Dexfenfluramine and the oestrogen-metabolizing enzyme CYP1B1 in the development of pulmonary arterial hypertension

Cardiovasc Res. 2013 Jul 1;99(1):24-34. doi: 10.1093/cvr/cvt064. Epub 2013 Mar 20.


Aims: 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.

Methods and 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.

Conclusion: 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.

Keywords: CYP1B1; Dexfenfluramine; Oestrogen; Pulmonary arterial hypertension; Tryptophan hydroxylase.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arterial Pressure
  • Aryl Hydrocarbon Hydroxylases / antagonists & inhibitors
  • Aryl Hydrocarbon Hydroxylases / deficiency
  • Aryl Hydrocarbon Hydroxylases / genetics
  • Aryl Hydrocarbon Hydroxylases / metabolism*
  • Cell Proliferation
  • Cells, Cultured
  • Cytochrome P-450 CYP1B1
  • Dexfenfluramine*
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / pharmacology
  • Estradiol / pharmacology
  • Familial Primary Pulmonary Hypertension
  • Female
  • Hypertension, Pulmonary / chemically induced
  • Hypertension, Pulmonary / enzymology*
  • Hypertension, Pulmonary / genetics
  • Hypertension, Pulmonary / pathology
  • Hypertension, Pulmonary / physiopathology
  • Hypertension, Pulmonary / prevention & control
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Muscle, Smooth, Vascular / drug effects
  • Muscle, Smooth, Vascular / enzymology*
  • Muscle, Smooth, Vascular / pathology
  • Muscle, Smooth, Vascular / physiopathology
  • Myocytes, Smooth Muscle / drug effects
  • Myocytes, Smooth Muscle / enzymology*
  • Myocytes, Smooth Muscle / pathology
  • Norfenfluramine / toxicity
  • Ovariectomy
  • Pulmonary Artery / enzymology
  • Pulmonary Artery / physiopathology
  • Serotonin / metabolism
  • Sex Factors
  • Tryptophan Hydroxylase / metabolism
  • Ventricular Function, Right
  • Ventricular Pressure


  • Enzyme Inhibitors
  • Norfenfluramine
  • Serotonin
  • Estradiol
  • Dexfenfluramine
  • Aryl Hydrocarbon Hydroxylases
  • CYP1B1 protein, human
  • Cyp1b1 protein, mouse
  • Cytochrome P-450 CYP1B1
  • Tph1 protein, mouse
  • Tryptophan Hydroxylase