The Inhibition of Mitochondrial Respiration by Indomethacin, a Non-Steroid Anti-Inflammatory Agent Possessing Inhibitory Effect on Prostaglandin Biosynthesis

Kawai, Kenji; Shiojiri, Hiroyuki; Fukushima, Hideki; Nozawa, Yoshinori

doi:10.1016/s0022-5347(17)47626-9

Cited by 6 publications

(9 citation statements)

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“…The lack of stereoselectivity in mitochondrial damage in the present study, which has also been shown with other chiral compounds,51 suggests the independence of uncoupling of mitochondrial oxidative phosphorylation from COX inhibition.…”

Section: Discussionsupporting

confidence: 84%

“…Previous in vitro26 27 29 30 42 50 51 studies indicated that increasing concentrations of acidic NSAIDs uncouple mitochondrial oxidative phosphorylation and then inhibit mitochondrial respiration, a response characteristic of the so called inhibitory uncouplers 49. The lack of stereoselectivity in mitochondrial damage in the present study, which has also been shown with other chiral compounds,51 suggests the independence of uncoupling of mitochondrial oxidative phosphorylation from COX inhibition.…”

Section: Discussionmentioning

confidence: 99%

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Enantiomers of flurbiprofen can distinguish key pathophysiological steps of NSAID enteropathy in the rat

Mahmud

Somasundaram

Sigthorsson

et al. 1998

Gut

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Background-Non-steroidal anti-inflammatory drugs (NSAIDs) cause gastrointestinal damage by a non-prostaglandin (PG) dependent "topical" action and by inhibiting cyclooxygenase. Aims-To discriminate between these two eVects by studying some key pathophysiological steps in NSAID enteropathy following administration of (R)-and (S)-flurbiprofen, the racemic mixture, and an uncoupler, dinitrophenol. (Gut 1998;43:775-782) Methods-The

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Section: Discussionsupporting

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Enantiomers of flurbiprofen can distinguish key pathophysiological steps of NSAID enteropathy in the rat

Mahmud

Somasundaram

Sigthorsson

et al. 1998

Gut

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“…Studies with these two drugs and a range of other acidic NSAIDs in isolated mitochondrial preparations have shown that they uncouple oxidative phosphorylation at concentrations between 0.03 mM and 1.5 mM (depending on the particular NSAID) and inhibit respiration at higher concentrations [6][7][8]. However, similar concentrations of the drugs showed no significant uncoupling effect in the present study.…”

Section: Discussioncontrasting

confidence: 64%

“…It is clear that several NSAIDs, such as aspirin and indomethacin, uncouple mitochondrial oxidative phosphorylation [5]. Studies with these and other acidic NSAIDs (but not with some of the selective cyclo-oxygenase-2 inhibitors, presumably because they are non-acidic [6]) in isolated mitochondrial preparations have shown that they uncouple oxidative phosphorylation at low concentrations and inhibit respiration at higher concentrations [6][7][8], thereby affecting energy metabolism. It has been suggested that this, in turn, leads to disruption of the intercellular barrier function, with a resultant increase in intestinal permeability, thereby leading to inflammation.…”

Section: Introductionmentioning

confidence: 99%

Effects of indomethacin on energy metabolism in rat and human jejunal tissue in vitro

Jacob¹,

BJARNASON

Simpson

2001

Clinical Science

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Non-steroidal anti-inflammatory drugs (NSAIDs) are known to cause enteropathy, but the mechanism by which this toxicity occurs is less well established. This paper sets out to test the hypothesis that these drugs affect oxidative phosphorylation in jejunal tissue, thereby interfering with energy metabolism and rendering the tissue vulnerable to damage. Jejunal tissue obtained from rats and humans was used for in vitro determinations of oxygen uptake, lactate production and energy charge levels in the presence of indomethacin, a commonly used NSAID. In the rat jejunal tissue, drug concentrations of 0.5 mM and 2.5 mM produced significant decreases in oxygen uptake (P<0.01) and energy charge levels in the tissue (P<0.05). There was a corresponding increase in lactate production by the tissue at these indomethacin concentrations (P<0.05). Rat jejunum examined by electron microscopy after incubation with various concentrations of indomethacin showed ultrastructural effects of the drug on mitochondrial morphology. In human tissue, an inhibitory effect of indomethacin on oxygen uptake was seen, but the effects on lactate production and energy charge were less conclusive. These findings suggest that indomethacin affects mitochondria and thereby impairs energy metabolism in jejunal tissue.

