title: Generation and characterization of a Cyp4b1 null mouse and the role of CYP4B1 in the activation and toxicity of Ipomeanol.
abstract: 4-Ipomeanol (IPO) is a prototypical pulmonary toxin that requires P450-mediated metabolic activation to reactive intermediates in order to elicit its toxic effects. CYP4B1 is a pulmonary enzyme that has been shown, in vitro, to have a high capacity for bioactivating IPO. In order to determine, unambiguously, the role of CYP4B1 in IPO bioactivation in vivo, we generated Cyp4b1 null mice following targeted disruption of the gene downstream of exon 1. Cyp4b1 (-/-) mice are viable and healthy, with no overt phenotype, and no evidence of compensatory upregulation of other P450 isoforms in any of the tissues examined. Pulmonary and renal microsomes prepared from male Cyp4b1 (-/-) mice exhibited no detectable expression of the protein and catalyzed the in vitro bioactivation of IPO at < 10% of the rates observed in tissue microsomes from Cyp4b1 (+/+) animals. Administration of IPO (20mg/kg) to Cyp4b1 (+/+) mice resulted in characteristic lesions in the lung, and to a lesser extent in the kidney, which were completely absent in Cyp4b1 (-/-) mice. We conclude that CYP4B1 is a critical enzyme for the bioactivation of IPO in vivo and that the Cyp4b1 (-/-) mouse is a useful model for studying CYP4B1-dependent metabolism and toxicity.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy and Medicine,University of Washington, Seattle, Washington 98195-7610, USA.
authors.forename: Oliver T
authors.initials: OT
authors.lastname: Parkinson
authors.forename: H Denny
authors.initials: HD
authors.lastname: Liggitt
authors.forename: Allan E
authors.initials: AE
authors.lastname: Rettie
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Kelly
mesh_terms: D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism*; D001711:Biotransformation; D007668:Kidney / Q000187:drug effects; D008168:Lung / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D060888:Real-Time Polymerase Chain Reaction; D013729:Terpenes / Q000493:pharmacokinetics* / Q000633:toxicity*; D014118:Toxins, Biological / Q000493:pharmacokinetics* / Q000633:toxicity*
chemical_list: D013729:Terpenes; D014118:Toxins, Biological; D001189:Aryl Hydrocarbon Hydroxylases; C095029:cytochrome P-450 CYP4B1; C001470:4-ipomeanol
keywords: cytochrome P450; knockouts; lung; metabolic activation; pulmonary or respiratory system.