Protection by lysosomal hydrolase inhibitors against cytotoxicity of 2-chloroethylethyl sulfide.
A possible participation of lysosomal hydrolases in the cytotoxicity of 2-chloroethylethyl sulfide in spleen lymphocytes was investigated using inhibitors of lysosomal phospholipases and proteases. Pepstatin (6 microM) and leupeptin (60 microM), inhibitors of lysosomal proteases, raised the viability of lymphocytes exposed to 2-chloroethylethyl sulfide from 63 to 87 and 88% of control, respectively. Serine protease inhibitors showed no significant effect on viability. Aminoglycoside inhibitors of lysosomal phospholipases were also found to prevent the decrease in viability of spleen lymphocytes exposed to 2-chloroethylethyl sulfide, and the effectiveness of these aminoglycosides (30 microM) was as follows: gentamicin > kanamycin > streptomycin, with viability increased to 89, 79 and 67%, respectively. In contrast to a co-operative action between leupeptin and gentamicin, the protection by pepstatin was reduced in the presence of gentamicin. Moreover, the order of the aminoglycosides in terms of the extent to which they antagonized the protective action of pepstatin was the same as their order of efficacy in preventing the cytotoxicity of CEES. It is suggested that inhibitors of lysosomal hydrolases reduce the cytotoxicity of 2-chloroethylethyl sulfide, presumably through lysosomal stabilization in spleen lymphocytes.
Sok
D E
DE
Advanced Technology Research Center, Agency for Defense Development, Yuseong, Taejon, Korea.
Choi
D S
DS
Park
Y K
YK
Kim
Y B
YB
Cha
S H
SH
D000478:Alkylation; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004347:Drug Interactions; D005839:Gentamicins / Q000494:pharmacology; D007612:Kanamycin / Q000494:pharmacology; D007976:Leupeptins / Q000494:pharmacology; D008247:Lysosomes / Q000201:enzymology; D051379:Mice; D008813:Mice, Inbred ICR; D009151:Mustard Gas / Q000031:analogs & derivatives* / Q000633:toxicity; D009842:Oligopeptides / Q000494:pharmacology; D010436:Pepstatins / Q000494:pharmacology; D010740:Phospholipases / Q000037:antagonists & inhibitors*; D011480:Protease Inhibitors / Q000494:pharmacology*; D013154:Spleen / Q000166:cytology / Q000187:drug effects*; D013307:Streptomycin / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects*
D005839:Gentamicins; D007976:Leupeptins; D009842:Oligopeptides; D010436:Pepstatins; D011480:Protease Inhibitors; C014195:Streptomyces pepsin inhibitor; D007612:Kanamycin; C031278:2-chloroethyl ethyl sulfide; C002101:chymostatin; D010740:Phospholipases; C032854:leupeptin; D009151:Mustard Gas; C031375:pepstatin; D013307:Streptomycin