Abrin

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Abrin a ( Abrus precatorius )
Abrin a (Abrus precatorius)
Structural model according to PDB  1abr . The A chain is highlighted in blue, the B chain in olive

Existing structural data : 1abr

Mass / length primary structure 518 = 251 + 267 amino acids (A + B)
Secondary to quaternary structure A + B chain
Identifier
External IDs
Enzyme classification
EC, category 3.2.2.22 ,  glycosidase
Response type Hydrolysis of an N-glycosidic bond
Substrate 28S rRNA
Products defective ribosome

Abrin is a vegetable toxin from the paternoster pea (also: Abrus bean , Abrus precatorius ) and is one of the deadliest poisons of all. The lethal dose is estimated at about 0.1 to 1000 µg / kg body weight, depending on the route of administration. Chemically, Abrin is a lectin and is related to the ricin of the miracle tree. Abrin is an inhibitor of protein synthesis .

Occurrence

Paternoster pea seeds (red), source of abrin

The toxin abrin is naturally produced exclusively by the paternoster pea. The seeds of the paternoster peas contain 0.08% abrin. The toxin is inside the seeds and is protected from being released by the seed coat. If the seed coat is injured or destroyed (e.g. by chewing), the toxin contained in the seeds can be released.

Extraction

Various methods have been described in the literature for isolating abrin. In general, they are based on an aqueous extraction of the protein in an acidic pH range followed by various purification steps. Foreign proteins can be separated off with the aid of affinity chromatography on Sepharose 4B. Ion exchange chromatography or centrifugation in a sucrose gradient are suitable for separating the abrus agglutinins . The yield is limited due to the low content of abrin in the seeds.

The toxic principle of abrin, the A chain of abrin a, can be produced biotechnologically with the help of genetically modified E. coli bacteria .

biochemistry

Biochemical properties

Comparison of ricin (shades of blue) and abrin (shades of red). The two proteins are very similar.

In isolated and purified form, Abrin is a white to brownish-yellow powder. It is soluble in water and sensitive to heat.

Chemically, Abrin is a mixture of substances that can be further subdivided into the four isotoxins (Abrin a, b, c and d). Occasionally, the biochemically completely different and nontoxic abruz hemagglutinin is also recorded as the fifth protein under the collective name of abrin.

Abrin a is the most potent of the four toxic proteins. It is encoded by an intron-free gene . The primary product of protein biosynthesis, preproabrin, consists of a signal peptide sequence, the amino acid sequences for subunits A and B and a linker. The abrin-a molecule, which consists of 528 amino acids and is about 65 kDa in size , is formed in the endoplasmic reticulum (ER) after cleavage of a signal peptide sequence and post-translational modifications such as glycosylation and disulfide bridge formation. In its structure, Abrin a is related to the ricin of the miracle tree.

toxicology

Symptoms of intoxication are diarrhea , vomiting , colic , tachycardia (accelerated pulse) and tremor (shaking). Death occurs after days from kidney failure , heart failure and / or respiratory paralysis .

toxicity

The toxicity of Abrin depends on the route of administration. There is no consensus on the level of the lethal dose in humans after oral ingestion. It is assumed that the consumption of 0.1 to 1 µg / kg body weight or the consumption of a single seed of the paternoster pea can be fatal, but this information has not been adequately proven. According to other estimates, the LD 50 value is between 10 and 1000 µg / kg and is comparable to that of ricin.

Abrin is significantly more toxic after intravenous administration. The LD 50 values determined in animal experiments vary, depending on the species, between 0.03 and 0.06 µg / kg in rabbits and 1.25 to 1.3 µg / kg in dogs. In clinical studies in cancer patients, up to 0.3 µg / kg IV of an abrin immunotoxin was tolerated without serious toxic symptoms.

The toxicity of abrin after inhalation is also relevant . In rats, the LD 50 for this route of exposure is 3.3 µg / kg. In contrast, there is no evidence of toxicity after skin contact.

Mode of action (toxicodynamics)

In its mode of action, Abrin is similar to ricin. Like ricin, abrin belongs to the group of ribosome inactivating proteins (RIP) of type 2 (RIP-II). Its toxic effect is due to a multi-stage process, which includes cell binding, transport through the cell, activation in the endoplasmic reticulum (ER) and ultimately a fatal inhibition of protein synthesis. Compared to ricin, abrin is the more potent protein biosynthesis-inhibiting substance.

The B-chain of the abrin, which functions as a haptomer , enables unspecific binding to glycoprotein on the cell surface. In addition, Abrin can specifically bind to cells that carry the mannose receptor. Since this receptor occurs in particularly high density on cells of the reticulohistiocytic system , this system in particular is affected by the toxicity of the abrin. Both the specific and the unspecific binding lead to an uptake of abrin into the cell by endocytosis , combined with a transport from the cell membrane into the endoplasmic reticulum (ER) and an activation of the A chain by splitting off the B chain. The activated A-chain of the abrin, the effectomer , which is absorbed into the cell , inhibits protein synthesis by cleaving an adenine (A4324) of the 28S rRNA of the ribosomes .

