Calmodulin antagonists chlorpromazine and W-7 inhibit exogenous cholesterol esterification and sphingomyelinase activity in human skin fibroblast cultures. Similarities between drug-induced and Niemann-Pick type C lipidoses.
In this report we showed that calmodulin antagonists chlorpromazine (CPZ) and W-7 (N-[6-aminohexyl]-5-chloro-1-naphtalenesulfonamide), when added to fibroblast cell cultures, gave rise to a time- and dose-dependent decrease of sphingomyelinase activity. CPZ and W-7 also significantly inhibited LDL- and non-LDL-dependent cholesterol esterification. Addition of these drugs to cell culture medium mimicked what is observed in the genetic disease Niemann-Pick type C. H-7 (1-[5-isoquinonylsulfonyl]-2-methylpiperazine), an inhibitor of protein kinase C and cyclic nucleotide-dependent kinases, had no effect on sphingomyelinase and cholesterol ester formation. Thus the possibility of a modulation of cell sphingomyelin and cholesterol esters by a calmodulin-dependent second messenger system must be considered.
Masson
M
M
Cellular Unit, INSERM U.134, Salpétrière Hospital, Paris, France.
Spezzatti
B
B
Chapman
J
J
Battisti
C
C
Baumann
N
N
D002147:Calmodulin / Q000037:antagonists & inhibitors*; D002746:Chlorpromazine / Q000494:pharmacology*; D002784:Cholesterol / Q000378:metabolism*; D002788:Cholesterol Esters / Q000096:biosynthesis*; D003864:Depression, Chemical; D005347:Fibroblasts / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D009542:Niemann-Pick Diseases / Q000378:metabolism* / Q000473:pathology; D015290:Second Messenger Systems / Q000187:drug effects; D012867:Skin; D013108:Sphingomyelin Phosphodiesterase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology*
D002147:Calmodulin; D002788:Cholesterol Esters; D013449:Sulfonamides; C017967:W 7; D002784:Cholesterol; D013108:Sphingomyelin Phosphodiesterase; D002746:Chlorpromazine