Effects of toluene and its metabolites on cerebral reactive oxygen species generation

Abstract

Abstract-The effects of toluene on lipid peroxidation and rates of reactive oxygen species (ROS) formation have been studied in isolated systems and in vivo. The induction of reactive oxygen species was assayed using the probe 2' ,7'-dichlorofluorescin diacetate (DCFH-DA). Toluene exposure (1 g/kg, 1 hr, i.p.) did not stimulate cortical lipid peroxidation as evaluated by measurement of conjugated dienes. Exposure to toluene, however, both in vivo and in vitro, caused a significant elevation of ROS formation within cortical crude synaptosomal fractions (P2) and microsomal fractions (P3). The ROSinducing properties of toluene were blocked in vivo in the presence of a mixed-function oxidase inhibitor, metyrapone. This suggested that a metabolite of toluene may catalyze reactive oxygen formation. Both benzyl alcohol and benzoic acid, in vitro, were found to have free radical quenching properties, while benzaldehyde exhibited significant induction of ROS generation. It appears that benzaldehyde is the metabolite responsible for the effect of toluene in accelerating reactive oxygen production within the nervous system. Benzaldehyde may also contribute to the overall neurotoxicity of toluene.

Free radical induction in the brain and liver by products of toluene catabolism

“…Prior studies with phenobarbital have also demonstrated that in vivo pretreatment accelerates hepatic metabolism of toluene and benzene, and thereby results in increased tolerance of the rats to the narcotic action of toluene (14). Pretreatment of rats IP 4611-H with metyrapone, a mixed-function oxidase inhibitor, significantly reduces the toluene-stimulated rate of ROS generation in cerebrocortical synaptosomal and hepatic microsomal fractions [7). This supports our finding that the first step in the catabolism of toluene (by cytochrome P450) can contribute to the enhancement of ROS formation.…”

“…Exposure to toluene, in vivo and in vitro, was found previously to result in the induction of both ROS formation and lipid peroxidation in the liver, lung, kidney and various brain regions [7,8]. Toluene is metabolized through the oxidation of its methyl group by mixed-function oxidases to benzyl alcohol, followed by oxidation to benzaldehyde with alcohol dehydrogenase.…”

“…§ Abbreviations: DCFH, 2' ,7' -dichlorodihydroftuorescin; DCFH-DA, DCFH diacetate; DCF, 2' ,7'-dichloroftuorescein; DETAPAC, diethylenetriaminepentaacetic acid; DMPO, 5,5-dimethyl-1-pyrroline N-oxide; GSH, glutathione; MBCI, monochlorobimane; ROS, reactive oxygen species; and SOD, superoxide dismutase. toluene may be related, in part, to induction of excess reactive oxygen species (ROS §) (7,8]. Both in vivo and in vitro exposure to toluene produced a broad systemic elevation in the rate of ROS formation, that persisted in the CNS long after toluene had been eliminated from the blood.…”

Three weeks' exposure of rats to dearomatized white spirit modifies indices of oxidative stress in brain, kidney, and liver

“…There is considerable evidence for the induction of excess free radicals and ROS* generation by various neurotoxic aromatic solvents. These compounds include benzene [16], toluene [17][18][19], xylenes [19][20][21], and styrene [22]. There is less evidence for the induction of oxidative stress by aliphatic organic solvents.…”

Toluene-induced oxidative stress in several brain regions and other organs

“…Exposure to toluene, both in vivo and in vitro, caused a significant elevation in ROS formation within cerebral cortical synaptosomal and microsomal fractions (Mattia et al, 1991). Reactive oxygen *species have been implicated in the action of a wide range of structurally and pharmacologically diverse compounds with an equally broad range of effects (Mason, 1982;Trush et al, 1982;Halliwell and Gutteridge, 1985).…”