Toluene-induced alterations in rat synaptosomal membrane composition and function.
Toluene is a widely used organic solvent that can produce acute central nervous system (CNS) effects. Since toluene reaches relatively high concentrations in the CNS and is extremely lipophilic, we investigated its effects on rat brain membrane composition and function. Toluene (1 g/kg, lh) did not alter total brain microsomal phospholipid (PL) or cholesterol (CL) content. However, synaptosomal PL was decreased (24%), while synaptosomal CL was unaltered. The PL/CL ratio, an indirect index of membrane fluidity, did not change, suggesting that toluene did not affect membrane fluidity. Fluorescence polarization studies employing 1,6-diphenyl-1,3,5-hexatriene (DPH) showed that toluene did not alter synaptosomal membrane fluidity after administration in vivo (1 g/kg) or in vitro (0.5 to 5.0 mM). Dose-response and time-course studies showed that toluene maximally decreased synaptosomal PL after 1 g/kg, 1 h. The dose-response and time-course studies also showed that the toluene-induced decreases in PL were a result of specific decreases in phosphatidylethanolamine (PE). Since PE was decreased, we assessed whether toluene altered synaptosomal membrane function by investigating phospholipid methylation, a reaction which uses PE as its initial substrate. Toluene decreased the incorporation of methyl groups into lipid when [3H]-methionine was used as the methyl donor, but did not affect methylation when [3H]-adenosylmethionine was the methyl donor. These data suggest that toluene-induced specific decreases in synaptosomal PE and inhibition of phospholipid methylation may alter normal synaptic function and play a critical role in the mechanism(s) of action of toluene's CNS effects.
Le Bel
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Toxicology Program, Northeastern University, Boston, MA 02115.
Schatz
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D000818:Animals; D008297:Male; D008560:Membrane Fluidity / Q000187:drug effects; D008745:Methylation; D008861:Microsomes / Q000187:drug effects; D010743:Phospholipids / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013574:Synaptosomes / Q000187:drug effects*; D014050:Toluene / Q000097:blood / Q000633:toxicity*
D010743:Phospholipids; D014050:Toluene