Reduction of acid sphingomyelinase activity in human fibroblasts induced by AY-9944 and other cationic amphiphilic drugs.
AY-9944 (trans-1,4-bis(2-chlorobenzylaminoethyl)cyclohexane dihydrochloride), a cationic amphiphilic drug, caused a rapid, irreversible and dose-dependent reduction of acid sphingomyelinase activity in normal human fibroblasts without changing the activities of other lysosomal hydrolases tested. Examinations of activities against synthetic substrates and of the pH-dependency of sphingomyelinase in the drug-treated cells also suggested that the reduction of activity was specific to acid sphingomyelinase. Such a specific reduction was also found with 12 other cationic amphiphilic drugs, most of which have been shown to be inducers of experimental phospholipidosis in animals and/or cultured cells. These results strongly suggest that acid sphingomyelinase is involved in the process of drug-induced lipidosis. The reduction of acid sphingomyelinase seemed not to be due to direct inhibition by these drugs, a specific loss of the enzyme into the culture medium, the presence of inhibitor in the drug-treated cells, or impaired synthesis of the enzyme. There was no indication that changes in the catalytic properties of the enzyme, or changes in the requirement of detergents for its activity occurred in the cell. These results suggest that AY-9944 and other cationic amphiphilic drugs may cause the reduction of acid sphingomyelinase activity by inducing an increased rate of degradation of the enzyme or by causing an irreversible inactivation via some undetected factor.
Y
Y
Yoshida
K
K
Arimoto
M
M
Sato
N
N
Sakuragawa
M
M
Arima
E
E
Satoyoshi
D002412:Cations / Q000494:pharmacology; D002738:Chloroquine / Q000494:pharmacology; D003510:Cyclohexanes / Q000494:pharmacology*; D003864:Depression, Chemical; D003984:Dibenzazepines / Q000494:pharmacology; D003992:Dibucaine / Q000494:pharmacology; D004790:Enzyme Induction / Q000187:drug effects; D005347:Fibroblasts / Q000201:enzymology*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008247:Lysosomes / Q000201:enzymology; D008297:Male; D010640:Phenothiazines / Q000494:pharmacology; D010727:Phosphoric Diester Hydrolases / Q000032:analysis*; D013108:Sphingomyelin Phosphodiesterase / Q000032:analysis* / Q000096:biosynthesis; D013449:Sulfonamides / Q000494:pharmacology; D001371:trans-1,4-Bis(2-chlorobenzaminomethyl)cyclohexane Dihydrochloride / Q000494:pharmacology*
D002412:Cations; D003510:Cyclohexanes; D003984:Dibenzazepines; D010640:Phenothiazines; D013449:Sulfonamides; D001371:trans-1,4-Bis(2-chlorobenzaminomethyl)cyclohexane Dihydrochloride; C017967:W 7; C034700:N-(6-aminohexyl)-1-naphthalenesulfonamide; D002738:Chloroquine; D010727:Phosphoric Diester Hydrolases; D013108:Sphingomyelin Phosphodiesterase; D003992:Dibucaine