Modification of CYP2E1 and CYP3A4 activities in haemoglobin E-beta thalassemia patients

Abstract

Thalassemia disease is a genetic haemoglobinopathy usually associated with an iron overload and some degree of organ impairment. The impact of the disease on the drug metabolising enzyme cytochrome P450 (CYP) is not known. CYP2E1 and CYP3A4 are responsible for the metabolism of a large number of drugs and changes in their activities may have clinical consequences. Haemoglobin E-beta thalassemia paediatric, blood transfusion-dependent patients apparently without complications (n = 35) and healthy controls (n = 42) were recruited in this study. The ratios of plasma 6-hydroxychlorzoxazone to chlorzoxazone, and urinary 6-beta-hydroxycortisol (6beta-OHF) to cortisol were used as indices for CYP2E1 and CYP3A4 activities, respectively. Blood and plasma samples were assayed for parameters of clinical biochemistry, oxidants and antioxidants. There were significant increases in serum iron, protein carbonyl and lipid peroxidation in thalassemia patients, whereas there was a decrease in blood glutathione, but unchanged plasma nitric oxide metabolites. CYP2E1 activity in the patients was unchanged; however, when the patients were stratified by splenectomy status, CYP2E1 activity was increased in non-splenectomised patients in comparison with the controls and splenectomised subjects. On the other hand, 6beta-OHF/cortisol ratios increased markedly in patients associated with depressed growth hormone levels. There were no correlations between CYP2E1 activity and oxidant stress or antioxidant parameters. This report is the first demonstration that thalassemia major is associated with an alteration of CYP2E1 and CYP3A4 activities; this could modify the sensitivity of thalassemia patients to the toxic or therapeutic effects of drugs.