Inhibition of cytochrome P450 2E1 induces an increase in extracellular dopamine in rat substantia nigra: a new metabolic pathway?
We presented data previously on dopamine (DA) synthesis and catabolism in the rat substantia nigra (SN) suggesting that a substantial part of the synthesized DA in this brain part is metabolized by unknown nonclassical metabolic pathways. On the basis of that a relatively high density of cytochrome P450 2E1 (CYP 2E1) has been detected in rat SN the aim of the present study was to investigate the possibility that this enzyme is involved in the metabolism of DA. Systemic administration of either phenylethyl isothiocyanate (100 mg/kg ip), diethyldithiocarbamate (500 mg/kg, ip) or diallyl sulfide (200 mg/kg, sc or ip), three different inhibitors of cytochrome P450 2E1, induced an increase of the extracellular DA concentration in the SN, measured with microdialysis in awake rats, by 130%, 90%, and 35%, respectively. A tendency to increased concentrations of the classical DA metabolites in the dialysate from the SN was also observed in some experiments. In the striatum, no profound effects were induced by the drugs on the concentrations of DA or its metabolites. The results show that CYP 2E1 activity affects dopaminergic neurotransmission in the SN, possibly by participating in DA metabolism. Other mechanisms, such as the influence on the DA transporter or the release process cannot, however, be ruled out.
Nissbrandt
H
H
Department of Pharmacology, Institute of Physiology and Pharmacology, Göteborg University, Göteborg, Sweden. hans.nissbrandt@pharm.gu.se
Bergquist
F
F
Jonason
J
J
Engberg
G
G
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000498:Allyl Compounds / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002614:Chelating Agents / Q000494:pharmacology; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D065691:Cytochrome P-450 CYP2E1 Inhibitors; D004050:Ditiocarb / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism*; D004734:Energy Metabolism / Q000187:drug effects* / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005110:Extracellular Space / Q000187:drug effects* / Q000378:metabolism; D006719:Homovanillic Acid / Q000378:metabolism; D017879:Isothiocyanates / Q000494:pharmacology; D008297:Male; D017551:Microdialysis; D017072:Neostriatum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013378:Substantia Nigra / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D013440:Sulfides / Q000494:pharmacology
D000498:Allyl Compounds; D000975:Antioxidants; D002614:Chelating Agents; D065691:Cytochrome P-450 CYP2E1 Inhibitors; D004791:Enzyme Inhibitors; D017879:Isothiocyanates; D013440:Sulfides; D015102:3,4-Dihydroxyphenylacetic Acid; C038491:allyl sulfide; C058305:phenethyl isothiocyanate; D004050:Ditiocarb; D019392:Cytochrome P-450 CYP2E1; D004298:Dopamine; D006719:Homovanillic Acid