title: Extrahepatic cancer suppresses nuclear receptor-regulated drug metabolism.
abstract: OBJECTIVE
  To determine the mechanisms by which tumors situated in extrahepatic sites can cause profound changes in hepatic drug clearance, contributing to altered drug response and chemotherapy resistance.
  
  
  METHODS
  We studied in wild-type or transgenic CYP3A4 reporter mice implanted with the murine Engelbreth-Holm-Swarm sarcoma changes in nuclear receptor and hepatic transcription factor expression and/or function, particularly related to CYP3A gene regulation.
  
  
  RESULTS
  Repression of hepatic CYP3A induction was dramatic and associated with reduced levels of C/EBPβ isoforms, impaired pregnane X receptor, and constitutive androstane receptor function. Unexpectedly, extrahepatic tumors strongly reduced nuclear accumulation of retinoid X receptor alpha (RXRα) in hepatocytes, providing a potential explanation for impaired function of nuclear receptors that rely on RXRα dimerization. Profiling revealed 38 nuclear receptors were expressed in liver with 14 showing between 1.5- and four-fold reduction in expression in livers of tumor-bearing animals, including Car, Trβ, Lxrβ, Pparα, Errα/β, Reverbα/β, and Shp. Altered Pparα and γ induction of target genes provided additional evidence of perturbed hepatic metabolic control elicited by extrahepatic tumors.
  
  
  CONCLUSIONS
  Extrahepatic malignancy can affect hepatic drug metabolism by nuclear receptor relocalization and decreased receptor expression and function. These findings could aid the design of intervention strategies to normalize drug clearance and metabolic pathways in cancer patients at risk of chemotherapy-induced toxicity or cancer cachexia.
authors.affiliation: Storr Liver Unit, Westmead Millennium Institute, University of Sydney, Westmead, New South Wales, Australia.
authors.forename: Marina
authors.initials: M
authors.lastname: Kacevska
authors.forename: Michael R
authors.initials: MR
authors.lastname: Downes
authors.forename: Rohini
authors.initials: R
authors.lastname: Sharma
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Evans
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Clarke
authors.forename: Christopher
authors.initials: C
authors.lastname: Liddle
authors.forename: Graham R
authors.initials: GR
authors.lastname: Robertson
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D015536:Down-Regulation / Q000502:physiology; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D008658:Inactivation, Metabolic / Q000235:genetics; D007763:Lac Operon; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D012513:Sarcoma, Experimental / Q000235:genetics / Q000473:pathology
chemical_list: D004364:Pharmaceutical Preparations; D018160:Receptors, Cytoplasmic and Nuclear; D051544:Cytochrome P-450 CYP3A