Protective effects of acetaminophen on ibuprofen-induced gastric mucosal damage in rats with associated suppression of matrix metalloproteinase

J Pharmacol Exp Ther. 2014 Apr;349(1):165-73. doi: 10.1124/jpet.113.210021. Epub 2014 Feb 4.

Abstract

Nonsteroidal anti-inflammatory drugs (NSAIDs) are known to cause gastric mucosal damage as a side effect. Acetaminophen, widely used as an analgesic and antipyretic drug, has gastroprotective effects against gastric lesions induced by absolute ethanol and certain NSAIDs. However, the mechanisms that underlie the gastroprotective effects of acetaminophen have not yet been clarified. In the present study, we examined the role and protective mechanism of acetaminophen on ibuprofen-induced gastric damage in rats. Ibuprofen and acetaminophen were administered orally, and the gastric mucosa was macroscopically examined 4 hours later. Acetaminophen decreased ibuprofen-induced gastric damage in a dose-dependent manner. To investigate the mechanisms involved, transcriptome analyses of the ibuprofen-damaged gastric mucosa were performed in the presence and absence of acetaminophen. Ingenuity pathway analysis (IPA) software revealed that acetaminophen suppressed the pathways related to cellular assembly and inflammation, whereas they were highly activated by ibuprofen. On the basis of gene classifications from the IPA Knowledge Base, we identified the following five genes that were related to gastric damage and showed significant changes in gene expression: interleukin-1β (IL-1β), chemokine (C-C motif) ligand 2 (CCL2), matrix metalloproteinase-10 (MMP-10), MMP-13, and FBJ osteosarcoma oncogene (FOS). Expression of these salient genes was confirmed using real-time polymerase chain reaction. The expression of MMP-13 was the most reactive to the treatments, showing strong induction by ibuprofen and suppression by acetaminophen. Moreover, MMP-13 inhibitors decreased ibuprofen-induced gastric damage. In conclusion, these results suggest that acetaminophen decreases ibuprofen-induced gastric mucosal damage and that the suppression of MMP-13 may play an important role in the gastroprotective effects of acetaminophen.

MeSH terms

  • Acetaminophen / administration & dosage
  • Acetaminophen / therapeutic use*
  • Administration, Oral
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / adverse effects*
  • Cytokines / genetics
  • Cytokines / metabolism
  • Dose-Response Relationship, Drug
  • Gastric Mucosa / drug effects*
  • Gastric Mucosa / enzymology
  • Gastric Mucosa / pathology
  • Gene Expression Profiling
  • Ibuprofen / adverse effects*
  • Male
  • Matrix Metalloproteinase 13 / genetics
  • Matrix Metalloproteinase 13 / metabolism*
  • Matrix Metalloproteinase Inhibitors / administration & dosage
  • Matrix Metalloproteinase Inhibitors / therapeutic use*
  • Peptic Ulcer Hemorrhage / chemically induced
  • Peptic Ulcer Hemorrhage / enzymology
  • Peptic Ulcer Hemorrhage / pathology
  • Peptic Ulcer Hemorrhage / prevention & control
  • Rats
  • Rats, Sprague-Dawley
  • Real-Time Polymerase Chain Reaction
  • Stomach Ulcer / chemically induced
  • Stomach Ulcer / enzymology
  • Stomach Ulcer / pathology
  • Stomach Ulcer / prevention & control

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • Cytokines
  • Matrix Metalloproteinase Inhibitors
  • Acetaminophen
  • Matrix Metalloproteinase 13
  • Mmp13 protein, rat
  • Ibuprofen