Aberrations in cells

Pyrrolizidine alkaloids are toxic to foreign organisms (Figure 89). This problem was largely studied in the i960s-1980s493'494'495'49M97'49M99-5()(). Serious livestock poisoning episodes are mentioned in literature from the effects of the pyrrolizidine alkaloid of the Senecio genus especially Senecio riddellii, Senecio douglasii and Senecio jacobaea411. The toxicity of pyrrolizidine alkaloids to livestock was considered coincidental. Johnson and Molyneux501 and Johnson et al.502 have stated that experimental feedings of pyrrolizidine alkaloids to cattle empirically proved that the threshold level of ingesting alkaloids must be excessive for toxicity to occur. On the other hand, there are also known cases of animal poisoning from pyrrolizidine alkaloids found in Cynoglossum officinale (Boraginaceae). Baker et al.503 have reported cases of calves being poisoned, and Knight et al.504 connected the deaths of two horses to poisoning by pyrrolizidine alkaloids. The acute toxicity of these alkaloids varies widely; it is recognized by the International Programme on Chemical Safety (IPCS) that for rats the LD50 of most alkaloids is 34-300 mg kg-1 475. Lasiocarpine doses equivalent to 0.2mgkg-1 body weight per day lead to the development

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1 Acobine

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4 Lasiocarpine

5 Lasiocarpine N-oxide

6 Monocrotaline

7 Retrorsine

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8 Retrorsine N-oxide

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5 6 7 8 Pyrrolizidine alkaloids

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Figure 89. Acute toxicity (LD50) of some pyrrolizidine alkaloids in male rats. (Sources: Refs [472, 473, 474, 475]).

of tumours in rats. For pigs, 1.8mgkg-1 doses cause chronic liver damage. For humans, the lowest reported intake level causing veno-occlusive disease (VOD) is estimated to be 0.015 mgkg-1 body weight per day475. Some pyrrolizidine alkaloids are thought to cause lung damage, affect blood pressure and lead to secondary effects of the functioning of the right side of the heart. Moreover, according to the WHO data, pyrrolizidine alkaloids produce chromosomal aberrations in mammalian cells. Some pyrrolizidine alkaloids and their N-oxides are active as tumour inhibitors500. They also can induce genetic changes and produce cancer in the livers of rats. The toxic effects of these alkaloids can be acute or chronic. Toxicity laboratory trials with retrorsine reported by White et al.505 resulted in centrilobular necrosis in rats, mice and guinea pigs, periportal necrosis in hamsters and focal necrosis in fowl and in monkeys. Even in the 1940s, Wakim et al.506 reported that senecionine produces necrosis in the periportal and midzonal areas of liver lobules. Later, Dueker et al.453 studied monocrotaline metabolism using rat and guinea pig hepatic microsomes. These results suggest that guinea pigs are resistant to pyrrolizidine alkaloid toxicity. Esterase hydrolysis was observed in the metabolism of the guinea pig, and in the case of rats, there was no esterase activity. This explains the guinea pig's resistance to pyrrolizidine alkaloid toxicity. Monocrotaline was also researched by Vaszar et al.459 Their results showed statistically significant increases in proteases in rats as a result of the activity of this alkaloid toxin. Moreover, Smith et al.458 have researched pyrrolizidine alkaloid toxicity in horses. They concluded that these alkaloids led to chronic active hepatitis and furthermore chronic heart damage, including right ventricular hypertropy as a consequence of pyrrolizidine lung damage. However, it is important to note that pyrrolizidine alkaloid toxicity depends on alkaloid structure and its possible reduction. The mechanism of toxic activity of these alkaloids is connected to metabolism in the parenchymal cells, where pyrrolizidine alkaloids change to pyrroles acting on hepatocytes and blood vessels in the liver or lungs. McLean507 reported that as a consequence of this, disaggregation of polyribosomes, absence of pyruvate oxidation and lysosomal activity and necrosis occur. It is important to note that pyrrolizidine alkaloids are inactive as a cell poison by themselves.

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