ArticleThe Journal of pharmacology and experimental therapeutics2012
Role of intestinal cytochrome p450 enzymes in diclofenac-induced toxicity in the small intestine.
Article in The Journal of pharmacology and experimental therapeutics, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 39 citations in OpenAlex.
- Re-assessment of monoclonal antibodies against diclofenac for their application in the analysis of environmental waters.Analytical methods : advancing methods and applications · 2024Article
- Article
- An adverse outcome pathway for immune-mediated and allergic hepatitis: a case study with the NSAID diclofenac.Archives of toxicology · 2020Article
- Hepatic and intestinal biotransformation gene expression and drug disposition in a dextran sulfate sodium-induced colitis mouse model.Acta pharmaceutica Sinica. B · 2020Article
- An update on the role of intestinal cytochrome P450 enzymes in drug disposition.Acta pharmaceutica Sinica. B · 2016Review
- Evidence of reduced oral bioavailability of paracetamol in rats following multiple ingestion of grapefruit juice.European journal of drug metabolism and pharmacokinetics · 2016Article
- Effect of Cytochrome P450 Reductase Deficiency on 2-Amino-9H-pyrido[2,3-b]indole Metabolism and DNA Adduct Formation in Liver and Extrahepatic Tissues of Mice.Chemical research in toxicology · 2015Article
- Intestinal epithelium-specific knockout of the cytochrome P450 reductase gene exacerbates dextran sulfate sodium-induced colitis.The Journal of pharmacology and experimental therapeutics · 2015Article
- Inhibition of cAMP-activated intestinal chloride secretion by diclofenac: cellular mechanism and potential application in cholera.PLoS neglected tropical diseases · 2014Article
- Mice deficient in intestinal epithelium cytochrome P450 reductase are prone to acute toxin-induced mucosal damage.Scientific reports · 2014Article
- Role of hepatic and intestinal p450 enzymes in the metabolic activation of the colon carcinogen azoxymethane in mice.Chemical research in toxicology · 2014Article
- Regulation of intestinal cytochrome P450 expression by hepatic cytochrome P450: possible involvement of fibroblast growth factor 15 and impact on systemic drug exposure.Molecular pharmacology · 2014Article
- Bacterial β-glucuronidase inhibition protects mice against enteropathy induced by indomethacin, ketoprofen or diclofenac: mode of action and pharmacokinetics.Xenobiotica; the fate of foreign compounds in biological systems · 2014Article
- The human microbiome is a source of therapeutic drug targets.Current opinion in chemical biology · 2013Review
- Multiple NSAID-induced hits injure the small intestine: underlying mechanisms and novel strategies.Toxicological sciences : an official journal of the Society of Toxicology · 2013Review
- NADPH-cytochrome P450 oxidoreductase: roles in physiology, pharmacology, and toxicology.Drug metabolism and disposition: the biological fate of chemicals · 2013Article
Corrections and comments
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
The aim of this study was to determine the role of small intestinal (SI) cytochrome P450 (P450) enzymes in the metabolic activation of diclofenac (DCF), a widely used nonsteroidal anti-inflammatory drug, and DCF-induced intestinal toxicity. DCF induces intestinal ulcers in humans and mice, but the underlying mechanisms, including the necessity for drug bioactivation in the target tissues and the sources and identities of reactive intermediates, are not fully understood. We found that the number of DCF-induced (at 50 mg/kg p.o.) intestinal ulcers was significantly smaller in an intestinal epithelium (IE)-specific P450 reductase (CPR) knockout (IE-Cpr-null) mouse model, which has little P450 activity in the IE, than in wild-type (WT) mice, determined at 14 h after DCF administration. The involvement of intestinal P450 enzymes was confirmed by large reductions (>80-90%) in the rates of in vitro formation, in SI microsomal reactions, of hydroxylated DCF metabolites and reactive intermediates, trapped as DCF-glutathione (GSH) conjugates, in the IE-Cpr-null, compared with WT mice. The SI levels of DCF-GSH conjugates (at 4 h after dosing) and DCF-protein adducts (at 14 h after dosing) were significantly lower in IE-Cpr-null than in WT mice. In additional experiments, we found that pretreatment of mice with grapefruit juice, which is known to inhibit SI P450 activity, ameliorated DCF-induced intestinal toxicity in WT mice. Our results not only strongly support the notion that SI P450 enzymes play an important role in DCF-induced intestinal toxicity, but also illustrate the possibility of preventing DCF-induced intestinal toxicity through dietary intervention.
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