Ricin toxicity

[unigirl]

I'm having problems sourcing data on the toxicity levels of ricin in the mammalian body. The species are unimportant as long as they are mammals. Can anyone help please?

Also, can I have a detailed explanation of why ricin is so toxic to mammals.

Thanks

[unigirl]

Oops should have said that LD figures are what I need ideally.

[theprof]

Taking the first part of your question first, the oral LDLo for humans is about 2 mg kg-1
Rat LDLo oral is 100 mg kg-1 . LC50 inhalation figures for mouse is 9 mg m-3, dog and rat 24-50 mg m-3 and monkey 100 mg m-3 . LD50 intraperitoneal rat 1.5-2 mg kg-1 LD100 intraperitoneal mouse 25 mg kg-1 LD50 subcutaneous mouse 22.1 mg kg-1 LD50 intravenous mouse 2.2 mg kg-1

The maximal tolerated dose seems to be 23 �g/m2 (4), or expressed in a different way, about 40 �g toxin for a human being of 60 kg. The minimal lethal dose for dogs is 1.75 �g/kg, and also a number of other animals have been tested and found to be sensitive to ricin, although to a variable extent. The horse seems to be the most sensitive animal tested so far (lethal dose: 0.1 g intact seed/kg). Fatal dose by intravenous route in laboratory animals is as low as 300 ng kg-1 body weight. As far as the raw beans are concerned, there are documented cases of a fatality in a child who ate 5 castor oil beans and an adult who ate 20 of the beans. Target organs for ricin toxicity are dependent on route of administration as shown by the variation in the figures above; following oral ingestion the gastro-intestinal tract is most severely affected; after parenteral administration it is preferentially distributed to the liver spleen and muscle

[theprof]

As for the mechanism of action, I�ll split the answer into two as I think it might give you a better understanding of the principles involved.

In simple terms, the toxin consists of two polypeptide chains (A and B) connected by a disulfide bond). The B-chain mediates binding to the cell surface, whereas the A-chain inhibits protein synthesis enzymatically after entry into the cytosol The toxin acts by removing one adenine from the 28SRNA of the 60 S ribosomal subunit. Due to the high enzymatic activity of the A-chain, an efficient entry mechanism into cells, and the resistance of the toxin to proteolytic enzymes, ricin is extremely toxic to humans and animals. Ricin belongs to a group of protein toxins that have one moiety that binds the molecule to cell surface receptors, and another moiety which enters the cytosol and inhibits protein synthesis.

[theprof]

I�ll now try to explain the mechanism of action in more detail (yes, it gets worse!)

In order to exert its cytoxic effect on cells the enzymatically active part of ricin (the A-chain) has to enter the cytosol This occurs after binding of the toxin to cell surface glycoproteins and glycolipids with terminal galactose, endocytosis of the toxin, and retrograde transport of ricin to the trans-Golgi network and the endoplasmic reticulum (ER). Not until the toxin reaches this location does the A-chain translocate to the cytosol.

Experiments with modified ricin molecule have shown that ricin can be sulphated in the trans-Golgi network and glycosylated in the ER, it was recently shown that ricin was glycosylated and the glycosylated form of ricin was translocated to the cytosol). The exact mechanism by which translocation of the A-chain from the ER to the cytosol occurs is not known, but there is evidence for the involvement of Sec61p, the protein translocator that is involved in transport of newly synthesized proteins into the ER, and transport of misfolded proteins from the ER to the cytosol, where they are then ubiquitinylated and degraded by the proteasome. Evidence for the involvement of Sec61p was obtained by coprecipitation with ricin A-chain and from experiments with yeast cells. It is thought that unfolding of the ricin A-chain is required for translocation to occur and the target for the A-chain, the ribosome, may participate in the refolding of the protein.

Incidentally, to summarise you could say that ricin induces hydrolytic fragmentation thereby blocking protein synthesis!

[theprof]

Addendum time. The last sentence should read:

"Incidentally, to summarise you could say that ricin induces hydrolytic fragmentation of ribosomes thereby blocking protein synthesis!"

The fact that Ricin and its other toxic analogues arrest cell protein biosynthesis by inactivating the 60S subunit of ribosomes has led to them becoming known as RIPs - ribosome-inactivating proteins. It's got to be one of my favourite acronyms.