Original articles
Xiaoyu Fan, Xinxin Ding, Qing-Yu Zhang. Hepatic and intestinal biotransformation gene expression and drug disposition in a dextran sulfate sodium-induced colitis mouse model[J]. Acta Pharmaceutica Sinica B, 2020, 10(1): 123-135

Hepatic and intestinal biotransformation gene expression and drug disposition in a dextran sulfate sodium-induced colitis mouse model
Xiaoyu Fana,b, Xinxin Dinga, Qing-Yu Zhanga,b
a Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ 85721, USA;
b Wadsworth Center, New York State Department of Health, School of Public Health, University at Albany, Albany, NY 12201, USA
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.
Key words:    Cytochrome P450    CYP    Colitis    Intestine    Inflammatory bowel disease    Drug metabolism    Pharmacokinetics    Gene expression   
Received: 2019-08-31     Revised: 2019-10-31
DOI: 10.1016/j.apsb.2019.12.002
Funds: We thank Ms. Weizhu Yang for assistance with mouse production. We gratefully acknowledge the use of the Histopathology Core of the Wadsworth Center (Albany, NY, USA). This work was supported in part by the National Institutes of Health (Grants GM082978 and ES006694, USA).
Corresponding author: Qing-Yu Zhang     Email:qyzhang@pharmacy.arizona.edu
Author description:
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Xiaoyu Fan
Xinxin Ding
Qing-Yu Zhang

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