In this study, we investigated the effect of type 1 diabetes mellitus on the modulation of the activities of CYP450s in dynamics by a UHPLC-MS/MS method. The diabetic rat model was constructed by an intraperitoneal single injection of streptozotocin . Fasting blood glucose levels > 16.7 mmol/L were considered as diabetic. The rats were given a cocktail of four probe drugs (10 mg/kg phenacetin , 1 mg/kg tolbutamide , 10 mg/kg metoprolol , and 10 mg/kg midazolam) by oral administration for the pharmacokinetic study. Thereafter, the metabolic ratio (MR) of the metabolites to probe substrates were determined. The results indicated that two weeks after diabetes was induced, diabetes increased the MRs of acetaminophen/phenacetin (CYP1A2) and 4-hydroxyl tolbutamide/tolbutamide (CYP2C9); however, it decreased the MRs of α-hydroxy metoprolol/metoprolol (CYP2D6) and 1-hydroxy midazolam/midazolam (CYP3A4). Two months after diabetes was induced, diabetes increased the MRs of acetaminophen/phenacetin and 4-hydroxyl tolbutamide/tolbutamide. The MR of α-hydroxy metoprolol/metoprolol was decreased and the MR of 1-hydroxy midazolam/midazolam was increased but the difference was not significant. According to the results, CYP1A2 and CYP2C9 activities were enhanced in the diabetic rats. and CYP2D6 activity was inhibited in a short period of diabetes; however, the decrease in CYP2D6 activity was not significant in the long period. CYP3A4 activity was decreased in a short period of diabetes and increased in a long period of diabetes but was not significant in the two periods. This study suggests the activity change rule of the CYP450 enzyme system in diabetes mellitus, which can provide a reference for precise clinical medication.
Yanhua Wang,You Weng,Lu Lv,Dou Wang,Guiling Yang,Yuanxiang Jin,Qiang Wang
The combined toxicity of heavy metals and pesticides to aquatic organisms is still largely unexplored. In this study, we investigated the combined impacts of cadmium (Cd) and carbofuran (CAR) on female zebrafish (F0 generation) and their following F1 generation. Results showed that mixtures of Cd and CAR induced acute synergistic effects on both zebrafish adults of the F0 generation and embryos of the F1 generation. Combined exposure to Cd and CAR could obviously alter the hepatic VTG level of females, and the individual exposures increased the relative mRNA levels of vtg1 and vtg2 . Through maternal transmission, co-exposure of Cd and CAR caused toxicity to 4-day-old larvae of the F1 generation, evidenced by the significant changes in T4 and VTG levels, CYP450 activity, and the relative transcriptional levels of genes related to the hormone, oxidative stress , and apoptosis. These effects were also reflected by the global gene expression pattern to 7-day-old larvae of F1 generation using the transcriptomic analysis, and they could also affect energy metabolism. Our results provided a more comprehensive insight into the transgenerational toxic impacts of heavy metal and pesticide mixtures. These findings highlighted that it was highly necessary to consider transgenerational exposures in the ecological risk assessment of chemical mixtures.
危险品化学品经营许可证（带存储）