Title: Characterization of CYP2B6 in a CYP2B6-humanized mouse model: inducibility in the liver by phenobarbital and dexamethasone and role in nicotine metabolism in vivo.
Authors: Liu, Zhihua; Li, Lei; Wu, Hong; Hu, Jing; Ma, Jun; Zhang, Qing-Yu; Ding, Xinxin
Published In Drug Metab Dispos, (2015 Feb)
Abstract: The aim of this study was to further characterize the expression and function of human CYP2B6 in a recently generated CYP2A13/2B6/2F1-transgenic (TG) mouse model, in which CYP2B6 is expressed selectively in the liver. The inducibility of CYP2B6 by phenobarbital (PB) and dexamethasone (DEX), known inducers of CYP2B6 in human liver, was examined in the TG mice, as well as in TG/Cyp2abfgs-null (or "CYP2B6-humanized") mice. Hepatic expression of CYP2B6 mRNA and protein was greatly induced by PB or DEX treatment in both TG and TG/Cyp2abfgs-null mice. Function of the transgenic CYP2B6 was first studied using bupropion as a probe substrate. In PB-treated mice, the rates of hepatic microsomal hydroxybupropion formation (at 50 μM bupropion) were >4-fold higher in TG/Cyp2abfgs-null than in Cyp2abfgs-null mice (for both male and female mice); the rate difference was accompanied by a 5-fold higher catalytic efficiency in the TG/Cyp2abfgs-null mice and was abolished by an antibody to CYP2B6. The ability of CYP2B6 to metabolize nicotine was then examined, both in vitro and in vivo. The rates of hepatic microsomal cotinine formation from nicotine were significantly higher in TG/Cyp2abfgs-null than in Cyp2abfgs-null mice, pretreated with PB or DEX. Furthermore, systemic nicotine metabolism was faster in TG/Cyp2abfgs-null than in Cyp2abfgs-null mice. Thus, the transgenic CYP2B6 was inducible and functional, and, in the absence of mouse CYP2A and CYP2B enzymes, it contributed to nicotine metabolism in vivo. The CYP2B6-humanized mouse will be valuable for studies on in vivo roles of hepatic CYP2B6 in xenobiotic metabolism and toxicity.
PubMed ID: 25409894
MeSH Terms: Animals; Anti-Inflammatory Agents/pharmacology; Aryl Hydrocarbon Hydroxylases/genetics; Aryl Hydrocarbon Hydroxylases/metabolism; Cytochrome P-450 CYP2B6 Inducers/pharmacology*; Cytochrome P-450 CYP2B6 Inhibitors/pharmacology; Cytochrome P-450 CYP2B6/chemistry; Cytochrome P-450 CYP2B6/genetics; Cytochrome P-450 CYP2B6/metabolism*; Cytochrome P-450 Enzyme System/genetics; Cytochrome P-450 Enzyme System/metabolism; Dexamethasone/pharmacology*; Enzyme Induction/drug effects; Female; Humans; Hypnotics and Sedatives/pharmacology; Liver/drug effects*; Liver/enzymology; Liver/metabolism; Male; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Nicotine/metabolism*; Phenobarbital/pharmacology*; Recombinant Proteins/chemistry; Recombinant Proteins/metabolism