Aidi injection altered the activity of CYP2D4, CYP1A2, CYP2C19, CYP3A2, CYP2E1 and CYP2C11 in normal and diethylnitrosamine-induced hepatocellular carcinoma in rats

Ethnopharmacological relevance: Aidi injection (ADI), a traditional chinese medicine preparation, is widely used in combination with chemotherapy for the treatment of various malignant tumors, such as hepatocellular carcinoma (HCC). Studies have shown that changes in cytochrome P450 (CYP450) activity in disease states would affect the metabolism of drugs in vivo, especially liver diseases. However, the changes of Aidi injection on the activities of CYP2D4, CYP1A2, CYP2C19, CYP3A2, CYP2E1 and CYP2C11 in normal and HCC states are still unknown. Aim of the study: The cocktail probe drugs method was used to investigate the effects of ADI on the activity of CYP2D4, CYP1A2, CYP2C19, CYP3A2, CYP2E1 and CYP2C11 in normal and HCC rats. Materials and methods: The HCC rats was induced by diethylnitrosamine (DEN). Then, both normal and HCC rats were randomly divided into 2 groups (n = 6). They were given saline or ADI (10 mL/kg/d, i.p) for 2 weeks, respectively. On the fifteenth day, cocktail probe mixing solution, including metoprolol (10 mg/kg), caffeine (1.0 mg/kg), omeprazole (2.0 mg/kg), midazolam (2.0 mg/kg), chlorzoxazone (4.0 mg/kg) and tolbutamide (0.5 mg/kg), was injected into tail vein of all rats in each group. The blood sample was obtained at specified time. After the protein is precipitated, six probe drugs are analyzed by ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). Results: Compared with control group, the activity of CYP3A2 and CYP2E1 was significantly lower in the ADI group. Compared with the model group, the activities of CYP1A2, CYP3A2, CYP2E1, and CYP2C11 enzymes in the ADI model group were significantly reduced. Additionally, the activity of CYP2D4, CYP1A2, CYP2C19, CYP3A2, CYP2E1 and CYP2C11 enzymes in model group was significantly lower than control group. Conclusions: ADI can inhibit a lot of CYP450 enzyme, so it may reduce the dosage of chemotherapeutic drugs to reach the required plasma concentration of chemotherapeutic drugs, which is of great significance for the combination of anti-tumor chemotherapeutic drugs and is worthy of further in-depth study and clinical attention.

Automated summary

This study investigated the effects of Aidi injection (ADI) on the activity of various cytochrome P450 (CYP450) enzymes in normal and hepatocellular carcinoma (HCC) rats. The results showed that ADI can inhibit the activity of multiple CYP450 enzymes, which may reduce the dosage of chemotherapeutic drugs and have significant implications for the combination of anti-tumor chemotherapy drugs.