title: Activation of the aryl hydrocarbon receptor by doxorubicin mediates cytoprotective effects in the heart.
abstract: OBJECTIVE
  Doxorubicin (DOX) is a highly effective chemotherapeutic agent; however, cumulative dose-dependent cardiotoxicity is a significant side effect of this therapy. Because DOX is a polyaromatic hydrocarbon, we hypothesized that it will be metabolized by the activation of the aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor that is involved in the metabolism of numerous xenobiotic agents. These studies were performed to determine whether DOX activates AhR and whether this activation modulates the toxicity of DOX in cardiomyocytes.
  
  
  RESULTS
  Treatment with DOX induced AhR migration to the nucleus, increased AhR binding with its co-factor, aryl hydrocarbon receptor nuclear translocator-1 (ARNT1), and increased the expression of AhR-regulated phase I (CYP1A1) and phase II (GSTA1) drug-metabolizing enzymes in both cardiomyocytes and in the intact heart. Knockdown of AhR in H9C2 cells abolished DOX-induced increases in CYP1A1 and GSTA1 expression. Similar results were obtained by treating adult rat ventricular myocytes with the AhR antagonist, CH-223191. Taken together, these findings indicate that DOX-induced upregulation of CYP1A1 and GSTA1 expression is AhR dependent. AhR null mice treated with 10 mg/kg DOX did not show any activation of CYP1A1 or GSTA1 expression. Moreover, lack of AhR in vivo resulted in a significant decrease in left ventricular function compared with wild-type animals, and increased p53 activation and apoptosis in the heart after treatment with DOX.
  
  
  CONCLUSIONS
  These findings indicate that AhR plays an important role in DOX metabolism by the heart and further demonstrate that AhR is cardioprotective against DOX-induced cardiotoxicity.
authors.affiliation: Section of Cardiovascular Medicine, Yale University School of Medicine, 333 Cedar Street, FMP 3, New Haven, CT 06520, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Volkova
authors.forename: Monica
authors.initials: M
authors.lastname: Palmeri
authors.forename: Kerry S
authors.initials: KS
authors.lastname: Russell
authors.forename: Raymond R
authors.initials: RR
authors.lastname: Russell
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000493:pharmacokinetics / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D054715:Cardiotoxins / Q000493:pharmacokinetics / Q000633:toxicity*; D004317:Doxorubicin / Q000493:pharmacokinetics / Q000633:toxicity*; D006321:Heart / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D034741:RNA, Small Interfering; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: C497398:ARNT protein, rat; D000903:Antibiotics, Antineoplastic; C497397:Arnt protein, mouse; D054715:Cardiotoxins; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D004317:Doxorubicin