TISSUE SPECIFIC TOXICITY

Tissue Specific Toxicity

Tissue Specific Toxicity

Introduction

Ricin pertains to the type II ribosome inactivating proteins which are heterodimeric glycoproteins that comprise a toxophoric A-chain and a lectin B-chain connected simultaneously by a disulfide bond (Endo, 1987a, b; Olsnes, 2004; Stirpe, 2004). The A-chain is moved over the cell membrane by the B-chain via endocytotic vesicles into units (Lord, 1998; Sandvig, 2002; Hartley, 2004; Roberts, 2004).The B chain binds to cell surface carbohydrates encompassing galactose or N-acetylgalactosamine residue which then allows the A-chain to go in the cell.one time interior the cell, the A-chain undergoes retrograde transport by receptor-mediated endocytosis, resulting in the toxin being transported through the Golgi complex into the cytosol after the decrease of the disulphide bond.one time in the cytosol, the A string of links displays RNA N-glycosidase activity and inactivates ribosomes by enzymatically eliminating a exact adenine residue from the 28S RNA of the 60S ribosomal subunit.The adenine residue taken by ricin action is vital for the binding of elongation factors. Aoutcome of the ricin-induced depurination is the cessation of protein synthesis (Olsnes, 1972; Endo, 1987a, b; Lord, 1998; Sandvig, 2002; Hartley, 2004; Roberts, 2004).The clinical latency between exposure and symptoms, ranging between 8 to 24 hours, has been attributed to the transport of the ricin to the central of the cell.

The accurate cause of ricin-induced cell death is unidentified but outcomes from some investigations have shown that, despite of the path of management, ricin A-chain origin organ and tissue lesions that might be the result of vascular disturbances induced by the toxin rather than a direct effect of the toxin itself (Franz, 1997; Howat, 1988).Clinical tests have shown that administration of ricin A-chain immunotoxin initiated vascular syndrome distinuished by hypoalbuminemia and edema (Soler-Rodriquez, 1993; Schnell, 2003).  In humans, the approximated lethal dose of ricin is 1 to 10 µg per kg body heaviness following inhalation or injection (Smallshaw, 2002).  In mice, rats, and primates, high doses of ricin by inhalation makes critical enough pulmonary damage to origin death likely due to hypoxemia resulting from huge pulmonary edema and alveolar inundating (Wilhelmsen, 1996; DaSilva, 2003; Roy, 2003).  In rats, inhaled ricin has an LD50 of 3.7 µg/kg and is affiliated with pulmonary edema, acute destructive alveolitis and necrosis/apoptosis of the lower respiratory tract epithelium (Gareth, 1995).Rats treated with ricin at a dose of 10 µg/kg body heaviness (intravenous management- iv) displayed no alterations in hepatic protein synthesis but remedy adversely influenced the sinusoidal units in the liver consequently producing in hepatocyte necrosis (Derenzini, 1976).Intravenous administration of ricin to mice (120 µg/kg body weight) produced in hemolytic uremic syndrome, encompassing thrombotic microangiopathy, hemolytic anemia, and acute renal malfunction (Korcheva, 2005; Fu, 2004).In vitro studies with human umbilical vein endothelial units showed that ricin damages endothelial cells (Baluna, 2000).The cytotoxicity of ricin and other ribosome-inactivating proteins are commonly attributed to the inhibition of protein synthesis consequent to ribosomal damage.A lesser known, but regardless important pathophysiologic event in ricin-induced toxicity appears to be oxidative stress (Schulze-Osthoff, 1992; ...