摘要
为了研究恩诺沙星与环丙沙星、氟苯尼考和磺胺二甲嘧啶三种抗生素的联合毒性及潜在机制,试验将16只雄性SD大鼠分为恩诺沙星+环丙沙星组(E+C组)、恩诺沙星+氟苯尼考组(E+F组)及恩诺沙星+磺胺二甲嘧啶组(E+S组)3个联合用药组和1个对照组(K组),每组4只,联合用药组中每种药物取等量混合制成100 mg/mL药物储备溶液,各组大鼠按体重0.005 mL/g灌服相应的药物储备溶液,对照组大鼠按体重0.005 mL/g灌服相应剂量的0.5%羧甲基纤维素钠溶液,以给药1 d停药2 d为一个用药周期,6个周期后麻醉并脱颈椎处死大鼠,剖检取出肝脏提取总RNA,然后进行转录组测序与分析。以对照组大鼠肝脏基因组作为参考,筛选出差异表达基因并进行GO功能注释和KEGG富集分析。结果表明:与对照组相比,E+C组、E+F组、E+S组分别筛选出2 155,2 130,727个差异表达基因,选择Cyp2e1和Cyp8b1等15个基因进行相对表达量聚类分析。E+C组GO功能主要注释在脂质、脂肪酸及有机酸等物质代谢过程等;E+F组GO功能主要注释在环氧合酶P450途径及激活MAPK次联途径等;E+S组GO功能主要注释在生物黏附、细胞黏附及对含氧化合物的反应等。3个联合用药组的差异表达基因均在细胞色素P450对异生素的代谢这一通路上富集。说明恩诺沙星与其他三种抗生素联用时主要通过影响肝脏中CYP450酶的代谢而产生联合毒性,Cyp2e1和Cyp8b1基因可能是联合毒性产生的关键基因。兽医临床用药需要考虑到抗生素联合毒性的影响,尽量避免将恩诺沙星与三种药物联用。
To investigate the combined toxicity and underlying mechanisms of enrofloxacin when combined with three other antibiotics(ciprofloxacin, florfenicol, and sulfamethazine), 16 male SD rats were divided into 4 groups, including enrofloxacin+ciprofloxacin group(E+C), enrofloxacin+florfenicol group(E+F), enrofloxacin+sulfamethazine group(E+S), and control group(K), with 4 rats in each group. Each drug in the combination group was mixed with an equal volume of 100 mg/mL drug stock solution, dose of the drug stock solution in the combination group was 0.005 mL/g according to body weight, and the rats in the control group was given 0.5% sodium carboxymethyl cellulose solution according to 0.005 mL/g of body weight by gavage. The treatment cycle was 1 day after administration and 2 days after discontinuation. After 6 administrations(once administration every 3 days), all rats were deeply anesthetized and sacrificed by cervical dislocation. The total RNA was collected from the lives, followed by transcriptome sequencing and analysis. The liver genome of control rats was used as a reference to screen out differentially expressed genes(DEGs) and perform GO functional annotation and KEGG enrichment analysis. The results showed that 2 155, 2 130, and 727 DEGs were selected from the three treatment groups compared with the control group, and 15 genes, including Cyp2 e1 and Cyp8 b1 were selected for relative expression cluster analysis. GO items in group E+C mainly included in the lipid、fatty acids and organic acids metabolism. GO terms in group E+F mainly included epoxygenase P450 pathway, and positive regulation of MAPK cascade. GO terms in group E+S mainly included biological adhesion, cell adhesion, and response to oxygen-containing compounds. KEGG enrichment analysis showed that the DEGs in drug-treated groups were enriched in the metabolic pathway of cytochrome P450. It indicated that the combined toxicity of enrofloxacin with the other three antibiotics mainly occurred by affecting the metabolism of CYP450 enzymes in th
作者
赵军杰
陈可心
栾业辉
陈亚南
程林丽
ZHAO Junjie;CHEN Kexin;LUAN Yehui;CHEN Ya'nan;CHENG Linli(College of Veterinary Medicine,China Agricultural University,Beijing 100193;National Veterinary Drug Residue Reference Laboratory/Beijing Key Laboratory of Animal Source Food Safety Testing Technology,Beijing 100193)
出处
《黑龙江畜牧兽医》
CAS
北大核心
2022年第23期14-19,132,共7页
Heilongjiang Animal Science And veterinary Medicine
基金
国家重点研发计划项目“畜禽中典型兽药残留混合污染联合效应”(2018YFC1603005)。
关键词
恩诺沙星
联合毒性
转录组学分析
差异表达基因
雄性SD大鼠
肝脏
enrofloxacin
combined toxicity
transcriptomics analysis
differentially expressed genes
male SD rats
liver
