Hepatic and intestinal biotransformation gene expression and drug disposition in a dextran sulfate sodium-induced colitis mouse model
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 down-regulated, accompanied by decre...
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| Format: | Article |
| Language: | English |
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Elsevier
2020-01-01
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| Series: | Acta Pharmaceutica Sinica B |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211383519312213 |
| _version_ | 1818362330077986816 |
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| author | Xiaoyu Fan Xinxin Ding Qing-Yu Zhang |
| author_facet | Xiaoyu Fan Xinxin Ding Qing-Yu Zhang |
| author_sort | Xiaoyu Fan |
| collection | DOAJ |
| description | 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 down-regulated, 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. Keywords: Cytochrome P450, CYP, Colitis, Intestine, Inflammatory bowel disease, Drug metabolism, Pharmacokinetics, Gene expression |
| first_indexed | 2024-12-13T21:30:52Z |
| format | Article |
| id | doaj.art-2dab75d104b9461693a2ec92ff9815b3 |
| institution | Directory Open Access Journal |
| issn | 2211-3835 |
| language | English |
| last_indexed | 2024-12-13T21:30:52Z |
| publishDate | 2020-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Acta Pharmaceutica Sinica B |
| spelling | doaj.art-2dab75d104b9461693a2ec92ff9815b32022-12-21T23:30:50ZengElsevierActa Pharmaceutica Sinica B2211-38352020-01-01101123135Hepatic and intestinal biotransformation gene expression and drug disposition in a dextran sulfate sodium-induced colitis mouse modelXiaoyu Fan0Xinxin Ding1Qing-Yu Zhang2Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ 85721, USA; Wadsworth Center, New York State Department of Health, School of Public Health, University at Albany, Albany, NY 12201, USADepartment of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ 85721, USADepartment of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ 85721, USA; Wadsworth Center, New York State Department of Health, School of Public Health, University at Albany, Albany, NY 12201, USA; Corresponding author: Tel.: +1 520 6213667; fax: +1 520 6262466.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 down-regulated, 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. Keywords: Cytochrome P450, CYP, Colitis, Intestine, Inflammatory bowel disease, Drug metabolism, Pharmacokinetics, Gene expressionhttp://www.sciencedirect.com/science/article/pii/S2211383519312213 |
| spellingShingle | 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 Acta Pharmaceutica Sinica B |
| title | Hepatic and intestinal biotransformation gene expression and drug disposition in a dextran sulfate sodium-induced colitis mouse model |
| title_full | Hepatic and intestinal biotransformation gene expression and drug disposition in a dextran sulfate sodium-induced colitis mouse model |
| title_fullStr | Hepatic and intestinal biotransformation gene expression and drug disposition in a dextran sulfate sodium-induced colitis mouse model |
| title_full_unstemmed | Hepatic and intestinal biotransformation gene expression and drug disposition in a dextran sulfate sodium-induced colitis mouse model |
| title_short | Hepatic and intestinal biotransformation gene expression and drug disposition in a dextran sulfate sodium-induced colitis mouse model |
| title_sort | hepatic and intestinal biotransformation gene expression and drug disposition in a dextran sulfate sodium induced colitis mouse model |
| url | http://www.sciencedirect.com/science/article/pii/S2211383519312213 |
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