title: Mitochondrial damage: a possible mechanism of the "topical" phase of NSAID induced injury to the rat intestine.
abstract: BACKGROUND
  The "topical" effect of non-steroidal anti-inflammatory drugs (NSAIDs) seems to be an important cause of NSAID induced gastrointestinal damage.
  
  
  OBJECTIVE
  To examine the possible mechanism of the "topical" phase of damage in the small intestine.
  
  
  METHODS
  Electron microscopy and subcellular organelle marker enzyme studies were done in rat small intestine after oral administration of indomethacin (doses varied between 5 and 30 mg/kg). The effect of conventional and non-acidic NSAIDs on rat liver mitochondrial respiration was measured in vitro in a Clarke-type oxygen electrode.
  
  
  RESULTS
  The subcellular organelle marker enzymes showed mitochondrial and brush border involvement within an hour of indomethacin administration. Electron microscopy showed dose dependent mitochondrial changes following indomethacin administration consistent with uncoupling of oxidative phosphorylation (or inhibition of electron transport) which were indistinguishable from those seen with the uncoupler dinitrophenol. Parenteral indomethacin caused similar changes, but not in rats with ligated bile ducts. A range of NSAIDs, but not paracetamol or non-acidic NSAIDs which have a favourable gastrointestinal tolerability profile, uncoupled oxidative phosphorylation in vitro at micromolar concentrations and inhibited respiration at higher concentrations. In vivo studies with nabumetone and aspirin further suggested that uncoupling or inhibition of electron transport underlies the "topical" phase of NSAID induced damage.
  
  
  CONCLUSIONS
  Collectively, these studies suggest that NSAID induced changes in mitochondrial energy production may be an important component of the "topical" phase of damage induction.
authors.affiliation: Department of Clinical Biochemistry, King's College School of Medicine and Dentistry, London, UK.
authors.forename: S
authors.initials: S
authors.lastname: Somasundaram
authors.forename: S
authors.initials: S
authors.lastname: Rafi
authors.forename: J
authors.initials: J
authors.lastname: Hayllar
authors.forename: G
authors.initials: G
authors.lastname: Sigthorsson
authors.forename: M
authors.initials: M
authors.lastname: Jacob
authors.forename: A B
authors.initials: AB
authors.lastname: Price
authors.forename: A
authors.initials: A
authors.lastname: Macpherson
authors.forename: T
authors.initials: T
authors.lastname: Mahmod
authors.forename: D
authors.initials: D
authors.lastname: Scott
authors.forename: J M
authors.initials: JM
authors.lastname: Wrigglesworth
authors.forename: I
authors.initials: I
authors.lastname: Bjarnason
mesh_terms: D000082:Acetaminophen / Q000009:adverse effects / Q000737:chemistry; D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects* / Q000737:chemistry; D001241:Aspirin / Q000009:adverse effects / Q000737:chemistry; D001646:Bile / Q000378:metabolism; D015415:Biomarkers / Q000032:analysis; D002074:Butanones / Q000009:adverse effects / Q000737:chemistry; D007213:Indomethacin / Q000009:adverse effects* / Q000737:chemistry; D007410:Intestinal Diseases / Q000139:chemically induced* / Q000201:enzymology / Q000473:pathology; D007421:Intestine, Small / Q000187:drug effects / Q000648:ultrastructure; D008297:Male; D008854:Microscopy, Electron; D008871:Microvilli / Q000187:drug effects / Q000201:enzymology; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000201:enzymology; D000077430:Nabumetone; D010085:Oxidative Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013047:Specific Pathogen-Free Organisms; D014456:Ulcer / Q000139:chemically induced* / Q000201:enzymology / Q000473:pathology; D014475:Uncoupling Agents / Q000009:adverse effects* / Q000737:chemistry
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D015415:Biomarkers; D002074:Butanones; D014475:Uncoupling Agents; D000082:Acetaminophen; D000077430:Nabumetone; D001241:Aspirin; D007213:Indomethacin