title: Phosphorylation of cytochromes P450: first discovery of a posttranslational modification of a drug-metabolizing enzyme.
abstract: Cytochromes P450 (CYP) are important components of xenobiotic-metabolizing monooxygenases (CYP-dependent monooxygenases). Their regulation by induction, most commonly by transcriptional activation, mediated by xenobiotics, normally substrates of the corresponding CYP, is well known and has been widely studied. Our team has discovered an additional important regulation of xenobiotic-metabolizing CYPs pertaining to posttranslational modification by phosphorylation. Individual CYPs are phosphorylated by different protein kinases, leading to CYP isoenzyme-selective changes in the metabolism of individual substrates and consequent drastic changes in the control of genotoxic metabolites. Best studied are the CYP phosphorylations by the cAMP-dependent protein kinase A. Most recently, we discovered that cAMP not only leads to drastic changes in the activity of individual CYPs, but also to drastic changes in the nuclear localization of the CYP-related transcription factor Ah receptor (AHR). The consequences are very different from those of AHR nuclear translocation mediated by the classical ligands (enzyme inducers such as dioxin) and are likely to represent the long-sought physiological function of the AHR, its persistent disturbance by long-lived ligands such as dioxin may well be the reason for its high toxicity.
authors.affiliation: Institute of Toxicology, University of Mainz, Obere Zahlbacherstr. 67, D-55131 Mainz, Germany. oeschb@uni-mainz.de
authors.forename: B
authors.initials: B
authors.lastname: Oesch-Bartlomowicz
authors.forename: F
authors.initials: F
authors.lastname: Oesch
mesh_terms: D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000166:cytology / Q000201:enzymology; D009153:Mutagens / Q000378:metabolism; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational / Q000502:physiology*
chemical_list: D009153:Mutagens; D003577:Cytochrome P-450 Enzyme System