title: Molecular imaging of cytochrome P450 activity in mice.
abstract: Detailed knowledge of drug metabolism is relevant information provided by preclinical drug development research. Oxidative enzymes such as those belonging to P450 family of cytochromes (CYP) play a prominent role in drug metabolism. Here, we propose an innovative method based on bioluminescence in vivo imaging which has the potential to simplify the in vivo measurement of CYP activity also providing a dynamic measure of the effects of a drug on a specific P450 enzyme complex in a living mouse. The method is based on a pro-luciferin which can be converted into the active luciferase substrate by a specific P450 activity. The pro-luciferin is administered to a luciferase reporter mouse which produces luminescent signals in relation to the cytochrome activity present in each tissue. The photon emission generated can be easily localized and quantified by optical imaging. To demonstrate the validity of the system, we pharmacologically induced hepatic Cyp3a in the reporter mouse and proved that pro-luciferin administration generates a Cyp3a selective signal in the chest area that can be efficiently detected by optical imaging. The kind of tool generated has the potential to be exploited for the study of additional CYPs.
authors.affiliation: Top (Transgenic Operative Products) Srl, via Einstein, 26900 Lodi, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Roncoroni
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Rizzi
authors.forename: Electra
authors.initials: E
authors.lastname: Brunialti
authors.forename: James J
authors.initials: JJ
authors.lastname: Cali
authors.forename: Dieter H
authors.initials: DH
authors.lastname: Klaubert
authors.forename: Adriana
authors.initials: A
authors.lastname: Maggi
authors.forename: Paolo
authors.initials: P
authors.lastname: Ciana
mesh_terms: D000080:Acetals / Q000378:metabolism; D000818:Animals; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology; D049454:Firefly Luciferin / Q000031:analogs & derivatives / Q000378:metabolism; D017930:Genes, Reporter; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D049409:Luciferases, Firefly / Q000235:genetics / Q000378:metabolism; D049408:Luminescent Agents / Q000378:metabolism; D008163:Luminescent Measurements; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D013379:Substrate Specificity; D014018:Tissue Distribution
chemical_list: D000080:Acetals; D049408:Luminescent Agents; D011994:Recombinant Proteins; C544336:luciferin-isopropyl acetal; D049454:Firefly Luciferin; D003907:Dexamethasone; D049409:Luciferases, Firefly; D051544:Cytochrome P-450 CYP3A