Enzyme mediated superoxide radical formation initiated by exogenous molecules in rat brain preparations

The ability of brain tissue preparation to generate superoxide from xenobiotic interactions has been investigated. We showed that a significant superoxide production occurred with different molecules known to undergo a single electron reductive pathway of metabolism, both in a homogenate derived from neuronal and glial cells and in isolated cerebral microvessels which form the blood-brain barrier. Determination of the nucleotide cofactors requirement and data obtained with different subcellular fractions indicated that this production was largely associated with the microsomal fraction in a NADPH-dependent pathway and was probably mediated by NADPH-cytochrome P450 (c) reductase. A significant xenobiotic-mediated production of superoxide also occurred in mitochondria under in vitro conditions. Thus the evidence of reductive pathways of xenobiotic metabolism and the generation of oxygenated free radicals observed are of neurotoxicological significance.