Chronic nicotine treatment induces rat CYP2D in the brain but not in the liver: an investigation of induction and time course.
OBJECTIVE
CYP2D6 levels are higher in many brain regions of human smokers in comparison with nonsmokers. We have shown that CYP2D is expressed in rat brain regions and that enzyme activities correlate with protein and messenger ribonucleic acid (mRNA) levels. The aims of this study were to investigate whether nicotine can induce rat brain CYP2D, to determine the recovery time course of the induction and to investigate the mechanism of induction through measuring mRNA levels over time.


METHODS
Rats were either treated once with either saline or nicotine (1 mg base/kg, subcutaneous and sacrificed 8 hours after the treatment or treated daily for 7 days and sacrificed 0.5-24 hours after the last injection. The CYP2D protein and mRNA levels were assessed by immunoblotting, immunocytochemistry and slot blotting.


RESULTS
There were no changes in brain CYP2D levels after a single nicotine injection. Following chronic nicotine treatment, levels were maximal at 8 hours and returned to control levels by 12 hours after nicotine treatment in all 3 regions assessed. At 8 hours after nicotine treatment, CYP2D levels were significantly (p < 0.05) higher than levels in saline-treated control animals in the cerebellum (1.4-fold), hippocampus (1.3-fold) and striatum (3.2-fold); they tended to be higher in the frontal cortex, brainstem and thalamus. Induction was specific to brain region and cell, for example, in some striatal neurons and in neurons in the cerebellar granular layer and white matter. At no time was there any increase in brain CYP2D mRNA levels. Hepatic CYP2D levels were unchanged at all times tested.


CONCLUSIONS
Chronic nicotine treatment induced CYP2D enzymes in rat brain but not rat liver. The induction was maximal 8 hours after the last injection and did not involve alterations in mRNA, indicating a posttranscriptional mechanism. These findings suggest that, in humans exposed to nicotine, response to centrally acting drugs metabolized by CYP2D, susceptibility to neurotoxins either activated or inactivated by CYP2D and the general homeostasis of endogenous neurochemicals metabolized by CYP2D may be affected, owing to increased CYP2D in the brain.
Yue
Jiang
J
The Centre for Addiction and Mental Health, Department of Pharmacology, University of Toronto, Toronto, Ontario, Canada.
Miksys
Sharon
S
Hoffmann
Ewa
E
Tyndale
Rachel F
RF
D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism* / Q000648:ultrastructure; D019389:Cytochrome P-450 CYP2D6 / Q000187:drug effects* / Q000378:metabolism*; D004334:Drug Administration Schedule; D007279:Injections, Subcutaneous; D008099:Liver / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D009538:Nicotine / Q000008:administration & dosage* / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
D012333:RNA, Messenger; D009538:Nicotine; D019389:Cytochrome P-450 CYP2D6