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Toluene and its metabolites have been studied with respect to their reactive oxygen species-enhancing potential in isolated systems and in vivo. The induction of reactive oxygen species (ROS) production was assayed using the probe 2′,7′-dichlorodihydrofluorescin diacetate (DCFH-DA). Intraperitoneal injection of toluene, benzyl alcohol or benzaldehyde caused a significant elevation in the rate of ROS formation within hepatic mitochondrial fractions (P2). In the brain, only toluene induced ROS formation, while benzyl alcohol and benzaldehyde did not have any effect. Glutathione (GSH) levels were depressed in liver and brain regions from toluene-treated rats. However, no such depression was evident in brains treated with toluene metabolites. P2 fractions from phenobarbital-pretreated rats exhibited a heightened ROS response when challenged with toluene, in vitro. Pretreatment of rats in vivo with 4-methylpyrazole, an alcohol dehydrogenase inhibitor, or sodium cyanamide, an aldehyde dehydrogenase inhibitor, prior to exposure to toluene, caused a significant decrease and increase, respectively, in toluene-stimulated rates of ROS generation in the CNS and liver. Electron spin resonance spectroscopy, employing the spin trap 5,5-dimethyl-1-pyrroline N-oxide (DMPO), was conducted. Incubation of the spin trap with P2 fractions and toluene or benzaldehyde elicited a spectrum corresponding to the hydroxyl radical. Incubation of benzaldehyde with aldehyde dehydrogenase produced a strong signal that was blocked completely by Superoxide dismutase and inhibited partially by catalase, suggesting the presence of Superoxide radicals and the involvement of the iron-catalyzed Haber-Weiss reaction leading to the production of hydroxyl radicals. Thus, ROS generation during toluene catabolism may occur at two steps: cytochrome P450 oxidation and aldehyde dehydrogenase oxidation. In addition, GSH may play an important role in protection against the induction of ROS generation in the CNS and liver following exposure to toluene. © 1993.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is neurotoxic to dopaminergic neurons in the midbrain and their projections into the striatum [I], It has been speculated that the mechanism of dopaminergic neurotoxicity involves at least two potential components: mitochondrial damage and oxidative stress. There is no question that MPTP is a mitochondrial toxin in vivo [2]. It is aiso widely accepted that MPTP induces oxidative stress in the lung in vivo [3,4], What is in question is which of these mechanisms might predominate in the neurotoxicity of MPTP. MPTP has been shown not to induce lipid peroxidation in vivo in the striatui [5]. Since lipid peroxidation may be a component of the toxicity of some oxidative stress-inducing agents, the lack of lipid peroxidation with MPTP might argue against oxidative stress as part of the neurotoxic mechanism. This study was performed to reexamine the induction of lipid peroxidation by MPTP, as measured by conjugated diene formation, in various brain regions as well as the striatum, In addition, vitamin E deficient mice were used since they are known to be more susceptible to oxidative stress than normal mice [6].