Rat brain CYP2B induction by nicotine is persistent and does not involve nicotinic acetylcholine receptors.
CYP2B is a drug-metabolizing enzyme expressed in the liver and brain that metabolizes a variety of centrally acting drugs (e.g. propofol, bupropion and nicotine), endogenous neurochemicals (e.g. serotonin and testosterone) and toxins (e.g. chlorpyrifos). Human CYP2B6 is found at higher levels in the brains of smokers, and 7-day nicotine treatment induces rat brain CYP2B while not altering hepatic CYP2B. We characterized the time course of rat brain CYP2B induction by nicotine and determined if nicotinic acetylcholine receptors (nAChRs) mediated this induction. Rats were treated once daily with 1mg/kg nicotine base or saline s.c. for 1 or 7days and sacrificed from 30minutes to 7days after the last injection. One-day nicotine treatment did not induce brain CYP2B, whereas 7-day nicotine treatment significantly increased CYP2B expression for up to 24hours in the frontal cortex and brainstem; these levels returned to baseline by 7days post-treatment. CYP2B activity was also higher at 24hours in these regions. No change was seen in the cerebellar CYP2B levels or in vivo activity following nicotine treatment. Time of day of treatment and sacrifice altered the magnitude of brain CYP2B induction while chlorisondamine, an irreversible nAChR blocker, pre-treatment did not block CYP2B induction. Seven-day nicotine treatment resulted in an induction of rat brain CYP2B protein and in vivo activity for up to 24hours, which would suggest greater local drug metabolism by brain CYP2B. Humans or animals exposed to nicotine may have altered therapeutic drug response, brain levels of neurotransmitters and/or neurotoxicity.
Khokhar
Jibran Y
JY
Centre for Addiction and Mental Health (CAMH), Toronto, and Departments of Pharmacology and Toxicology and Psychiatry, University of Toronto, Toronto, Ontario, Canada.
Miksys
Sharon L
SL
Tyndale
Rachel F
RF
D000818:Animals; D001921:Brain / Q000033:anatomy & histology / Q000187:drug effects*; D002714:Chlorisondamine / Q000494:pharmacology; D002940:Circadian Rhythm / Q000187:drug effects / Q000502:physiology; D019362:Cytochrome P-450 CYP2B1 / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects*; D008297:Male; D009538:Nicotine / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology*; D018733:Nicotinic Antagonists / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011978:Receptors, Nicotinic / Q000378:metabolism*; D013997:Time Factors
D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; D009538:Nicotine; D019362:Cytochrome P-450 CYP2B1; D002714:Chlorisondamine