关键词: 关键词：鸦胆子苦醇, 肝毒性, 药物代谢酶, 裸鼠, 顺铂

Abstract: Abstract：Objective Hepatotoxicity of Brucea javanica picryl with broad-spectrum anticancer effect in nude mice based on hepatic drug metabolizing enzyme CYP450 activity. Methods Fifty-six nude mice were randomly divided into blank group, Brucea javanica low-dose group (2 mg●kg-1), Brucea javanica high-dose group (4 mg●kg-1), and cisplatin group (2 mg●kg-1), with 14 mice in each group. The blank group was injected with the same amount of normal saline every 3 days for 6 weeks.Calculate the mortality rate of nude mice in each group, observe the general growth state of nude mice, record the weight change of nude mice before and after administration, weigh and record the liver weight after taking materials, and calculate the liver coefficient (liver weight/weight mass×100%), observe and record the liver color and morphology. Hematoxylin-eosin (HE) staining was used to observe the pathological changes of liver tissue; Detection of alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), alkaline phosphatase (AKP) and albumin (ALB) levels in serum of nude mice by ELISA; Real-time PCR and Western blot were used to detect the mRNA and protein expression levels of CYP2E1, CYP3A11, CYP2C19, CYP1A2, CYP2D6 and CYP2C9, which were key enzymes of drug metabolism in nude mice liver. Results Compared with the blank group, the mortality rate of nude mice in the low-dose Brucea javanica bitter alcohol group was 0, the growth state was good, the diet, movement, and mental state were normal, the weight change and liver coefficient ratio were consistent, the liver color was ruddy, the liver lobule morphology was complete under the microscope, the structure was clear, the liver cells were arranged regularly, and there was no inflammatory cell infiltration. There was no significant difference in the content of ALT, AST, LDH, AKP, and ALB. There was no significant difference in the mRNA and protein expression of CYP2E1, CYP3A11, CYP2C19, CYP1A2, CYP2D6, and CYP2C9 (all P < 0.05 or P < 0.01).Compared with the blank group, the mortality rate of nude mice in the high-dose group of Brucea javanica bitter alcohol was 14.3%, the growth state was slightly poor, the diet, movement, and mental state were reduced, the weight growth was slow, the liver coefficient ratio was increased, the liver color was reddish brown, some liver lobule boundaries were unclear, a small number of liver cells were loosely arranged, the contents of ALT, AST, LDH, AKP, and ALB were significantly increased, the mRNA levels of CYP2E1, CYP3A11, CYP2C19, CYP1A2, CYP2D6, and CYP2C9 were significantly reduced, and the protein expressions of CYP2E1, CYP3A11, CYP1A2, and CYP2D6 were significantly reduced (all P < 0.05 or P < 0.01), but there was no statistical difference in the mRNA and protein expression of CYP2C19, and the protein expression of CYP2C9 (P > 0.05).Compared with the blank group, the mortality rate of nude mice in the cisplatin group was 35.7%, the growth state was poor, the diet, action, and mental state were low, the weight gain was less, the liver coefficient ratio was significantly increased, the liver color was dark red, the liver sinusoids and central veins were congested, the hepatocytes were disordered, the nuclei were consolidated and contracted, and the arrangement was loose, the contents of ALT, AST, LDH, AKP, and ALB were significantly increased, and the mRNA and protein expressions of CYP2E1, CYP3A11, CYP2C19, CYP1A2, CYP2D6, and CYP2C9 were significantly reduced (all P < 0.05 or P < 0.01).tiple subtypes of enzymes in the key enzyme CYP450 of liver drug metabolism, and then reducing the metabolism of toxic substances.

Key words: Keywords: Brucea javanica bitter alcohol, Hepatotoxicity, Drug metabolizing enzymes, Nude mice, Cisplatin