Mitochondrial damage: a possible mechanism of the ''topical'' phase of NSAID induced injury to the rat intestine

被引:268
作者
Somasundaram, S
Rafi, S
Hayllar, J
Sigthorsson, G
Jacob, M
Price, AB
Macpherson, A
Mahmod, T
Scott, D
Wrigglesworth, JM
Bjarnason, I
机构
[1] UNIV LONDON KINGS COLL,SCH MED & DENT,DEPT CLIN BIOCHEM,LONDON,ENGLAND
[2] UNIV LONDON KINGS COLL,SCH MED & DENT,DEPT MED,LONDON,ENGLAND
[3] NORTHWICK PK HOSP & CLIN RES CTR,DEPT CELLULAR PATHOL,LONDON,ENGLAND
[4] ST MARYS HOSP,LONDON,ENGLAND
[5] UNIV LONDON KINGS COLL,DEPT BIOCHEM,LONDON WC2R 2LS,ENGLAND
关键词
intestinal inflammation; intestinal toxicity; mitochondrial function; drug induced toxicity;
D O I
10.1136/gut.41.3.344
中图分类号
R57 [消化系及腹部疾病];
学科分类号
摘要
Background-The ''topical'' effect of non-steroidal anti-inflammatory drugs (NSAIDs) seems to be an important cause of NSAID induced gastrointestinal damage. Aim-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 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. Conclusion-Collectively, these studies suggest that NSAID induced changes in mitochondrial energy production may be an important component of the ''topical'' phase or damage induction.
引用
收藏
页码:344 / 353
页数:10
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