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)bgsnull] 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)bgsnull 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)bgsnull 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.

Characterization of CYP2B6 in a CYP2B6-Humanized Mouse Model: Inducibility in the Liver by Phenobarbital and Dexamethasone and Role in Nicotine Metabolism In Vivo

“…The role of mouse CYP2A and 2B enzymes in nicotine metabolism and nicotine's pharmacological effects and behavioral responses were demonstrated recently using a Cyp2a(4/5)bgs-null mouse model (Li et al, 2013). In the present study, the lack of a substantial induction by PB or DEX of nicotine oxidase activity in the Cyp2abfgs-null mice supports the notion that the residual mouse P450s that are also induced by PB or DEX in the Cyp2abfgs-null mice, including CYP3A and CYP2C (Fig.…”

Role of CYP2B in Phenobarbital-Induced Hepatocyte Proliferation in Mice

“…Among the deleted genes, only Cyp2a4/5 and Cyp2b9/10/13 are expressed in liver, and Cyp2a4 and Cyp2b9/13 are female predominant (Damiri et al, 2012;Li et al, 2013). The deletion of the gene cluster did not lead to any notable developmental or morphologic changes, and there was no significant compensatory change in the expression of CPR or various other major P450 enzymes, including CYP2C, CYP3A, CYP2E1, and CYP1A1/2 (Wei et al, 2013).…”

“…Of the Cyp2b genes, whereas Cyp2b9, 2b10, and 2b13 are all expressed in the liver, Cyp2b9 and 2b13 are female predominant (Damiri et al, 2012;Li et al, 2013) and Cyp2b10 is the most highly induced by PB (Li-Masters and Morgan, 2001). Thus, it can be deduced that Cyp2b10 was involved in PB-induced hepatocyte proliferation in male mice.…”

Involvement of the H+/Organic Cation Antiporter in Nicotine Transport in Rat Liver

“…In humans, the genetic polymorphisms of CYP2A6, the hepatic enzyme involved in nicotine metabolism (Nakajima et al, 2000), alter pharmacokinetics of nicotine, and individuals with a higher activity of CYP2A6 tend to develop tobacco dependence (Ray et al, 2009). In an in vivo study in mice lacking the P450 enzyme involved in nicotine metabolism, the pharmacokinetic parameters for nicotine, such as its half-life in blood and the area under the blood concentration-time curve, were altered to increase the sensitivity to rewarding effects of nicotine (Li et al, 2013). These lines of evidence strongly suggest that the hepatic clearance of nicotine affects the pharmacological response to nicotine.…”