Regional distribution of ethanol-inducible cytochrome P450 IIE1 in the rat central nervous system

Abstract

A specific form of cytochrome P450, P450 IIE1, active in ethanol oxidation, is known to be induced about 10-fold in rat liver following ethanol treatment. This isozyme of P450 participates effectively in the metabolic activation of precarcinogens, such asN-dimethylnitrosamines, and of solvents such as carbon tetrachloride and benzene. In the present investigation, two different polyclonal antisera against P450 IIEl were used in order to map the regional distribution of this P450 form in the rat central nervous system. The presence of P450 IIEl in various brain regions was confirmed by Western blot analysis. The P450 IIEl-immunoreactivity was heterogeneously distributed between brain areas. Neuronal cell bodies and glial cells of presumed astroglial as well as oligodendroglial identity contained immuno-reactivity. All fiber tracts harbored P450 IIEl-immunoreactive glial cells as did the ependymal lining of the ventricular wall as well as small and large vessels throughout the brain. P450 HEl-immunoreactive glial cells were present in all areas of the neocortex, in the olfactory bulb, in the piriform cortex and in several different thalamic nuclei. In the cerebellum, P450 IIE-immunoreactivity was found in all cell layers and was exclusively localized to glial cells and their processes. Staining of blood vessels was prominent in the white matter where P450 IIEl-immunoreactive glial cells were seen to have end-feet on the vessels. A subgroup of pyramidal cells of the frontal cortex showed strong P450 IIEl-immunoreactivity, as did a component of the olfactory nerve which innervates the accessory bulb. In the hippocampal region, the pyramidal cells of all subfields were P450 IIEl-immunoreactive. Some polymorphic cells of the hilus and subfield CA stained intensely with the P450 IIE1 antibodies. A high density of P450 IIE1-immunoreactiviy was detected throughout the striatal complex. The immunoreactivity was localized to neuronal cell bodies as well as the neurophil. Fibers of the nigrostriatal system were strongly P450 IIEl-immunoreactive. Mechanical lesions of this pathway showed an accumulation of P450 IIEl-immunoreactivity proximal to the lesion relative to the striatum and a depletion in the reticular part of the substantia nigra, suggesting that the antigen may be transported from the striatum to the substantia nigra. In the brain stem a high density of P450 IIE-immunoreactive neurons was detected in the substantia nigra, the pontine nucleus, lateral superior olive and the nucleus of the trigeminal nerve and facial nucleus. A great number of large- to medium-sized immunoreactive neurons were situated in the central gray and in the reticular formation. The present study shows that ethanol-inducible hepatic P450 IIE1 is constitutively expressed in the rat brain. The distribution of this P450 form in certain populations of nerve cells might have implications for the regioselective toxicity of substrates for P450 IIEl.