Thiophene is toxic to cerebellar granule cells in culture after bioactivation by rat liver enzymes

Several compounds that are not neurotoxic by themselves can cause toxic effects in vivo after enzymatic bioactivation. Thiophene is an industrial solvent known to produce degeneration primarily of the granule cells in the cerebellum when administered to animals in vivo. The mechanism for thiophene toxicity is not known, although it has been suggested that thiophene metabolism may lead to formation of oxidative intermediates that could function as the ultimate toxicants. In the present work we have used rat cerebellar granule cells (CGCs) in culture combined with rat liver postmitochondrial (S9) fraction as a source of biotranformation enzymes to test the toxicity of thiophene in vitro. The results demonstrate that thiophene is toxic to rat cerebellar granule cells in culture only after biotran formation. Furthermore, the toxic effects were reduced by cytochrome P450 (CYP) inhibitors and by scavengers of reactive molecules (alpha-tocopherol, reduced glutathione, and phenyl-N-tert-butylnitrone). These findings support the hypothesis that thiophene requires metabolism to produce the ultimate toxicant, and that the cytochrome P450 enzymesystem is involved in the metabolism. (C) 2004 Elsevier Inc. All rights reserved.