Hepatic and intestinal biotransformation gene expression and drug disposition in a dextran sulfate sodium-induced colitis mouse model

• 来源期刊: 药学学报（英文版）
• 关键词: Cytochrome P450 CYP Colitis Intestine Inflammatory bowel disease Drug metabolism Pharmacokinetics Gene expression
• 年，卷（期）: 2020,（1）
• 页码范围: 123-135
• 页数: 13页
• 语种: 英文

摘要

We examined the impact of gut inflammation on the expression of cytochrome P450 (P450) and other biotransformation genes in male mice using a dextran sulfate sodium (DSS)-induced colitis model.Several P450 isoforms,including CYP1A,CYP2B,CYP2C,and CYP3A,were downregulated,accompanied by decreases in microsomal metabolism of diclofenac and nifedipine,in the liver and small intestine.The impact of the colitis on in vivo clearance of oral drugs varied for four different drugs tested:a small decrease for nifedipine,a relatively large decrease for lovastatin,but no change for pravastatin,and a large decrease in the absorption of cyclosporine A.To further assess the scope of influence of gut inflammation on gene expression,we performed genome-wide expression analysis using RNA-seq,which showed down-regulation of many CYPs,non-CYP phase-Ⅰ enzymes,phase-Ⅱ enzymes and transporters,and up-regulation of many other members of these gene families,in both liver and intestine of adult C57BL/6 mice,by DSS-induced colitis.Overall,our results indicate that gut inflammation suppresses the expression of many P450s and other biotransformation genes in the intestine and liver,and alters the pharmacokinetics for some but not all drugs,potentially affecting therapeutic efficacy or causing adverse effects in a drug-specific fashion.