title: Extra-hepatic cancer represses hepatic drug metabolism via interleukin (IL)-6 signalling.
abstract: OBJECTIVE
  In many cancer patients, the malignancy causes reduced hepatic drug clearance leading to potentially serious complications from the use of anticancer drugs. The mechanisms underlying this phenomenon are poorly understood. We aimed to identify tumor-associated inflammatory pathways that alter drug response and enhance chemotherapy-associated toxicity.
  
  
  METHODS
  We studied inflammatory pathways involved in extra-hepatic tumor mediated repression of CYP3A, a major hepatic drug metabolizing cytochrome P450 subfamily, using a murine Engelbreth-Holm-Swarm sarcoma model. Studies in IL-6 knockout mice determined the source of elevated IL-6 in tumor-bearing animals and monoclonal antibodies against IL-6 were used to intervene in this inflammatory pathway.
  
  
  RESULTS
  Our studies confirm elevated plasma IL-6 levels and reveal activation of Jak/Stat and Mapk signalling pathways and acute phase proteins in livers of tumor-bearing mice. Circulating IL-6 was predominantly produced by the tumor xenograft, rather than being host derived. Anti IL-6 antibody intervention partially reversed tumor-mediated inflammation and Cyp3a gene repression.
  
  
  CONCLUSIONS
  IL-6 is an important player in cancer-related repression of CYP3A-mediated drug metabolism and activation of the acute phase response. Targeting IL-6 in cancer patients may prove an effective approach to alleviating cancer-related phenomena, such as adverse drug-related outcomes commonly associated with cancer chemotherapy.
authors.affiliation: Storr Liver Unit, Westmead Millennium Institute, University of Sydney, Westmead, NSW, 2145, Australia.
authors.forename: Marina
authors.initials: M
authors.lastname: Kacevska
authors.forename: Andre
authors.initials: A
authors.lastname: Mahns
authors.forename: Rohini
authors.initials: R
authors.lastname: Sharma
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Clarke
authors.forename: Graham R
authors.initials: GR
authors.lastname: Robertson
authors.forename: Christopher
authors.initials: C
authors.lastname: Liddle
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism*; D051544:Cytochrome P-450 CYP3A / Q000276:immunology / Q000378:metabolism*; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology*; D008099:Liver / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012513:Sarcoma, Experimental / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D015850:Interleukin-6; D051544:Cytochrome P-450 CYP3A