220.127.116.11 a-Aminopropionic acid derivatives a-Aminopropionic acid derivatives occur in peas of certain Lathyrus species. These substances are known to cause skeletal malformations (osteolathyrism) and neurotoxic effects
Table 11.1 Nonnutritive natural food components that have given or still give rise to concern
Main toxic effect(s)
(fatty acid)/rapeseed Cyclopropane and cyclopropene fatty acids/cottonseed oil
Carotatoxin (poly-acetylene)/carrots Thujone (a- and P-) (monoterpene)/spices (component of absinthe liqueur) D-limonene (monoterpene)/ citrus oil
Cucurbitacin E (triterpene)/ squash or zuchini (as glucoside)
Safrole (phenol derivative, occurring in plants)/spices (mainly sassafras oil) Coumarin/various plants
(e.g., woodruff) and spices Quercetin/many plants (free and as glycosides)
Lathyrus odoratus fibrotic myocardial lesions (in the rat) promotion of aflatoxin-
induced carcinogenesis (in the trout)
mutagenicity (in Ames'test; in mammalian test systems mainly negative) skeletal malformations (osteolathyrism) and neurotoxicity (neurolathyrism)
varieties free from erucic acid have been bred the acids are largely removed during food processing; the main problem is their presence in feed low levels in edible carrots absinthe is prohibited; for use as food additive, not more than 10 ppm is allowed. intake is considered to pose no toxicological risks to man rarely present in bitter summer squash; may originate from crossbreeding with a wild species allowed for use as food additive in the EU, prohibited in the US. see above under safrole evaluation needs further research
(neurolathyrism). The peas are easily grown on poor soil and are often used as feed. Both diseases have occurred as epidemic in Northern India in years with a poor harvest. At present, osteolathyrism has largely disappeared. Neurolathyrism still poses a serious health problem.
Neurolathyrism is associated with the long-term intake of the peas of L. sativus. The disease is characterized by muscular weakness, degeneration of spinal motor nerves, and paralysis. The peas have been found to contain a neurotoxin: N-oxalyl-diaminopropionic acid (ODAP). In addition, the peas may be contaminated with a vetch species (Vicia sativa), also containing a neurotoxic a-aminopropionic acid derivative, P-cyano-L-alanine.
The neurotoxicity of the amino acids is attributed to their structural relationship with the neurotransmitter glutamic acid. ODAP and P-cyano-L-alanine are believed to bind irreversibly to the glutamate receptors on specific nerve cells. Long occupation of the glutaminergic receptors has been reported to result in neurodamage.
N - oxalyl - diamino -propionic acid
Agaritine is a member of a series of hydrazine derivatives, occurring in mushrooms, including the common edible mushroom Agaricus bisporus. It is the most important derivative.
Agaritine undergoes degradation on cooking. It is partly left intact when heated in oil. In the body, it is hydrolyzed by glutamyltransferase into glutamic acid and 4-(hydroxymethyl)phenylhydrazine (Figure 11.1). Agaritine has proved to be mutagenic in the Salmonella/mammalian microsome assay. If glutamyltransferase is added, the mutage-nicity increases, suggesting that 4-(hydroxymethyl)phenylhydrazine is a more potent mutagen. Since the 4-(hydroxymethyl) phenyldiazonium ion is highly mutagenic, it is assumed to be the ultimate mutagen. 4-(Hydroxymethyl)phenylhydrazine induces tumors in soft mouse tissues at the injection site. Recently, also in mice, tumors have been found after mushroom feeding. Further studies are needed to confirm this.
4 - (Hydroxymethyl) -phenyl diazonium ion hoch2-
4 - (Hydroxymethyl) -Phenylhydrazine
Figure 11.1 Hydrolysis of agaritine, followed by its activation.
18.104.22.168 Biogenic amines Biogenic amines are formed by decarboxylation of amino acids. The term biogenic amines usually refers to the catecholamine neurotransmitters dopamine, norepinephrine, and epinephrine, the indoleamine neurotransmitter serotonin, and the mediator of inflammation histamine.
Examples of biogenic amines as food components are serotonin in bananas and pineapple, tryptamine in tomatoes, and tyramine in certain kinds of fully mature cheese. The precursor of serotonin is 5-hydroxytryptophan, that of tryptamine, tryptophan, and that of tyramine, tyrosine. Biogenic amines in food can also originate from fermentation (beer, wine, cheese) or bacterial contamination (meat). Tyramine in fermentation products results from the bacterial decarboxylation of tyrosine.
Well-known toxic effects include hypertension, palpitations and severe headache. Under normal conditions, tyramine is detoxicated by monoamine oxidase (MAO). Patients taking MAO-inhibitors as antidepressants may suffer from headache, and attacks of palpitation and hypertension, if they consume foods containing considerable amounts of tyramine.
