Somparn Nuntiya, Kukongviriyapan Upa, Tassaneeyakul Wichittra, Jetsrisuparb Arunee, Kukongviriyapan Veerapol
Department of Pharmacology, Faculty of Medicine, Khon Kaen University, 40002 Khon Kaen, Thailand.
Eur J Clin Pharmacol. 2007 Jan;63(1):43-50. doi: 10.1007/s00228-006-0224-x. Epub 2006 Nov 21.
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.
地中海贫血是一种遗传性血红蛋白病，通常与铁过载和一定程度的器官损害有关。该疾病对药物代谢酶细胞色素P450（CYP）的影响尚不清楚。CYP2E1和CYP3A4负责大量药物的代谢，其活性变化可能会产生临床后果。
本研究招募了明显无并发症的血红蛋白E-β地中海贫血儿科输血依赖患者（n = 35）和健康对照者（n = 42）。血浆6-羟基氯唑沙宗与氯唑沙宗的比率以及尿6-β-羟基皮质醇（6β-OHF）与皮质醇的比率分别用作CYP2E1和CYP3A4活性的指标。对血液和血浆样本进行临床生化、氧化剂和抗氧化剂参数检测。
地中海贫血患者的血清铁、蛋白质羰基和脂质过氧化显著增加，而血液谷胱甘肽减少，但血浆一氧化氮代谢产物不变。患者的CYP2E1活性未改变；然而，当根据脾切除状态对患者进行分层时，与对照组和脾切除患者相比，未行脾切除患者的CYP2E1活性增加。另一方面，与生长激素水平降低相关的患者中6β-OHF/皮质醇比率显著增加。CYP2E1活性与氧化应激或抗氧化参数之间无相关性。
本报告首次证明重型地中海贫血与CYP2E1和CYP3A4活性改变有关；这可能会改变地中海贫血患者对药物毒性或治疗作用的敏感性。
