: Cassava, Manioc

Toxins: The primary toxins are the cyanogenic glycosides linamarin and lotaustralin, which are concentrated in the roots.

Chemical Abstracts Service Registry Numbers: 554-35-8 (linamarin); 534-67-8 (lotaustralin)

Molecular Formulas: C10H17NO6 (linamarin); C11H19NO6 (lotaustralin)

Chemical Structures:

Mechanism of Action: Cyanide binds to the ferric form’of cytochrome oxidase, which blocks cellular respiration.

Effects: Ingestion occurs primarily through consumption of improperly processed cassava root. As with amygdalin, linamarin and lotaustralin require hydrolysis in the gastrointestinal tract to release cyanide. Consumption of improperly processed cassava root may cause abdominal pain, sweating, convulsions, and cardiovascular collapse.

Scientific Name: Prunus spp.

Common Name: Apricot tree(s)

Toxin: The primary toxin is amygdalin, which is located in the apricot pit.

Chemical Abstracts Service Registry Number: See Malus’spp.

Molecular Formula: See Malus spp.

Chemical Structure: See Malus spp.

Mechanism of Action: See Malus spp.

Effects: The pits must be crushed or pulverized to release amygdalin. Consumption may cause abdominal pain, sweating, convulsions, and cardiovascular collapse.

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