title: Role of nuclear factor-erythroid 2-related factor 2 (Nrf2) in the transcriptional regulation of brain ABC transporters during acute acetaminophen (APAP) intoxication in mice.
abstract: Changes in expression of liver ABC transporters have been described during acute APAP intoxication. However, the effect of APAP on brain ABC transporters is poorly understood. The aim of this study was to evaluate the effect of APAP on brain ABC transporters expression and the role of the oxidative stress sensor Nrf2. Male C57BL/6J mice were administered APAP (400mg/kg) for analysis of brain mRNA and protein expression of Mrp1-6, Bcrp and P-gp. The results show induction of P-gp, Mrp2 and Mrp4 proteins, with no changes in Bcrp, Mrp1 or Mrp5-6. The protein values were accompanied by corresponding changes in mRNA levels. Additionally, brain Nrf2 nuclear translocation and expression of two Nrf2 target genes,
  quinone oxidoreductase 1 (Nqo1) and Hemoxygenase 1 (Ho-1), was evaluated at 6, 12 and 24h after APAP treatment. Nrf2 nuclear content increased by 58% at 12h after APAP along with significant increments in mRNA and protein expression of Nqo1 and Ho-1. Furthermore, APAP treated Nrf2 knockout mice did not increase mRNA or protein expression of Mrp2 and Mrp4 as observed in wildtypes. In contrast, P-gp induction by APAP was observed in both genotypes. In conclusion, acute APAP intoxication induces protein expression of brain P-gp, Mrp2 and Mrp4. This study also suggests that brain changes in Mrp2 and Mrp4 expression may be due to in situ Nrf2 activation by APAP, while P-gp induction is independent of Nrf2 function. The functional consequences of these changes in brain ABC transporters by APAP deserve further attention.
authors: Instituto de Investigaciones Farmacológicas (ININFA), Facultad de Farmacia y Bioquímica, CONICET, Universidad de Buenos Aires, Buenos Aires, Argentina; Cátedra de Fisiopatología. Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina.
authors: Carolina I
authors: CI
authors: Ghanem
authors: Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT, United States.
authors: Swetha
authors: S
authors: Rudraiah
authors: Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT, United States.
authors: Amy M
authors: AM
authors: Bataille
authors: Instituto de Investigaciones Farmacológicas (ININFA), Facultad de Farmacia y Bioquímica, CONICET, Universidad de Buenos Aires, Buenos Aires, Argentina.
authors: María B
authors: MB
authors: Vigo
authors: Office of Translational Science, Rutgers University, Piscataway, NJ 08854, United States.
authors: Michael J
authors: MJ
authors: Goedken
authors: Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT, United States. Electronic address: jose.manautou@uconn.edu.
authors: José E
authors: JE
authors: Manautou
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000082:Acetaminophen / Q000506:poisoning*; D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D017931:DNA Primers; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051267:NF-E2-Related Factor 2 / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D014158:Transcription, Genetic / Q000502:physiology*
chemical_list: D018528:ATP-Binding Cassette Transporters; D017931:DNA Primers; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D012333:RNA, Messenger; D000082:Acetaminophen
keywords: ABC transporters; Acetaminophen; Brain; Nrf2