title: Impact of nicotine metabolism on nicotine's pharmacological effects and behavioral responses: insights from a Cyp2a(4/5)bgs-null mouse.
abstract: Nicotine metabolism is believed to affect not only nicotine's pharmacological effects but also nicotine addiction. As a key step toward testing this hypothesis, we have studied nicotine metabolism and nicotine's pharmacological and behavioral effects in a novel knockout mouse model [named Cyp2a(4/5)bgs-null] lacking a number of cytochrome P450 genes known to be or possibly involved in nicotine metabolism, including two Cyp2a and all Cyp2b genes. We found that, compared with wild-type mice, the Cyp2a(4/5)bgs-null mice showed >90% decreases in hepatic microsomal nicotine oxidase activity in vitro, and in rates of systemic nicotine clearance in vivo. Further comparisons of nicotine metabolism between Cyp2a(4/5)bgs-null and Cyp2a5-null mice revealed significant roles of both CYP2A5 and CYP2B enzymes in nicotine clearance. Compared with the behavioral responses in wild-type mice, the decreases in nicotine metabolism in the Cyp2a(4/5)bgs-null mice led to prolonged nicotine-induced acute pharmacological effects, in that null mice showed enhanced nicotine hypothermia and antinociception. Furthermore, we found that the Cyp2a(4/5)bgs-null mice developed a preference for nicotine in a conditioned place preference test, a commonly used test of nicotine's rewarding effects, at a nicotine dose that was 4-fold lower than what was required by wild-type mice. Thus, CYP2A/2B-catalyzed nicotine clearance affects nicotine's behavioral response as well as its acute pharmacological effects in mice. This result provides direct experimental support of the findings of pharmacogenetic studies that suggest linkage between rates of nicotine metabolism and smoking behavior in humans.
authors.affiliation: Wadsworth Center, New York State Department of Health, and School of Public Health, State University of New York at Albany (L.L., K.J., X.Z., X.D.) and Center for Neuropharmacology and Neuroscience, Albany Medical College (S.E.M., L.B.H.), Albany, New York.
authors.forename: Lei
authors.initials: L
authors.lastname: Li
authors.forename: Kunzhi
authors.initials: K
authors.lastname: Jia
authors.forename: Xin
authors.initials: X
authors.lastname: Zhou
authors.forename: Sarah E
authors.initials: SE
authors.lastname: McCallum
authors.forename: Lindsay B
authors.initials: LB
authors.lastname: Hough
authors.forename: Xinxin
authors.initials: X
authors.lastname: Ding
mesh_terms: D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D001522:Behavior, Animal / Q000187:drug effects*; D001831:Body Temperature / Q000187:drug effects; D003216:Conditioning, Operant / Q000187:drug effects; D065637:Cytochrome P-450 CYP2A6; D000072467:Cytochrome P450 Family 2; D006207:Half-Life; D007101:Immersion; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009538:Nicotine / Q000378:metabolism* / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000378:metabolism* / Q000494:pharmacology*; D010147:Pain Measurement / Q000187:drug effects; D011930:Reaction Time / Q000187:drug effects; D012201:Reward; D013250:Steroid Hydroxylases / Q000235:genetics*
chemical_list: D018722:Nicotinic Agonists; D009538:Nicotine; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C460223:Cyp2a4 protein, mouse; C585520:Cyp2a5 protein, mouse; D065637:Cytochrome P-450 CYP2A6; D000072467:Cytochrome P450 Family 2
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