Nicotine self-administration in mice is associated with rates of nicotine inactivation by CYP2A5.
BACKGROUND
Cyp2a5, the mouse homologue of human CYP2A6, encodes for the enzyme responsible for the primary metabolism of nicotine. Variation in human CYP2A6 activity can alter the amount smoked such as number of cigarettes smoked per day and smoking intensity. Different mouse strains self-administer different amounts of oral nicotine and quantitative trait loci analyses in mice suggested that Cyp2a5 may be involved in differential nicotine consumption behaviors.


OBJECTIVE
The goal of this study was to examine whether in vivo nicotine consumption levels were associated with CYP2A5 protein levels and in vitro nicotine metabolism in mice.


METHODS
F2 mice propagated from high (C57Bl/6) and low (St/bJ) nicotine consuming mice were analyzed for CYP2A5 hepatic protein levels and in vitro nicotine metabolizing activity.


RESULTS
We found that F2 male high-nicotine (n=8; 25.1+/-1.2 microg nicotine/day) consumers had more CYP2A5 protein, compared to low (n=11; 3.8+/-1.4 microg nicotine/day) consumers (10.2+/-1.0 vs 6.5+/-1.3 CYP2A5 units). High consumers also metabolized nicotine faster than the low consumers (6 microM: 0.18+/-0.04 vs 0.14+/-0.07; 30 microM: 0.36+/- 0.06 vs 0.26+/-0.13; 60 microM: 0.49+/-0.05 vs 0.32+/-0.17 nmol/min/mg). In contrast, female high- (25.1+/-2.1 microg nicotine/day) and low-nicotine (4.7+/-1.4 microg nicotine/day) consumers did not show pronounced differences in nicotine metabolism or CYP2A4/5 protein levels; this is consistent with other studies of sex differences in response to nicotine.


CONCLUSIONS
These data suggested that among male F2 mice, increased nicotine self-administration is associated with increased rates of nicotine metabolism, most likely, as a result of greater CYP2A5 protein levels.
Centre for Addiction & Mental Health and Department of Pharmacology, University of Toronto, Toronto, Canada.
Eric C K
EC
Siu
Dieter B
DB
Wildenauer
Rachel F
RF
Tyndale
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D003433:Crosses, Genetic; D065637:Cytochrome P-450 CYP2A6; D000072467:Cytochrome P450 Family 2; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D008099:Liver / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL / Q000196:embryology; D008815:Mice, Inbred Strains / Q000235:genetics; D006899:Mixed Function Oxygenases / Q000235:genetics*; D009538:Nicotine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D010641:Phenotype; D040641:Quantitative Trait Loci / Q000235:genetics; D012646:Self Administration; D012737:Sex Factors; D014029:Tobacco Use Disorder / Q000235:genetics*
D009538:Nicotine; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C585710:CYP2A6 protein, human; C585520:Cyp2a5 protein, mouse; D065637:Cytochrome P-450 CYP2A6; D000072467:Cytochrome P450 Family 2