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Cytochrome P4502E (CYP2E) in Brain: Constitutive Expression, Induction by Ethanol and Localization by Fluorescence in Situ Hybridization

https://doi.org/10.1006/abbi.1999.1477Get rights and content

Abstract

Cytochrome P4502E (P4502E), the major ethanol-inducible P450 metabolizes ethanol to acetaldehyde and bioactivates procarcinogens to ultimate carcinogens. Metabolism of ethanol to acetaldehyde in the brain could be deleterious since it can react with cytoskeletal proteins, forming adducts. In the present study, rats were administered ethanol chronically to evaluate its effect on chlorzoxazone hydroxylation in rat brain regions. Chlorzoxazone hydroxylation in brains from the treated rats was induced in hippocampus and cortex, downregulated in brainstem, and unchanged in cerebellum, striatum, and thalamus. The presence of functionally active P4502E was also seen in human brain regions obtained at autopsy from traffic accident victims. Northern blot analysis of rat and human brain poly(A)+ RNA hybridized with cDNA to rat CYP2E1 revealed the constitutive presence of a corresponding transcript in rat and human brain. Localization of CYP2E by fluorescence in situ hybridization demonstrated the constitutive expression of CYP2E preferentially in the neuronal cells in rat and human brain. CYP2E expression was seen in neurons within the cerebral cortex, Purkinje and granule cell layers of cerebellum, granule cell layer of dentate gyrus, and pyramidal neurons of CA1, CA2, and CA3 subfields of hippocampus in both rat and human brain. The present studies demonstrate constitutive expression of P4502E1 in brain, its differential induction in rat brain regions by chronic ethanol treatment, and its topographic distribution in rat and human brain.

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      Of note, CYP2E1 is also induced in the liver, while CYP2D is not (Howard, Micu, Sellers, & Tyndale, 2001; Yue et al., 2008). Ethanol pretreatment also increases CYP2D and CYP2E1 protein in the rat brain, as well as inducing CYP2E1 in the rat liver (Upadhya, Tirumalai, Boyd, Mori, & Ravindranath, 2000; Warner & Gustafsson, 1994; Yue et al., 2009). CYP2B1 is induced by daily nicotine pretreatments in the rat brain and liver, although mRNA is also increased suggesting that transcriptional regulation may be involved (Miksys, Hoffmann, et al., 2000; Yue et al., 2009).

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    This research was supported by National Institutes of Health Grant MH55494.

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