22.214.171.124 Cyanogenic glycosides Cyanogenic glycosides are monosaccharide or disaccharide conjugates of cyanohydrins. There is evidence that the cyanohydrins are derived from amino acids. Cyanogenic glyco-sides are widely present in plants where they are the principal precursors of hydrocyanic acid. Their presence is believed to provide protection against herbivores.
Representatives of importance identified in edible plants are:
- amygdalin, the gentiobiose conjugate of mandelonitrile. It is present in bitter almonds, apple pips, and kernels of cherries, apricots, and peaches;
- primasin, the D-glucose conjugate of mandelonitrile. It is also found in bitter almonds and other fruit kernels;
- dhurrin, the D-glucose conjugate of p-hydroxybenzaldehyde cyanohydrin. It occurs in sorghum and related grasses;
- linamarin, the D-glucose conjugate of acetone cyanohydrin. It occurs in pulses, linseed, and cassava;
- lotaustralin, the D-glucose conjugate of 2-butanone cyanohydrin. See for its occurrence under linamarin.
Many cases of cyanide poisoning in man after dietary intake have been reported.
The formation of hydrogen cyanide from cyanogenic glycosides in plants takes place via a sequence of enzymic hydrolyses. In a first step, the glycosides are hydrolyzed by P-glycosidases to the cyanohydrins and mono- or disaccharides (see Figure 11.2). The cyanohydrins undergo further hydrolysis by lyases to hydrogen cyanide and the carbonyl compounds involved.
Mandelonitrile hydroxynitrile lyase
Figure 11.2 Hydrolysis of amygdalin.
Hydrolysis of the cyanogens requires tissue disruption, such as crushing of the wet, unheated tissues. The destruction of the compartmental organization of the cells brings the glycosides in contact with the hydrolytic enzymes.
The occasional intake of small amounts of cyanogenic glycosides does not involve danger. The cyanide formed is generally detoxicated by conversion to thiocyanate. This reaction is catalyzed by the sulfurtransferase rhodanase.
Overloading of the detoxication route by taking in large amounts of cyanogenic glycosides can lead to cyanide intoxication. Fatal poisonings of children have been reported as a result of eating 7 to 10 bitter almonds.
In addition, there are the toxicological risks due to chronic consumption of improperly prepared cassava. Damage to the nervous system after chronic intake of cassava in a number of African countries is believed to be a long-term effect of cyanide or, perhaps, of thiocyanate, resulting from insufficient removal of the cyanogen.
126.96.36.199 Glucosinolates Glucosinolates are thioglucosides. They have a sulfur atom between the glucosyl group and the aglycon. Glucosinolates also derive from amino acids.
_ R = a variety of alkane and N — O — SO3 aromatic groupings
Glucosinolates are thyroid agents. Their main effects are hypothyroidism and thyroid enlargement.
The glucosinolates themselves are not the active agents. They need activation by hydrolysis. All thioglucosides of natural origin are associated with enzymes that can hydrolyze them to an aglycone, glucose and bisulfate. The aglycone can undergo intramolecular rearrangements to yield isothiocyanate, nitrile, or thiocyanate (Figure 11.3).
Figure 11.3 Hydrolysis of glucosinolates.
Thiocyanates contribute to the antithyroid activity, isothiocyanates are alkylating agents, and the nitriles have also been found to be toxic. Glucosinolates occur in plants belonging to the Cruciferae. The main food sources are cabbage, broccoli, turnips, rutabaga, and mustard greens. Each cruciferous plant may contain up to 10 different glucosinolates. Major representavies are sinigrin (in the above general structure of glucosinolates, R = allyl), progoitrin (R = 2-hydroxy-3-butenyl) and glucobrassicin (R = 3-indolylmethyl).
Sinigrin occurs in cabbage species and black mustard. Its hydrolysis product, allylisothiocyanate, has been shown to be a mutagen in the Ames' test. Swelling of the throat in rats fed on a diet containing Ethiopian rapeseed has also been attributed to the formation of the reactive metabolite. At high concentrations, allylisothiocyanate acts as lachrymator and vesicant. There are no indications that the present consumption of mustards can lead to the induction of adverse effects.
Progoitrin is a major component of rutabaga and a minor one of cabbage, kale, Brussels sprouts, and cauliflower. As its name indicates, progoitrin is a goitrogen or antithyroid. Two types of reactive metabolites are believed to be responsible for the goitrogenic activity: (2-hydroxy-3-butenyl) isothiocyanate and 5-vinyloxazolidine-2-thione (goitrin). Goitrin is formed from the isothiocyanate in a cyclization reaction (Figure 11.4).