Toxicokinetics

Little and sometimes controversial information is available on the toxicokinetics of abrin. Due to its biochemical properties and its similarity to ricin, it is assumed that abrin is at least partially broken down in the gastrointestinal tract . The size of the molecules also restricts absorption through the gastrointestinal tract. Nevertheless, the numerous deaths after consuming paternoster pea seeds confirm that at least a small part of the toxin can be absorbed into the systemic circulation via the gastrointestinal tract.

Animal studies on mice show an accumulation of abrin after injection in the liver , kidneys , spleen , blood cells, lungs and heart . Excretion takes place after proteolytic cleavage via the kidneys and the urine.

use

Medical application

Various parts of the plant, including the seeds, of the paternoster pea are used in traditional Ayurvedic medicine . In addition, abrin, as a free toxin or as an immunotoxin in complex with an antibody , at least under experimental conditions, has an anti-tumor effect on various forms of cancer.

Potential use as a bioweapon

Due to its high toxicity and the possibility of processing it into an aerosol, it is in principle possible to use Abrin as a biological weapon. On the other hand, there is the low yield, which excludes a larger investment. Abrin is classified in the US as a so-called Selected Agent , a substance with a potential danger to public safety and health. In Germany, unlike ricin, Abrin is not subject to the War Weapons Control Act .

Individual evidence

  1. ↑ a b c d e f Dickers KJ, Bradberry SM, Rice P, Griffiths GD, Vale JA: Abrin poisoning . In: Toxicol Rev . 22, No. 3, 2003, pp. 137-42. PMID 15181663 .
  2. ↑ a b Johnson RC, Zhou Y, Jain R, Lemire SW, Fox S, Sabourin P, Barr JR: Quantification of L-abrine in human and rat urine: a biomarker for the toxin abrin . In: J Anal Toxicol . 2, pp. 77-84. PMID 19239732 .
  3. ↑ Olsnes S: Toxic and nontoxic lectins from Abrus precatorius . In: Meth. Enzymol. . 50, 1978, pp. 323-30. PMID 661585 .
  4. ↑ Olsnes S: Abrin and ricin: structure and mechanism of action of two toxic lectins . In: Bull Inst Pasteur . 74, 1976, pp. 85-99.
  5. ↑ Lin JY, Lee TC, Hu ST, Tung TC: Isolation of four isotoxic proteins and one agglutinin from jequiriti bean (Abrus precatorius) . In: Toxicon . 19, No. 1, 1981, pp. 41-51. PMID 7222088 .
  6. ↑ Hung CH, Lee MC, Chen JK, Lin JY: Cloning and expression of three abrin A-chains and their mutants derived by site-specific mutagenesis in Escherichia coli . In: Eur J Biochem . 219, No. 1-2, 1994, pp. 83-87. PMID 8307038 .
  7. ↑ Fodstad O, Johannessen JV, Schjerven L, Pihl A: Toxicity of abrin and ricin in mice and dogs . In: J Toxicol Environ Health . 5, No. 6, 1979, pp. 1073-1084. PMID 529341 .
  8. ↑ Griffiths GD, Rice P, Allenby AC, et al .: Inhalation toxicology and histopathology of ricin and abrin toxins . In: Inhal Toxicol . 7, 1995, pp. 269-288.
  9. ↑ Griffiths GD, Lindsay CD, Upshall DG: Examination of the toxicity of several protein toxins of plant origin using bovine pulmonary endothelial cells . In: Toxicology . 90, No. 1-2, May 1994, pp. 11-27. PMID 8023336 .
  10. ↑ Lin JY, Kao CL, Tung TC: Study on the effect of tryptic digestion on the toxicity of abrin . In: Taiwan Yi Xue Hui Za Zhi . 69, No. 2, 1970, pp. 61-63. PMID 5270832 .
  11. ↑ Fodstad Ø, Olsnes S, Pihl A: Toxicity, distribution and elimination of the cancerostatic lectins abrin and ricin after parenteral injection into mice . In: Br J Cancer . 34, 1976, pp. 418-425.
  12. ↑ CP Khare (Ed.): Indian Herbal Remediess: Rational Western Therapy, Ayurvedic, and Other Traditional Usage, Botany . Springer, 2004, ISBN 540010262, pp. 4-5.
  13. ^ Pastan I, Kreitman RJ: Immunotoxins for targeted cancer therapy . In: Adv Drug Deliv Rev . 31, No. 1-2, April 1998, pp. 53-88. PMID 10837618 .

Web links

Wiktionary: Abrin  - explanations of meanings, word origins, synonyms, translations