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Acute murine colitis reduces colonic 5-aminosalicylic acid metabolism by regulation of N-acetyltransferase-2
- Source :
- American Journal of Physiology-Gastrointestinal and Liver Physiology. 306:G1002-G1010
- Publication Year :
- 2014
- Publisher :
- American Physiological Society, 2014.
-
Abstract
- Pharmacotherapy based on 5-aminosalicylic acid (5-ASA) is a preferred treatment for ulcerative colitis, but variable patient response to this therapy is observed. Inflammation can affect therapeutic outcomes by regulating the expression and activity of drug-metabolizing enzymes; its effect on 5-ASA metabolism by the colonic arylamine N-acetyltransferase (NAT) enzyme isoforms is not firmly established. We examined if inflammation affects the capacity for colonic 5-ASA metabolism and NAT enzyme expression. 5-ASA metabolism by colonic mucosal homogenates was directly measured with a novel fluorimetric rate assay. 5-ASA metabolism reported by the assay was dependent on Ac-CoA, inhibited by alternative NAT substrates (isoniazid, p-aminobenzoylglutamate), and saturable with Km (5-ASA) = 5.8 μM. A mouse model of acute dextran sulfate sodium (DSS) colitis caused pronounced inflammation in central and distal colon, and modest inflammation of proximal colon, defined by myeloperoxidase activity and histology. DSS colitis reduced capacity for 5-ASA metabolism in central and distal colon segments by 52 and 51%, respectively. Use of selective substrates of NAT isoforms to inhibit 5-ASA metabolism suggested that mNAT2 mediated 5-ASA metabolism in normal and colitis conditions. Western blot and real-time RT-PCR identified that proximal and distal mucosa had a decreased mNAT2 protein-to-mRNA ratio after DSS. In conclusion, an acute colonic inflammation impairs the expression and function of mNAT2 enzyme, thereby diminishing the capacity for 5-ASA metabolism by colonic mucosa.
- Subjects :
- Male
Aminosalicylic acid
Arylamine N-Acetyltransferase
Colon
Physiology
Pharmacology
Inflammatory bowel disease
Gene Expression Regulation, Enzymologic
Inflammation/Immunity/Mediators
Mice
chemistry.chemical_compound
Intestinal mucosa
Physiology (medical)
medicine
Animals
Humans
Intestinal Mucosa
Colitis
Mesalamine
Hepatology
biology
Arylamine N-acetyltransferase
Anti-Inflammatory Agents, Non-Steroidal
Dextran Sulfate
Gastroenterology
medicine.disease
Ulcerative colitis
digestive system diseases
Mice, Inbred C57BL
Biochemistry
chemistry
Myeloperoxidase
biology.protein
Drug metabolism
Subjects
Details
- ISSN :
- 15221547 and 01931857
- Volume :
- 306
- Database :
- OpenAIRE
- Journal :
- American Journal of Physiology-Gastrointestinal and Liver Physiology
- Accession number :
- edsair.doi.dedup.....78c446141a1382285f51160af0e12b87