title: Effect of Traumatic Brain Injury, Erythropoietin, and Anakinra on Hepatic Metabolizing Enzymes and Transporters in an Experimental Rat Model.
abstract: In contrast to considerable data demonstrating a decrease in cytochrome P450 (CYP) activity in inflammation and infection, clinically, traumatic brain injury (TBI) results in an increase in CYP and UDP glucuronosyltransferase (UGT) activity. The objective of this study was to determine the effects of TBI alone and with treatment with erythropoietin (EPO) or anakinra on the gene expression of hepatic inflammatory proteins, drug-metabolizing enzymes, and transporters in a cortical contusion impact (CCI) injury model. Microarray-based transcriptional profiling was used to determine the effect on gene expression at 24 h, 72 h, and 7 days post-CCI. Plasma cytokine and liver protein concentrations of CYP2D4, CYP3A1, EPHX1, and UGT2B7 were determined. There was no effect of TBI, TBI + EPO, or TBI + anakinra on gene expression of the inflammatory factors shown to be associated with decreased expression of hepatic metabolic enzymes in models of infection and inflammation. IL-6 plasma concentrations were increased in TBI animals and decreased with EPO and anakinra treatment. There was no significant effect of TBI and/or anakinra on gene expression of enzymes or transporters known to be involved in drug disposition. TBI + EPO treatment decreased the gene expression of Cyp2d4 at 72 h with a corresponding decrease in CYP2D4 protein at 72 h and 7 days. CYP3A1 protein was decreased at 24 h. In conclusion, EPO treatment may result in a significant decrease in the metabolism of Cyp-metabolized drugs. In contrast to clinical TBI, there was not a significant effect of experimental TBI on CYP or UGT metabolic enzymes.
authors.affiliation: Department of Pharmacy, University of Washington, Seattle, Washington, 98195, USA, gaila@washington.edu.
authors.forename: Gail D
authors.initials: GD
authors.lastname: Anderson
authors.forename: Todd C
authors.initials: TC
authors.lastname: Peterson
authors.forename: Cole
authors.initials: C
authors.lastname: Vonder Haar
authors.forename: Fred M
authors.initials: FM
authors.lastname: Farin
authors.forename: Theo K
authors.initials: TK
authors.lastname: Bammler
authors.forename: James W
authors.initials: JW
authors.lastname: MacDonald
authors.forename: Eric D
authors.initials: ED
authors.lastname: Kantor
authors.forename: Michael R
authors.initials: MR
authors.lastname: Hoane
mesh_terms: D000818:Animals; D001930:Brain Injuries / Q000150:complications* / Q000188:drug therapy / Q000503:physiopathology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D004921:Erythropoietin / Q000494:pharmacology*; D005786:Gene Expression Regulation; D014453:Glucuronosyltransferase / Q000378:metabolism; D007249:Inflammation / Q000473:pathology; D053590:Interleukin 1 Receptor Antagonist Protein / Q000494:pharmacology*; D015850:Interleukin-6 / Q000097:blood; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D026901:Membrane Transport Proteins / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
chemical_list: D016207:Cytokines; D053590:Interleukin 1 Receptor Antagonist Protein; D015850:Interleukin-6; D026901:Membrane Transport Proteins; D004921:Erythropoietin; D003577:Cytochrome P-450 Enzyme System; D014453:Glucuronosyltransferase