Acute and Subchronic Toxicity of the Protease Inhibitor N-α-Tosyl-L-Lysyl-Chloromethylketone (TLCK) in Mice

ABSTRACT

The acute and subchronic toxicity of TLCK (N-α-tosyl-L-lysyl-chloromethylketone) was determined in mice using several different treatment regimens and several different strains of mice. The single dose LD₅₀ was 59 mg/kg following intraperitoneal (ip) administration and was 64 mg/kg following subcutaneous administration to male Balb/c mice. When various doses (0,5,10,20,40 mg/kg) were administered ip to male Balb/c mice either two or three times per week for four weeks, mortality occurred in both regimens at the highest dose. Weight loss was recorded in all animals treated with 20 mg/kg. Histologic lesions in chronically treated mice were restricted to inflammation of the diaphragm and hepatic necrosis. No lesions were observed following administration of a single lethal dose. When TLCK was administered ip to males and females of 7 strains of mice, female NIH Swiss and female C57B1/6 mice were more resistant to TLCK-induced mortality than were males of the same strains. No other strain-related differences in sensitivity were noted.