title: "Blue heart": characterization of a mifepristone-dependent system for conditional gene expression in genetically modified animals.
abstract: A detailed characterization of a cardiac muscle-specific, ligand-regulated gene expression system was performed in transgenic mice using the inducing ligand mifepristone (MFP). Several lines of double transgenic mice were created that expressed a bacterial lacZ reporter gene in the heart, under the control of a MFP-activated transcription factor constitutively expressed in cardiac muscle. The transgenic mice, which were administered MFP at a dose of 1 micromol/l in the drinking water, responded to the ligand within 24 h. Induction of beta-galactosidase enzyme activity in the heart continued for up to 21 days and resulted in an average 17-fold increase in enzyme activity. The highest individual animal response measured was a 94-fold increase in enzyme activity. The EC(50) for MFP induction of beta-galactosidase activity in the heart was 0.7 micromol/l when MFP was administered in the drinking water. Pharmacokinetic analysis of MFP dosing in wild-type FVB/N mice showed that absorption was very rapid (T(max) 1-10 min), bioavailability was modest ( approximately 10%) and the t(1/2) of MFP in mouse plasma was determined to be approximately 5 h. Thus, the system functions effectively in transgenic mouse heart where induction of gene expression is sensitive and can be accomplished by a simple and broadly applicable drinking water protocol.
authors.affiliation: Genomics Division, Wyeth Research, One Burtt Road, Andover, MA 01810, USA. babijp@wyeth.com
authors.forename: Philip
authors.initials: P
authors.lastname: Babij
authors.forename: George
authors.initials: G
authors.lastname: Psaltis
authors.forename: Di
authors.initials: D
authors.lastname: Song
authors.forename: John
authors.initials: J
authors.lastname: Kulik
authors.forename: Nevena
authors.initials: N
authors.lastname: Mollova
authors.forename: Ronald V
authors.initials: RV
authors.lastname: Abruzzese
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Nordstrom
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000502:physiology*; D005809:Genes, Regulator; D006367:HeLa Cells; D006321:Heart / Q000502:physiology*; D006801:Humans; D007763:Lac Operon / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D015735:Mifepristone / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics; D013997:Time Factors
chemical_list: D015735:Mifepristone