Abstract
The objective of this study was to investigate the regulation of X-ray irradiation and its effect on the activity and protein and mRNA expression levels of CYP1A2 and CYP2E1 in rats. Rats were randomly divided into 0 Gy (control), 1 Gy (low-dose irradiation), and 5 Gy (high-dose irradiation) groups. CYP1A2 and CYP2E1 activity was evaluated from changes in pharmacokinetic parameters of caffeine and chlorzoxazone, respectively. The plasma concentrations of the probe drugs were determined by high-performance liquid chromatography (HPLC). Enzyme-linked immunosorbent assay (ELISA) and real-time polymerase chain reaction (PCR) tests were used to analyze the protein and mRNA expression levels of CYP1A2 and CYP2E1, respectively. The AUC0-12 of caffeine was decreased by 1.7- and 2.5-fold, and the CL was increased by 1.8- and 2.6-fold in the 1 Gy and 5 Gy groups, respectively, compared to the 0 Gy group. The AUC0-10 of chlorzoxazone was 1.4- and 1.8-fold lower, and the CL was 1.4- and 1.9-fold higher in the 1 Gy and 5 Gy groups, respectively, compared to the 0 Gy group. The metabolism of caffeine and chlorzoxazone increased under X-ray irradiation as CL levels increased and AUC levels decreased, suggesting that CYP1A2 and CYP2E1 activity is enhanced in rats after X-ray irradiation. Compared to that of the 0 Gy group, the protein expression level of CYP1A2 was measured as 28.3% and 38.9% higher in the 1 Gy and 5 Gy groups, respectively. The protein expression level of CYP2E1 was 48.4% higher in the 5 Gy group compared to the 0 Gy group, and there was no statistically significant difference between 0 Gy and 1 Gy. Compared to the 0 Gy group, the mRNA expression level of CYP1A2 was 200% and 856.3% higher in the 1 Gy and 5 Gy group, respectively, whereas the mRNA expression level of CYP2E1 was 89.0% and 192.3% higher in the 1 Gy and 5 Gy groups, respectively. This study reveals significant changes in the activity and protein and mRNA expression levels of CYP1A2 and CYP2E1 in rats after exposure to X-ray irradiation.
Highlights
Cytochrome P450 enzyme-based drug metabolism is dependent on oxygen
Due to differences observed among individuals, there are some limitations in evaluating CYP450 activity from the ratio of probe drugs and their metabolites at a certain time point
Caffeine and chlorzoxazone were selected as probe drugs for CYP1A2 and CYP2E1, respectively, and CYP1A2 and CYP2E1 activity was evaluated from pharmacokinetic changes in the probes
Summary
Cytochrome P450 enzyme-based drug metabolism is dependent on oxygen. Interindividual differences in P450 isozyme activity are attributable to genetic polymorphisms and specific xenobiotic induction or inhibition (Eichelbaum et al, 1992; Guengerich, 1995). Our understanding of the role of nonchemical factors, including biophysical influences, disorders, pathological states, and various constitutional properties of interindividual variations in hepatic drug metabolism, remains limited (Jones et al, 1989; Vesell, 1997). Compared to g-rays, X-ray irradiation units are less expensive and have no radioactive source. Scientists have uncovered a series of physiological variations and pathological divergences induced by irradiation, and these influence drug absorption, distribution, metabolism, and excretion from the body (Rendic and Guengerich, 2012; Qiao et al, 2017). Additional changes in drug metabolism observed after irradiation have been reported with an increasing amount of cancer patients treated conventionally with radiotherapy methods (Rendic and Guengerich, 2010; Rendic and Guengerich, 2012; Qiao et al, 2017)
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