IN-VITRO NEUROTOXICITY OF THE ANTITUMOR AGENT 9-METHOXY-N-2-METHYLELLIPTICINIUM ACETATE (MMEA) - ROLE OF BRAIN CYTOCHROME-P-450

9-Methoxy-N-2-methylellipticinium acetate (MMEA) is representative of a series of quaternized ellipticine derivatives that are selectively c ytotoxic to human brain tumor cell lines derived from non-neuronal (gl ial) cells (Acton et al, 1994). In an attempt to determine whether MME A may exhibit toxicity to normal brain cells, we have examined the eff ect of the drug, in vitro, using sagittal slices of rat brain. Incubat ion of rat brain slices in an artificial cerebrospinal fluid medium co ntaining MMEA resulted in dose-dependent leakage of lactate dehydrogen ase (LDH) into the surrounding medium. However, other subcellular mark er enzymes such as Na+-K(+)ATPase (plasma membrane), cytochrome c oxid ase, isocitrate dehydrogenase, NADH- dehydrogenase (mitochondrial), N- acetylglucosaminidase, acid phosphatase (lysosomal), glyceraldehyde-3- phosphate dehydrogenase and enolase (glycolytic enzymes) were unaffect ed even at the highest tested concentrations of MMEA (10 and 100 mu M) . Preincubation of slices with reserpine (1 nM) or, dopamine or seroto nin-specific reuptake inhibitors abolished MMEA-induced toxicity in br ain slices. Pretreatment of slices with piperonyl butoxide and metyrap one, inhibitors of cytochrome P-450, also prevented the toxicity of MM EA. Further, brain slices prepared from phenobarbital-treated rats sho wed enhanced sensitivity to MMEA.