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“…The homogenate was then centrifuged at 500s for 10 minutes to remove excess blood, nuclei, and cell debris. The supernatant was centrifuged at 11, OOOg for another 10 minutes, after which the mitochondrial pellet was carefully removed and resuspended in 40 ml of homogenizing solution. The last centrifugation step was repeated and the mitochondrial pellet resuspended in 1-2 ml of homogenizing buffer.…”

Section: Methodsmentioning

confidence: 99%

Nonsteroidal antiinflammatory drugs and uncoupling of mitochondrial oxidative phosphorylation

Mahmud

Rafi

Scott

et al. 1996

Arthritis & Rheumatism

163

114

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Objective. There is a lack of correlation between cyclooxygenase (COX) inhibition and nonsteroidal antiinflammatory drug (NSAID)-induced gastrointestinal (GI) damage; it has been suggested that mucosal damage may be initiated by a "topical" action of NSAIDs involving mitochondrial injury. We evaluated the effect of a range of NSAIDs and related compounds on mitochondria] function and assessed the differences between them in relation to their physicochemical properties.Methods. Stimulation of respiration, as an indicator of mitochondrial uncoupling, was measured in isolated coupled rat liver mitochondrial preparations, using an oxygen electrode.Results. Conventional NSAIDs and acidic prodrugs all had stimulatory effects on mitochondrial respiration at micromolar concentrations (0.02-2.7 +If); higher concentrations were inhibitory. The uncoupling potency was inversely correlated with drug pKa (r = -0.87, P < 0.001; n = 12). Drugs known to have good GI tolerability, including modified flurbiprofen (dimeroflurbiprofen and nitrobutyl-flurbiprofen), nabumetone (a non-acidic prodrug), and non-acidic highly selective COX-2 inhibitors, did not cause uncoupling.Conclusion. The ability to uncouple mitochondrial oxidative phosphorylation is a common characteristic of antiinflammatory agents with an ionizable group. Modification or absence of an ionizable moiety reduces the effect on mitochondria and could lead to improved NSAID GI safety.Nonsteroidal antiinflammatory drugs (NSAIDs) are widely used, with more than 26 million and 100 million annual prescriptions in the UK and USA, respectively. The main concern about NSAID treatment is the risk of gastrointestinal (GI) damage. Non-ulcer endoscopic gastroduodenal lesions are seen in some 30-40% of patients receiving regular NSAID treatment, and peptic ulceration in 10-30% (1,2). In addition, long-term NSAID treatment causes small intestinal inflammation (NSAID enteropathy) (associated with blood and protein loss) in -65% of patients (3).The mechanism of this NSAID toxicity is unknown, but, similar to the mechanism of the drugs' antiinflammatory therapeutic effects (4), is widely believed to be related to inhibition of cyclooxygenase (COX) activity. However, there is substantial evidence that COX inhibition is not the only pertinent event, since 95% inhibition of COX activity has been achieved without apparent morphologic mucosal change ( 5 ) and mice with a disabled prostaglandin synthase 1 gene (resulting in the virtual absence of endogenous prostaglandin) do not spontaneously develop GI lesions. Paradoxically, these mice have been shown to be equally or less sensitive to the damaging effects of indomethacin, compared with controls (6). An alternative hypothesis is that NSAID-induced GI damage is initiated by a "topical" effect in which mitochondrial energy metabolism is disrupted (7), but alteration in prostanoid production is probably an important cofactor in the development of ulcers. NSAID ingestion results in increased activity of specific mitochondrial enzymes in rats a...

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The Inhibition of Mitochondrial Respiration by Indomethacin, a Non-Steroid Anti-Inflammatory Agent Possessing Inhibitory Effect on Prostaglandin Biosynthesis

Cited by 6 publications

References 0 publications

Enantiomers of flurbiprofen can distinguish key pathophysiological steps of NSAID enteropathy in the rat

Enantiomers of flurbiprofen can distinguish key pathophysiological steps of NSAID enteropathy in the rat

Effects of indomethacin on energy metabolism in rat and human jejunal tissue in vitro

Nonsteroidal antiinflammatory drugs and uncoupling of mitochondrial oxidative phosphorylation

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