title: Functional coupling of ATP-binding cassette transporter Abcb6 to cytochrome P450 expression and activity in liver.
abstract: Although endogenous mechanisms that negatively regulate cytochrome P450 (P450) monooxygenases in response to physiological and pathophysiological signals are not well understood, they are thought to result from alterations in the level of endogenous metabolites, involved in maintaining homeostasis. Here we show that homeostatic changes in hepatic metabolite profile in Abcb6 (mitochondrial ATP-binding cassette transporter B6) deficiency results in suppression of a specific subset of hepatic P450 activity. Abcb6 null mice are more susceptible to pentobarbital-induced sleep and zoxazolamine-induced paralysis, secondary to decreased expression and activity of Cyp3a11 and Cyp2b10. The knock-out mice also show decrease in both basal and xeno-inducible expression and activity of a subset of hepatic P450s that appear to be related to changes in hepatic metabolite profile. These data, together with the observation that liver extracts from Abcb6-deficient mice suppress P450 expression in human primary hepatocytes, suggest that this mouse model may provide an opportunity to understand the physiological signals and the mechanisms involved in negative regulation of P450s.
authors.affiliation: From the Departments of Pharmacology, Toxicology and Therapeutics.
authors.forename: Hemantkumar
authors.initials: H
authors.lastname: Chavan
authors.affiliation: From the Departments of Pharmacology, Toxicology and Therapeutics.
authors.forename: Feng
authors.initials: F
authors.lastname: Li
authors.affiliation: From the Departments of Pharmacology, Toxicology and Therapeutics.
authors.forename: Robert
authors.initials: R
authors.lastname: Tessman
authors.affiliation: From the Departments of Pharmacology, Toxicology and Therapeutics.
authors.forename: Kristen
authors.initials: K
authors.lastname: Mickey
authors.affiliation: From the Departments of Pharmacology, Toxicology and Therapeutics, the Cell Isolation Core, University of Kansas Medical Center, Kansas City, Kansas 66160 and.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Dorko
authors.affiliation: Surgery.
authors.forename: Timothy
authors.initials: T
authors.lastname: Schmitt
authors.affiliation: Surgery.
authors.forename: Sean
authors.initials: S
authors.lastname: Kumer
authors.affiliation: Molecular and Integrative Physiology, and Biostatistics and.
authors.forename: Sumedha
authors.initials: S
authors.lastname: Gunewardena
authors.affiliation: the Departments of Nutrition and Environmental Toxicology and the West Coast Metabolomics Center, University of California, Davis, California 95616.
authors.forename: Nilesh
authors.initials: N
authors.lastname: Gaikwad
authors.affiliation: From the Departments of Pharmacology, Toxicology and Therapeutics, pkasturi@kumc.edu.
authors.forename: Partha
authors.initials: P
authors.lastname: Krishnamurthy
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D017931:DNA Primers; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D013058:Mass Spectrometry; D051379:Mice
chemical_list: D018528:ATP-Binding Cassette Transporters; C514489:Abcb6 protein, mouse; D017931:DNA Primers; D003577:Cytochrome P-450 Enzyme System
keywords: ABC Transporter; Cytochrome P450; Gene Regulation; Membrane Transport; Metabolic Regulation