Enhanced synthesis de novo of phosphatidylinositol in lymphocytes treated with cationic amphiphilic drugs.
A variety of amphiphilic cations caused very large increases in the rates of incorporation of Pi and glycerol into phosphatidylinositol in pig mesenteric small lymphocytes. This synthesis de novo of phosphatidylinositol led to a doubling of the phosphatidylinositol concentration in the cells within 3.5 h. The increase in synthesis of phosphatidylinositol labelled with [3H]- or [14C]-glycerol was matched by an approximately equivalent decrease in incorporation of glycerol into phosphatidylcholine, phosphatidylethanolamine and triacylglycerol. Amphilic cations which produced these effects included, in order of decreasing effectiveness, trifluoperazine (half-maximal effect at about 70 mum) greater than chlorpromazine approximately promethazine approximately imipramine greater than cinchocaine greater than amethocaine approximately cetyltrimethylammonium greater than fenfluramine greater than amphetamine greater than 2-phenethylamine greater than cocaine approximately procaine; the most effective compounds were those with the largest and most hydrophobic non-polar substituents. The response to cations was not changed by varying the extracellular Ca2+ concentration in the range 10 nm-1mm. The active amphiphilic cations interacted with anionic phospholipids causing aggregation of aqueous dispersions and/or changes in chromatographic behaviour. These results indicate that amphiphilic cations redirect glycerolipid synthesis de novo, probably owing to inhibition of phosphatidate phosphohydrolase, so that phosphatidylinositol synthesis is increased at the expense of other glycerolipids.
D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D002593:Cetrimonium Compounds / Q000494:pharmacology; D002746:Chlorpromazine / Q000494:pharmacology; D003042:Cocaine / Q000494:pharmacology; D003992:Dibucaine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005277:Fenfluramine / Q000494:pharmacology; D007099:Imipramine / Q000494:pharmacology; D037102:Lectins / Q000494:pharmacology; D008214:Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D010627:Phenethylamines / Q000494:pharmacology*; D010716:Phosphatidylinositols / Q000096:biosynthesis*; D011343:Procaine / Q000494:pharmacology; D011398:Promethazine / Q000494:pharmacology; D013552:Swine; D013997:Time Factors; D014268:Trifluoperazine / Q000494:pharmacology
D002593:Cetrimonium Compounds; D037102:Lectins; D010627:Phenethylamines; D010716:Phosphatidylinositols; D014268:Trifluoperazine; D005277:Fenfluramine; D011343:Procaine; D000661:Amphetamine; D011398:Promethazine; D003042:Cocaine; D003992:Dibucaine; D007099:Imipramine; D002746:Chlorpromazine