CYTOTOXICITY AND LAMELLAR BODY INDUCTION POTENTIAL OF A RACEMIC BENZAMIDE ANTIARRHYTHMIC COMPOUND AND ENANTIOMERS IN CULTURED RAT HEPATOCYTES

A wide variety of cationic amphiphilic compounds induce cytoplasmic lamellar bodies, accompanied by phospholipidosis and often coincidental with toxicity. The in vitro cytotoxic and lamellar body-inducing potentials of a racemic cationic amphiphilic benzamide antiarrhythmic compound and its trans-enantiomers were examined. Cultured rat hepatocytes were treated for 24 hr with the racemate and (+) and (-) trans-enantiomers in increasing concentrations to 1.0mM. All compounds produced significant cytotoxicity at concentrations of 250 mu M and greater, as assessed by lactate dehydrogenase release, but the (-) enantiomer was less cytotoxic than the racemate and (+) enantiomer at 500 mu M. Electron microscopy revealed significant formation of lamellar bodies in all treated cultures at concentrations of 100 mu M and higher for all compounds, with the (-) enantiomer producing significantly fewer lamellar bodies than the (+) enantiomer or racemic mixture. Acid phosphatase cytochemistry indicated that most, but not all, lamellar bodies were lysosomes. Fluorescence distributional studies with a phospholipid analogue, 1-acyl-2-[12-(7-nitro-2-1-,3-benzoxadiazol-4-yl)amino]dodecanoyl phosphatidyl-choline, in living cells confirmed drug-induced cytoplasmic vacuoles to be formed from labelled plasma membrane at racemate drug concentrations as low as 10 mu M, and suggested that lamellar body formation proceeds by a dynamic process involving the plasma membrane. These data indicate stereo-selective lamellar body- and cytotoxicity-inducing potentials between enantiomers, and that these are dissociable processes.