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Xenogen Corporation, Alameda, California (W.Z., A.F.P., K.C., J.W., L.L., P.R.C., D.B.W.); and Xenogen Biosciences, Cranbury, New Jersey (R.C.)
Cytochrome P450 3A4 (CYP3A4) plays an important role in drug metabolism,
and the enzymatic activity of CYP3A4 contributes to many adverse drug-drug
interactions. Here we describe a transgenic mouse model that is useful in
monitoring the in vivo transcriptional regulation of the human CYP3A4
gene. A reporter construct consisting of 13 kilobases of the human CYP3A4
promoter controlling the firefly luciferase gene was used to generate a
transgenic mouse line [FVB/N-Tg(CYP3A4-luc)Xen]. Reporter gene
expression was assessed using an in vivo imaging system (IVIS) in anesthetized
mice. Basal expression of the reporter was highest in liver and kidney, and
moderate in the duodenum in male transgenic mice, whereas the basal luciferase
activity was highest in the duodenum and lower in kidney and liver in females.
Injections of pregnenolone, phenobarbital, rifampicin, nifedipine,
dexamethasone, 5-pregnen-3ß-ol-20-one-16
-carbonitrile (PCN), and
clotrimazole resulted in a time-dependent induction of luciferase expression,
primarily in liver, that peaked at 6 h post injection. The greatest induction
was found with clotrimazole, dexamethasone, and PCN, whereas the lowest
induction followed pregnenolone, phenobarbital, and rifampicin injection. In
general, male mice responded to these drugs more strongly than did females.
Our results suggest that the human CYP3A4 promoter functions in transgenic
mice and that this in vivo model can be used to study transcriptional
regulation of the CYP3A4 gene.
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