Ricin: An Ancient Story for a Timeless Plant Toxin

Abstract

The castor plant (Ricinus communis L.) has been known since time immemorial in traditional medicine in the pharmacopeia of Mediterranean and eastern ancient cultures. Moreover, it is still used in folk medicine worldwide. Castor bean has been mainly recommended as anti-inflammatory, anthelmintic, anti-bacterial, laxative, abortifacient, for wounds, ulcers, and many other indications. Many cases of human intoxication occurred accidentally or voluntarily with the ingestion of castor seeds or derivatives. Ricinus toxicity depends on several molecules, among them the most important is ricin, a protein belonging to the family of ribosome-inactivating proteins. Ricin is the most studied of this category of proteins and it is also known to the general public, having been used for several biocrimes. This manuscript intends to give the reader an overview of ricin, focusing on the historical path to the current knowledge on this protein. The main steps of ricin research are here reported, with particular regard to its enzymatic activity, structure, and cytotoxicity. Moreover, we discuss ricin toxicity for animals and humans, as well as the relation between bioterrorism and ricin and its impact on environmental toxicity. Ricin has also been used to develop immunotoxins for the elimination of unwanted cells, mainly cancer cells; some of these immunoconjugates gave promising results in clinical trials but also showed critical limitation.

Keywords: bioterrorism; cancer therapy; castor bean; folk medicine; immunotoxins; plant toxins; rRNA N-glycosylase activity; ribosome-inactivating proteins; ricin; traditional medicine.

Figure 1

The main milestones of ricin research.

Figure 2

(a) Ribbon model of the crystal structure of ricin at 2.5 Å (accession number Protein Data Bank 2AAI). The A chain domains are colored in green, blue, and light blue; the B chain domains are colored in yellow and orange. (b) Catalytic site of ricin. The key residues are indicated and colored in blue, whereas adenine substrate is depicted in red. (c) Proposed mechanism of depurination reaction catalyzed by ricin. The hydrolysis proceeds through a dissociative mechanism forming an oxocarbenium transition state. Arg180 protonates the leaving group and the N-glycosidic bond is broken. Glu177 deprotonates the hydrolytic water (highlighted by a red dotted rectangle) that attacks carbon to complete the depurination reaction. Figure 2a and 2b were produced by PyMOL (version 2.3.1); Figure 2c was produced by ACD/ChemSketch (version 2015.2.5).