title: Importance of the Evaluation of N-Acetyltransferase Enzyme Activity Prior to 5-Aminosalicylic Acid Medication for Ulcerative Colitis.
abstract: 5-aminosalicylic acid (5-ASA) is a classic anti-inflammatory drug for the treatment of ulcerative colitis. N-acetyltransferase (NAT) enzymes convert 5-ASA to its metabolite N-acetyl-5-ASA, and it is unresolved whether 5-ASA or N-acetyl-5-ASA is the effective therapeutic molecule. We previously demonstrated that colonic production of N-acetyl-5-ASA (NAT activity) is decreased in dextran sulfate sodium-induced colitis. Our hypothesis is that 5-ASA is the therapeutic molecule to improve colitis, with the corollary that altered NAT activity affects drug efficacy. Since varying clinical effectiveness of 5-ASA has been reported, we also ask if NAT activity varies with inflammation in pediatric or adult patients.
  
  
  
  Acute colonic inflammation was induced in C57BL/6 NAT wild-type (WT) or knockout mice, using 3.5% dextran sulfate sodium (w/v) concurrent with 5-ASA treatment. Adult and pediatric rectosigmoid biopsies were collected from control or patients with ulcerative colitis. Tissue was analyzed for NAT and myeloperoxidase activity.
  
  
  
  Dextran sulfate sodium-induced colitis was of similar severity in both NAT WT and knockout mice, and NAT activity was significantly decreased in NAT WT mice. In the setting of colitis, 5-ASA significantly restored colon length and decreased myeloperoxidase activity in NAT knockout but not in WT mice. Myeloperoxidase activity negatively correlated with NAT activity in pediatric patients, but correlation was not observed in adult patients.
  
  
  
  Inflammation decreases NAT activity in the colon of mice and human pediatric patients. Decreased NAT activity enhances the therapeutic effect of 5-ASA in mice. A NAT activity assay could be useful to help predict the efficacy of 5-ASA therapy.
authors.affiliation: *Department of Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, Ohio;†Division of Biostatistics and Epidemiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio;‡Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio; and§Division of Digestive Disease, Department of Internal Medicine, University of Cincinnati, Ohio.
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Matthis
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.forename: Lee A
authors.initials: LA
authors.lastname: Denson
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Yacyshyn
authors.forename: Eitaro
authors.initials: E
authors.lastname: Aihara
authors.forename: Marshall H
authors.initials: MH
authors.lastname: Montrose
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000378:metabolism / Q000627:therapeutic use*; D001191:Arylamine N-Acetyltransferase / Q000235:genetics / Q000378:metabolism*; D001706:Biopsy; D016022:Case-Control Studies; D002648:Child; D003093:Colitis, Ulcerative / Q000139:chemically induced / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D012809:Colon, Sigmoid / Q000201:enzymology / Q000473:pathology; D016264:Dextran Sulfate; D005260:Female; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D008297:Male; D019804:Mesalamine / Q000378:metabolism / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D009195:Peroxidase / Q000187:drug effects / Q000378:metabolism*; D012007:Rectum / Q000201:enzymology / Q000473:pathology; D055815:Young Adult
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D007527:Isoenzymes; D019804:Mesalamine; D016264:Dextran Sulfate; D009195:Peroxidase; D001191:Arylamine N-Acetyltransferase; C089384:N-acetyltransferase 1; C524206:Nat2 enzyme, mouse