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Regulation and Function of CYP2B6 in A CYP2A13/2B6/2F1‐transgenic Mouse Model
Author(s) -
Liu Zhihua,
Li Lei,
Wu Hong,
Ding Xinxin
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.1180.3
Subject(s) - cyp2b6 , transgene , genetically modified mouse , in vivo , pharmacology , inducer , endocrinology , medicine , cytochrome p450 , chemistry , biology , metabolism , biochemistry , cyp3a4 , microbiology and biotechnology , gene
In CYP2A13/2B6/2F1‐transgenic (TG) mice, the tissue distribution of CYP2B6 transgene expression agreed with the known hepatic expression of CYP2B6 in humans (Wei et al., Drug Metab. Dispos. 40:1144–1150, 2012). The aim of this study is to further characterize the expression and function of CYP2B6 in the TG mouse. We examined inducibility of the CYP2B6 transgene by phenobarbital (PB) and dexamethasone (DEX), known inducers of CYP2B6 in human liver. Expression of CYP2B6 mRNA and protein was dramatically induced by both PB and DEX (80 mg/kg/day, i.p. for three days) in the liver, but not in other tissues examined, including lung, brain, small intestine, and kidney, where CYP2B6 protein was undetected. To determine whether the transgenic CYP2B6 is functional, we studied a CYP2B6‐humanized (TG/Cyp2abfgs‐null) mouse, generated by intercrossing between TG mice and newly generated Cyp2abfgsnull mice. We found that the rates of cotinine formation from nicotine in hepatic microsomes of the TG/Cyp2abfgs‐null mice were significantly higher than those in Cyp2abfgs‐null mice, either before or after CYP2B6 induction by DEX. These results indicate that the transgenic CYP2B6 is functional, and its expression in the liver can be induced by known CYP2B6 inducers. The TG/Cyp2abfgs‐null mouse is thus a useful in vivo model to study functional consequences of hepatic CYP2B6 expression/induction on drug metabolism and toxicity.