Ototoxic and nephrotoxic drugs inhibit agonist-induced inositol phosphate formation in rat brain synaptoneurosomes.
Neomycin (an aminoglycoside antibiotic), ethacrynate (a loop diuretic), cisplatin (an anticancer drug) and mercuric chloride are chemically unrelated drugs which present similar ototoxic and nephrotoxic properties. We have found that all these molecules inhibit inositol phosphate turnover induced by carbachol or glutamate in rat brain synaptoneurosomes. Since this second messenger system appears to be a key mechanism for cell functioning and even survival, our observations raise the possibility that the expression of the specific toxicity of these compounds may result from excessive inhibition of the phosphoinositide cascade.
Guiramand
J
J
INSERM U-254, Laboratoire de Neurobiologie de l'Audition, Hôpital St Charles, Montpellier, France.
Lenoir
M
M
Pujol
R
R
Récasens
M
M
D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002217:Carbachol / Q000037:antagonists & inhibitors / Q000494:pharmacology; D002945:Cisplatin / Q000633:toxicity*; D004976:Ethacrynic Acid / Q000633:toxicity*; D018691:Excitatory Amino Acid Antagonists; D005971:Glutamates / Q000494:pharmacology; D007295:Inositol Phosphates / Q000378:metabolism*; D008627:Mercuric Chloride / Q000633:toxicity*; D009355:Neomycin / Q000633:toxicity*; D010716:Phosphatidylinositols / Q000378:metabolism; D051381:Rats; D015290:Second Messenger Systems / Q000187:drug effects; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism*
D018691:Excitatory Amino Acid Antagonists; D005971:Glutamates; D007295:Inositol Phosphates; D010716:Phosphatidylinositols; D008627:Mercuric Chloride; D002217:Carbachol; D009355:Neomycin; D004976:Ethacrynic Acid; D002945:Cisplatin