title: CYP2B6 is expressed in African Green monkey brain and is induced by chronic nicotine treatment.
abstract: CYP2B6 is a drug-metabolizing enzyme expressed in human tissues that can activate bupropion (a smoking cessation drug) and tobacco smoke nitrosamines and can inactivate drugs such as nicotine. Smokers have higher brain CYP2B6 protein levels compared to non-smokers but the cause of this elevation is unknown. We investigated the basal expression and the effect of chronic nicotine treatment on CYP2B6 protein in African Green monkey (Cercopithecus aethiops) brain. Basal expression of brain CYP2B6 was strong in specific cells such as the frontal cortical pyramidal cells, the cerebellar Purkinje cells and the neurons in the substantia nigra. Basal CYP2B6 protein levels varied 2.7-fold (non-significant) among 12 brain regions. All monkeys were given a subcutaneous 0.1 mg/kg nicotine test dose prior to treatment and the maximum plasma concentration achieved was 87 +/- 69 ng/ml and the half-life was 2.6 +/- 1.5 h. Monkeys were treated subcutaneously twice daily with nicotine at 0.05 mg/kg for 2 days, 0.15 mg/kg for 2 days followed by 0.3 mg/kg for 18 days (n = 6) or saline (n = 6). Chronic nicotine treatment induced CYP2B6 expression in specific cells such as astrocytes and neurons in the frontal cortex, caudate, thalamus and hippocampus. CYP2B6 protein levels were induced 1.5-fold in the frontal cortex (p < 0.01). Hepatic CYP2B6 expression was not altered by nicotine. In conclusion, CYP2B6 protein is expressed in specific cells in monkey brain and is induced by chronic nicotine treatment which may impact central metabolism of CYP2B6 substrates such as bupropion and nicotine.
authors.affiliation: Department of Pharmacology, Centre for Addiction and Mental Health, University of Toronto, 1 King's College Circle, Ontario, Canada.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Lee
authors.forename: Sharon
authors.initials: S
authors.lastname: Miksys
authors.forename: Roberta
authors.initials: R
authors.lastname: Palmour
authors.forename: Rachel F
authors.initials: RF
authors.lastname: Tyndale
mesh_terms: D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis*; D001921:Brain / Q000201:enzymology*; D002540:Cerebral Cortex / Q000201:enzymology; D002522:Chlorocebus aethiops; D065702:Cytochrome P-450 CYP2B6; D004790:Enzyme Induction / Q000187:drug effects*; D005625:Frontal Lobe / Q000201:enzymology; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D007700:Kinetics; D008297:Male; D009538:Nicotine / Q000494:pharmacology*; D010089:Oxidoreductases, N-Demethylating / Q000096:biosynthesis*; D012907:Smoking
chemical_list: D009538:Nicotine; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6; D010089:Oxidoreductases, N-Demethylating