Regional and cellular distribution of CYP2E1 in monkey brain and its induction by chronic nicotine.
CYP2E1 is expressed in liver and extrahepatic tissues, including brain. It metabolizes ethanol and other drugs and toxins, such as acetaminophen, chlorzoxazone and tobacco-derived nitrosamines. Hepatic CYP2E1 is inducible by nicotine, and cigarette smoke accelerates chlorzoxazone metabolism. Smokers have higher levels of brain CYP2E1 expression than non-smokers, but the specific regions and cell types which have the higher expression differ from nicotine-induced rat brain. We therefore investigated the expression and distribution of brain CYP2E1 in a non-human primate, the African green monkey, and determined the effect of nicotine treatment. CYP2E1 levels varied among saline-treated monkey brain regions (P < 0.01) and expression was cell-type specific. Chronic nicotine treatment induced CYP2E1 expression in the frontal cortex (1.5-fold, P < 0.05) and cerebellum (1.5-fold, P < 0.01), specifically in cortical pyramidal neurons and cerebellar Purkinje cells but no change was seen in temporal cortex (P = 0.20), hippocampus (P = 0.29), putamen (P = 0.26) and thalamus (P = 0.08). CYP2E1 expression pattern in monkey brain following chronic nicotine treatment is similar to that in smokers, suggesting that nicotine may be the primary component in cigarette smoke that induces CYP2E1. Increased CYP2E1 in brain may contribute to oxidative stress and alter localized metabolism, and resulting pharmacology, of centrally acting drugs metabolized by CYP2E1.
Joshi
Meenal
M
Centre for Addiction and Mental Health, Department of Pharmacology, University of Toronto, Toronto, ON, Canada M5S 1A8.
Tyndale
Rachel F
RF
D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western / Q000379:methods; D001921:Brain / Q000187:drug effects* / Q000201:enzymology; D002522:Chlorocebus aethiops; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism*; D004334:Drug Administration Schedule; D005786:Gene Expression Regulation / Q000187:drug effects; D007150:Immunohistochemistry / Q000379:methods; D008297:Male; D009538:Nicotine / Q000008:administration & dosage*; D018722:Nicotinic Agonists / Q000008:administration & dosage*
D018722:Nicotinic Agonists; D009538:Nicotine; D019392:Cytochrome P-450 CYP2E1