RESUMEN
The pharmacokinetic characteristics of drugs were altered under high altitude hypoxia, thereby affecting the absorption, distribution, metabolism, and excretion of drug. However, there are few literatures on the pharmacokinetic changes of antipyretic and pain-relieving drugs and cardiovascular system drugs at high altitude. This study aimed to evaluate the pharmacokinetics of acetaminophen and metformin hydrochloride in rats under simulated high altitude hypoxia condition. Mechanically, the protein and mRNA expression of uridine diphosphate glucuronyltransferase 1A1 (UGT1A1) and organic cation transporter 2 (OCT2) were investigated by enzyme linked immunosorbent assay (ELISA) and quantitative real-time polymerase chain reaction (qRT-PCR), respectively. Compared with the normoxia group, the t1/2 and AUC of acetaminophen were significantly increased, and the CL/F was significantly decreased in rats after exposure to simulated high altitude hypoxia. The t1/2 of metformin hydrochloride was significantly increased by simulated high altitude hypoxia. No significant differences in AUC and CL/F of metformin hydrochloride were observed when comparing the hypoxia group with the normoxia group. The protein and mRNA expression of UGT1A1 and OCT2 were decreased significantly under hypoxia in rats. This study found obvious changes in the pharmacokinetics of acetaminophen and metformin hydrochloride in rats after exposure to simulated high altitude hypoxia, and they might be due to significant decreases in the expressions of UGT1A1 and OCT2. To sum up, our data suggested that the pharmacokinetics of acetaminophen and metformin hydrochloride should be reexamined, and the optimal dose should be reassessed under hypoxia exposure.
RESUMEN
Little is known about what roles the pregnane X receptor (PXR) and constitutive androstane receptor (CAR) play in drug metabolism in high-altitude hypoxia. Likewise, the potential interaction of nuclear receptors and drug metabolism enzymes during drug metabolism of high-altitude hypoxia is not fully understood. In this work, we investigated the effects of high-altitude hypoxia on transcriptional regulation of cytochrome P450 (CYP450) and UDP-glucuronosyltransferase 1A1 (UGT1A1) genes mediated by PXR and CAR proteins. The protein and mRNA expressions of CYP450, UGT1A1, PXR, and CAR were determined by enzyme-linked immunosorbent assay and qPCR in rats and HepG2 cell lines under hypoxia. Hypoxia potently inhibited the CYP450 isoforms, UGT1A1, PXR, and CAR protein and mRNA expression. To clarify whether PXR and CAR regulate various genes involved in drug metabolism of high-altitude hypoxia, we investigated the expression of CYP1A2, CYP2C9, CYP2E1, CYP3A4, and UGT1A1 using a dual-luciferase reporter assay after treatment with Ketoconazole (KCZ) and Retinoic acid (RA), or silenced PXR and CAR gene expression. In HepG2 cells, hypoxia, KCZ, and RA inhibited CYP450 isoforms and UGT1A1 expression. Activation of PXR and CAR in cells treated with 6-(4-chlorophenyl)-imidazo (2,1-b) thiazole-5-carbaldehyde (CITCO) and rifampicin (Rif) resulted in the enhancement of CYP450 isoforms, UGT1A1, PXR, and CAR. In contrast, this effect was not observed under hypoxia. Taken together, our results suggest that hypoxia inhibits CYP1A2, CYP2C9, CYP2E1, CYP3A4, and UGT1A1 expression via the PXR and CAR regulatory pathway.
RESUMEN
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.
RESUMEN
OBJECTIVE: To study the protective effect of Lycium ruthenicum on peripheral blood system against radiation injury in mice. METHODS: Kunming mice were randomly divided into control group, model group, positive group and Lycium ruthenicum high dose (8 g/kg), middle dose (4 g/kg) and low dose (2 g/kg)treatment groups that experimented three days after irradiation. In the same way, groups were set at 7 days and 14 days after irradiation respectively. Lycium ruthenicum extract were administered orally to the mice in the three Lycium ruthenicum treatment groups and normal saline were administered orally to the mice in control group and model group for 14 days. Positive group were treated with radioprotective agent amifostine (WR-2721) at 30 min before irradiation. Except control group, mice in other groups received quantity of 5 Gy X-radiation whole body evenly with one time. Hemogram, organ index, DNA, Caspase-3, Caspase-6 and P53 contents were observed at the 3rd, 7th and 14th day after irradiation. RESULTS: Lycium ruthenicum significantly increased the total red blood cell count, hemoglobin count, the indexes of spleen and thymus and bone marrow DNA contents (P < 0.05), as well as decreased Caspase-3 and Caspase-6 contents in serum and the expression of P53 in intestinal crypt epithelial cells. CONCLUSION: The results showed that Lycium ruthenicum had protective effects on peripheral blood system against radiation injury in mice.
