Evaluation of CYP1A2 Activity in Thalassemia Patients

Abstract

The thalassemias are common genetic diseases among the Thai population. The

autooxidation of globin chains and iron overload are the suggested mechanisms for the

enhanced generation of reactive oxygen species and ensuing oxidative stress. It has been

reported that the oxidative stress alters function of the drug metabolizing enzymes system.

However, several cellular adaptive compensations against oxidative stress may modify the

outcome of the activity of the enzymes. The aim of this study was to evaluate the drug

metabolizing enzyme status in thalassemia patients, particularly to examine the activity of

CYP1A2, and to determine factors influencing its activity. The study included the regular

blood transfusion β-thalassemia I HbE patients (n = 23) and the healthy controls (n = 25).

The CYP1A2 activity was assessed by using caffeine as a probe drug. The caffeine and

its major metabolite, paraxanthine, in saliva and plasma at 6 h after drug intake, were

analyzed by high performance liquid chromatography (HPLC). The enzyme activity was

determined from the caffeine metabolic ratio (CMR), paraxanthine I caffeine. The oxidative

status was quantified by measuring the concentrations of plasma and whole blood total

glutathione. Moreover, the concentrations of hemoglobin, uric acid, total bilirubin. ALT

and AST were analysed in both groups. The results showed that the salivary CMR

highly correlated with the plasma CMR (r = 0.9772, p = 0.0001). The salivary and plasma

CMR in thalassemia patients were not significantly different in comparison with the

control group (plasma CMR : 0.759 ± 0.043 vs 0.775 ± 0.062 for control group and

thalassemia patients, respectively). Similarly, there was no significant difference between

the two groups in the concentrations of plasma total glutathione, whereas, the whole

blood total glutathione was significantly decreased in thalassemia patients (p < 0.05).

Correlations between parameters were analysed by using multiple linear regression

analysis. In the control group, none of the parameters correlated with the CMRs. In

contrast, the plasma CMR correlated significantly with the concentrations of total

glutathione, total bilirubin, ALT and AST in the thalassemia patients (r = 0.65 , p < 0.05).

In conclusion the CYP1A2 activity in thalassemia patients was not significantly altered

and its activity in these patients may be affected by the oxidative stress responses.