Modulation of ricin toxicity in mice by biologically active substances.
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 ricin 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 LD100 of 25 micrograms kg-1 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.
Muldoon
D F
DF
Department of Pharmacology, Creighton University Health Sciences Center, Omaha, NE 68178.
Stohs
S J
SJ
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use*; D003907:Dexamethasone / Q000494:pharmacology / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D000518:Eflornithine / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D007274:Injections, Intraperitoneal; D007928:Lethal Dose 50; D051379:Mice; D009705:Nucleosides / Q000494:pharmacology / Q000627:therapeutic use*; D011041:Poisoning / Q000517:prevention & control; D012276:Ricin / Q000037:antagonists & inhibitors / Q000633:toxicity*; D013997:Time Factors
D000975:Antioxidants; D009705:Nucleosides; D003907:Dexamethasone; D012276:Ricin; D000518:Eflornithine