Hydroxyurea Therapy Mobilises Arachidonic Acid from Inner Cell Membrane Aminophospholipids in Patients with Homozygous Sickle Cell Disease

A A Daak,K Ghebremeskel,Z Hassan,M A Crawford,M I Elbashir,A Bakhita

doi:10.1155/2011/718014

A A Daak, K Ghebremeskel + Show 4 more

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https://doi.org/10.1155/2011/718014

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Abstract

The cytotoxic compound hydroxyurea (HU) is effective therapy for sickle cell disease. However, its effect on unsaturated membrane lipids is unknown. Red cell fatty acids were investigated in HU-treated (n = 19) and HU-untreated (n = 17) sickle cell patients and controls (n = 20). The HU-treated compared with the HU-untreated patients had lower arachidonic (AA) acid level in ethanolamine, physphoglycerids (EPG) (22.9 ± 1.2 versus 24.0 ± 1.1%, P < 0.05) serine SPG (22.13 ± 2.2 versus 24.9 ± 2.3%, P < 0.01) phosphoglycerides. The treated patients and controls had comparable levels of docosahexaenoic (DHA) and total n-3 fatty acids in EPG and choline phosphoglycerides (CPG). In contrast, the untreated group had significantly (P < 0.05) lower DHA and total n-3 compared with the controls in EPG (2.7 ± 0.4 versus 3.2 ± 0.6% and 4.6 ± 0.5 versus 5.2 ± 0.7%) and CPG (0.7 ± 0.2 versus 1.0 ± 0.2% and 1.2 ± 0.2 versus 1.4 ± 0.3). HU is known to activate cytosolic phospholipase A2 and cyclooxygenase 2, and from this study, it appears to induce mobilisation of AA from the inner cell membrane EPG and SPG. Hence, eicosanoids generated from the released AA may play a role in clinical improvements which occur in HU-treated patients.

Highlights

Hydroxyurea (HU) is effective therapy for adults, children and infants with severe sickle cell disease [1,2,3,4]
Steady-state sickle cell patients not treated with HU have abnormal red blood cell (RBC), platelets and mononuclear cell fatty acids, which is characterised by an increase in arachidonic acid (AA, 20:4n-6) and a decrease in linoleic acid (LA, 18:2n-6), eicosapentaenoic acid (EPA, 20:5n-3), and docosahexaenoic acid (DHA, 22:6n-3) [13,14,15]
These findings have led to the postulation that “an imbalance of blood cell membrane n-3 and n-6 fatty acids may be the antecedent of loss of membrane asymmetry, blood cell adhesion, aggregation and, vasoocclusion in SCD’’ [16]

Summary

Introduction

Hydroxyurea (HU) is effective therapy for adults, children and infants with severe sickle cell disease [1,2,3,4]. Steady-state sickle cell patients not treated with HU have abnormal RBC, platelets and mononuclear cell fatty acids, which is characterised by an increase in arachidonic acid (AA, 20:4n-6) and a decrease in linoleic acid (LA, 18:2n-6), eicosapentaenoic acid (EPA, 20:5n-3), and docosahexaenoic acid (DHA, 22:6n-3) [13,14,15]. These findings have led to the postulation that “an imbalance of blood cell membrane n-3 and n-6 fatty acids may be the antecedent of loss of membrane asymmetry, blood cell adhesion, aggregation and, vasoocclusion in SCD’’ [16]. The aim of this study was to elucidate whether HU treatment modulates RBC membrane fatty acids of steadystate homozygous sickle cell patients (HbSS)

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