Cytochrome P450 2E1 in the substantia nigra: relevance for dopaminergic neurotransmission and free radical production.

• Cytochrome P450 2E1 (CYP2E1) has been detected in brain regions which are of relevance for the pathophysiology of Parkinson's disease, such as the substantia nigra (SN). Furthermore, CYP2E1 is known to generate reactive oxygen species (ROS), toxic molecules which have been implicated in the pathogenesis of the disease. We have previously reported that CYP2E1 inhibition increases extracellular dopamine (DA) in the SN. The aims of the present study were by using in vivo microdialysis in rat, to elucidate the mechanisms responsible for the increase in extracellular DA induced by CYP2E1 inhibition and to explore whether ROS is produced in the SN, both with and without the presence of an exogenous CYP2E1 substrate. The effect of inhibition of CYP2E1 by phenylethyl isothiocyanate (100 mg/kg) on extracellular DA in the SN was unaltered following pretreatment with gamma-butyrolactone and GBR-12909, drugs that inhibit firing of DA neurons and DA re-uptake, respectively. Preadministration of tetrodotoxin or reserpine, however, abolished the effect of CYP2E1 inhibition. Administration of isoflurane, an anesthetic which is metabolized by CYP2E1, increased the production of *OH in the SN, as measured by the transformation of 4-hydroxybenzoic acid to 3,4-dihydroxybenzoic acid during local perfusion compared with animals given other anesthetics. The results support the notion that CYP2E1 is located near or in the same compartment in the SN as stored DA, tentatively the endoplasmatic reticulum, and that the enzyme activity might modulate the amount of DA that is available for release. Furthermore, our findings indicate that the production of ROS can be stimulated by CYP2E1 substrates.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Fysiologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Physiology (hsv//eng)

Nyckelord

4-Butyrolactone

pharmacology

Adrenergic alpha-Agonists

pharmacology

Anesthetics

Dissociative

pharmacology

Anesthetics

Inhalation

pharmacology

Animals

Cytochrome P-450 CYP2E1

antagonists & inhibitors

metabolism

Dopamine

metabolism

physiology

Dopamine Antagonists

pharmacology

Dopamine Uptake Inhibitors

pharmacology

Enzyme Inhibitors

pharmacology

Extracellular Space

drug effects

metabolism

Free Radicals

metabolism

GABA Modulators

pharmacology

Hydroxybenzoic Acids

metabolism

Isoflurane

pharmacology

Ketamine

pharmacology

Male

Microdialysis

Parabens

metabolism

Piperazines

pharmacology

Rats

Rats

Sprague-Dawley

Reserpine

pharmacology

Substantia Nigra

enzymology

Synaptic Transmission

physiology

Tetrodotoxin

pharmacology

Xylazine

pharmacology

Publikations- och innehållstyp

ref (ämneskategori)

art (ämneskategori)