Figure 11.4 Formation of 5-vinyloxazolidine-2-thione.
Oxazolidine-2-thiones inhibit the production of thyroid hormones by preventing the incorporation of iodine in tyrosine.
Glucobrassicin occurs in a variety of cabbage species. Hydrolysis of this glucosinolate results in the formation of a number of products: indole-3-acetonitrile, indole-3-carbinol (I3C) and indole. I3C can cause sedation, ataxia, and sleep. Further, given orally, it is a potent inducer of hepatic as well as intestinal phase I and phase II drug-metabolizing enzymes. On parenteral administration and in isolated hepatocytes, however, it does not induce enzymes. Under the acidic conditions of the stomach, I3C undergoes oligomeriza-tion to yield products such as diindolylmethane. Diindolylmethane is also an enzyme inducer.
Indole - 3 - carbinol
Indole - 3 - carbinol
In some cases, the prevention of cancer has been related to the intake of glucosinolates. The formation of I3C is believed to decrease tumor induction by a variety of carcinogens. Further, feeding of cabbage to experimental animals prior or during the treatment with carcinogens was found to result in inhibition of tumor induction. Cabbage-feeding after administration of the carcinogens led to promotion of carcinogenesis. Probably, the protection against carcinogens is related to a more effective detoxication resulting from enzyme induction.
188.8.131.52 Glycoalkaloids Steroidal alkaloids are mainly present as glycosides in the family of the Solanaceae, including the potato and the tomato. The major glycoalkaloids in potatoes are a-solanine and a-chaconine, both glycosides of solanidine.
Solanine and chaconine are potent irritants of the intestinal mucosa and cholinesterase inhibitors, the first being the most active. Poisoning with either substance results in gastrointestinal and neurological symptoms. The gastrointestinal symptoms can include vomiting and diarrhea, and the neurological symptoms include irritability, confusion, delirium, and respiratory failure, which may ultimately result in death. Further, poisoning is often accompanied by high fever.
gal = galactosyl glu = glucosyl rham = rhamnosyl
In general, the glycoalkaloid contents of potato tubers do not pose adverse effects in humans. Serious poisonings have been reported following the consumption of potatoes with high glycoalkaloid contents (>200 mg/kg). Potatoes that have been exposed to light, and those that are diseased by fungal infection or have been mechanically bruised may contain toxic levels of glycoalkaloids.
Results of epidemiological studies on birth defects in regions with fungous potato disease suggested a relationship between the severity of the fungal infection and the occurrence of spina bifida and anencephaly. In animal studies, teratogenic effects and fetal mortality have been observed at dose levels that caused maternal mortality, either on administration of the pure alkaloids or on feeding with diseased potatoes. As far as testing for teratogenicity is concerned, the WHO Expert Task Group on Updating the Principles for the Safety Assessment of Food Additives and Contaminants in Food stated: "If the test substance injures reproduction or development at levels comparable with levels that cause toxicity in adults, then no special concern should be attached to the results of the reproduction/development toxicity studies." Recently, a Dutch expert, however, added to this statement: "It is advisable that for the selection of new varieties the guideline of about 60-70 mg glycoalkaloids/kg is followed in potato breeding, until an appropriate acceptable level has been set." The major glycoalkoloid in tomatoes is a-tomatidine, with tomatidenol as the aglycone. It is present in all parts of the plant. In the fruit, the concentration decreases during ripening. Poisonings in humans due to the consumption of tomatoes have not been reported.
184.108.40.206 Pyrimidine glycosides For more than a century, a disease caused by the ingestion of fava beans has attracted the attention of toxicologists. The disease, called favism, is characterized by acute hemolysis, in serious cases accompanied by jaundice and hemoglobinuria. It is mainly found in Mediterranean populations with a congenital deficiency of NADPH-dependent glucose-6-phosphate dehydrogenase (G6PD). Fava beans contain two pyrimidine glycosides that have been shown to induce hemolysis: vicine and convicine. The aglycons are divicine and isouramil, respectively.
Divicine and isouramil are powerful reducing agents. In red cells, they are readily oxidized by oxyhemoglobin under the formation of methemoglobin, H2O2, and Heinz bodies (thought to consist of denaturated hemoglobin). The oxidation products undergo reduction by glutathione, and H2O2 is reduced by glutathione peroxidase. The oxidized
Isouramil glutathione produced by these reactions is reduced by NADPH, generated from glucose-6-phosphate and G6PD.
The defect leading to hemolysis lies in the red cells which have insufficient G6PD, i.e., diminished levels of reduced glutathione, to protect them against oxidative attack.
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