title: Dexfenfluramine and the oestrogen-metabolizing enzyme CYP1B1 in the development of pulmonary arterial hypertension.
abstract: OBJECTIVE
  Pulmonary arterial hypertension (PAH) occurs more frequently in women than men. Oestrogen and the oestrogen-metabolising enzyme cytochrome P450 1B1 (CYP1B1) play a role in the development of PAH. Anorectic drugs such as dexfenfluramine (Dfen) have been associated with the development of PAH. Dfen mediates PAH via a serotonergic mechanism and we have shown serotonin to up-regulate expression of CYP1B1 in human pulmonary artery smooth muscle cells (PASMCs). Thus here we assess the role of CYP1B1 in the development of Dfen-induced PAH.
  
  
  RESULTS
  Dfen (5 mg kg(-1) day(-1) PO for 28 days) increased right ventricular pressure and pulmonary vascular remodelling in female mice only. Mice dosed with Dfen showed increased whole lung expression of CYP1B1 and Dfen-induced PAH was ablated in CYP1B1(-/-) mice. In line with this, Dfen up-regulated expression of CYP1B1 in PASMCs from PAH patients (PAH-PASMCs) and Dfen-mediated proliferation of PAH-PASMCs was ablated by pharmacological inhibition of CYP1B1. Dfen increased expression of tryptophan hydroxylase 1 (Tph1; the rate-limiting enzyme in the synthesis of serotonin) in PAH-PASMCs and both Dfen-induced proliferation and Dfen-induced up-regulation of CYP1B1 were ablated by inhibition of Tph1. 17β-Oestradiol increased expression of both Tph1 and CYP1B1 in PAH-PASMCs, and Dfen and 17β-oestradiol had synergistic effects on proliferation of PAH-PASMCs. Finally, ovariectomy protected against Dfen-induced PAH in female mice.
  
  
  CONCLUSIONS
  CYP1B1 is critical in the development of Dfen-induced PAH in mice in vivo and proliferation of PAH-PASMCs in vitro. CYP1B1 may provide a novel therapeutic target for PAH.
authors.affiliation: Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, Glasgow University, West Medical Building, Glasgow G12 8QQ, UK.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Dempsie
authors.forename: Neil A
authors.initials: NA
authors.lastname: MacRitchie
authors.forename: Kevin
authors.initials: K
authors.lastname: White
authors.forename: Ian
authors.initials: I
authors.lastname: Morecroft
authors.forename: Audrey F
authors.initials: AF
authors.lastname: Wright
authors.forename: Margaret
authors.initials: M
authors.lastname: Nilsen
authors.forename: Lynn
authors.initials: L
authors.lastname: Loughlin
authors.forename: Kirsty M
authors.initials: KM
authors.lastname: Mair
authors.forename: Margaret R
authors.initials: MR
authors.lastname: MacLean
mesh_terms: D000818:Animals; D062186:Arterial Pressure; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation; D002478:Cells, Cultured; D065633:Cytochrome P-450 CYP1B1; D020372:Dexfenfluramine; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004958:Estradiol / Q000494:pharmacology; D065627:Familial Primary Pulmonary Hypertension; D005260:Female; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D009642:Norfenfluramine / Q000633:toxicity; D010052:Ovariectomy; D011651:Pulmonary Artery / Q000201:enzymology / Q000503:physiopathology; D012701:Serotonin / Q000378:metabolism; D012737:Sex Factors; D014365:Tryptophan Hydroxylase / Q000378:metabolism; D016278:Ventricular Function, Right; D017725:Ventricular Pressure
chemical_list: D004791:Enzyme Inhibitors; D009642:Norfenfluramine; D012701:Serotonin; D004958:Estradiol; D020372:Dexfenfluramine; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; C585498:Cyp1b1 protein, mouse; D065633:Cytochrome P-450 CYP1B1; C487801:Tph1 protein, mouse; D014365:Tryptophan Hydroxylase
keywords: CYP1B1; Dexfenfluramine; Oestrogen; Pulmonary arterial hypertension; Tryptophan hydroxylase