Ricin is a highly toxic protein produced by the castor bean (Ricinus communis). It is one of various protein toxins that consist of two subunits joined by a disulfide bridge. One chain facilitates entry of the toxin into the cell while the other chain exhibits RNA N-glycosidase activity, which attacks a specific site on 28s rRNA, preventing polypeptide elongation and leading to cell death. Although rich and other protein toxins are potential health hazards, no antidote against these toxins exists. Thus, a number of selected compounds were screened for their ability to alter ricin lethality in mice, based on percentage survival and time to death following a ricin L D , ~ of 25 p g kg--' i.p. While no compound tested prevented lethality, dexamethasone and difluoromethylornithine (DFMO) significantly extended survival time. The effects of DFMO on ricin toxicity were markedly influenced by altering various pharmacokinetic parameters. The antioxidants butylated hydroxyanisole and vitamin E succinate also extended survival time in response to a lethal dose of ricin, but to a lesser extent than did dexamethasone and DFMO. The Golgi apparatus inhibitors monensin, swainsonine and tunicamycin enhanced ricin toxicity, as evidenced by shortened survival times. In addition, various nucleoside analogs, including acyclovir and trifluridine as well as adenosine, guanosine and dibutyryl cyclic AMP, also potentiated the toxicity of ricin. The results demonstrate that the toxicity of ricin is modulated by a wide variety of structurally distinct chemicals and may involve different mechanisms. Furthermore, the extent and direction of the modulation of ricin toxicity is highly dependent upon pharmacokinetic variables, including dose and dosing interval.
~~
MATERIALS AND METHODS
Toxins and chemicals
Ricin stock solution (Ricinus communis toxin, RCAa, Catalog no. L 8508), 2.5 mg ml-', was obtained from Sigma Chemical Co. (St. Louis, MO). This solution was diluted to a final concentration of 2.5 Fg ricin ml-' for administration by intraperitoneal (i.p.) injection. All other chemicals were of the highest grade available and purchased from Sigma Chemical Co.
Animals and treatment
Female CF-1 mice (Sasco Inc., Omaha, NE), weighing 20-25 g at the time of use, were maintained on a 12 h lightldark cycle and allowed free access to Purina Rodent Laboratory Chow (Ralston Purina Co., St.