Abstract
It is widely believed that the toxic effects of non-steroidal anti-inflammatory drugs are solely due to inhibition of cyclo-oxygenase. However, this view is no longer tenable as it is possible to inhibit cyclo-oxygenase activities without mucosal injury and cyclo-oxygenase 1-deficient mice do not have gastrointestinal lesions from indomethacin. Alternatively, non-steroidal anti-inflammatory agents may initiate damage by direct mitochondrial toxicity. The current experiments were designed to relate NSAID uncoupling of mitochondrial oxidative phosphorylation to drug pK a and to determine the effect of modification of the NSAID carboxyl group.
Effects of non-steroidal anti-inflammatory drugs and modified NSAIDs were tested on isolated coupled rat liver mitochondrial preparations using a Clark-type oxygen electrode.
All non-steroidal anti-inflammatory drugs tested uncoupled mitochondrial oxidative phosphorylation to a similar degree, increasing oxygen consumption by 2–3-fold. The uncoupling potency was inversely related to the drug pK a (correlation coefficient r = –0.74; p= 0.05). Modification of the carboxyl moiety (dimero-flurbiprofen and nitrobutyl flurbiprofen) abolished uncoupling.
The NSAID potency to uncouple oxidative phosphorylation correlated with drug pK a; modification of the NSAID carboxyl moiety may improve their safety profile by reducing the ‘topical’ phase of damage.
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References
Lakari EN, Lacey-Smith L, Lidsky MD, Graham DY. Gastroduodenal damage and dyspeptic symptoms in arthritis in patients during chronic nonsteroidal anti-inflammatory drug use. Am J Gastroenterol. 1987;82:1153–8.
Vane JR. Inhibition of prostaglandin synthesis as mechanism of action of aspirin-like drugs. Nature (New Biology). 1971;231:232–5.
Whittle BJR. Temporal relationship between cyclo-oxygenase in inhibition, as measured by prostacyclin biosynthesis, and gastro-intestinal damage induced by indomethacin in the rat. Gastroenterology. 1981;80:94–8.
Langenbach R, Morham SG, Tiano HF et al. Prostaglandin synthase 1 gene disruption in mice reduces arachidonic acid-induced inflammation and indomethacin-induced gastric ulceration. Cell. 1995;83:483–92.
Somasundaram S, Hayllar J, Rafi S, Wrigglesworth JM, Macpherson AJS, Bjarnason I. The biochemical basis of non-steroidal anti-inflammatory drug-induced damage to the gastro-intestinal tract: a review and a hypothesis. Scand J Gastroenterol. 1995;30:289–99.
Whitehouse MW. Biochemical properties of anti-inflammatory drugs. III. Uncoupling of oxidative phosphorylation in a connective tissue (cartilage) on liver mitochondria by salicylate analogues: relationship of structure to activity. Biochem Pharmacol. 1964;13:319–36.
Kawai K, Shiojiri H, Fukushima H, Norawa Y. The inhibition of mitochondrial respiration by indomethacin, a nonsteroidal anti-inflammatory agent possessing inhibitory effect on prostaglandin biosynthesis. Res Commun Chem Path Pharmacol. 1985;48(2):267–74.
Tokumitsu Y, Lee S, Ui M. In vitro effects of nonsteroidal anti-inflammatory drugs on oxidative phosphorylation in rat liver mitochondria. Biochem Pharmacol. 1977;26:2101–6.
Schneider WC, Hogeboom KEO. Intracellular distribution of enzymes (V). Further studies on the distribution of cytochrome C in liver homogenate. J Biol Chem. 1950;183:123–8.
Chance B, Williams GR. Respiratory chain and oxidative phosphorylation. Adv Enzymol. 1956;17:65–134.
Mehlman MA. Tobin RB, Sporn EM. Oxidative phosphorylation and respiration by rat liver mitochondria from aspirin treated rats. Biochem Pharmacol. 1972;21:3279–85.
Fuhro R, Fromm D. Effects of compounds chemically related to salicylate on isolated antral mucosa of rabbits. Gastroenterology. 1978;75:661–7.
Rainsford KD, Whitehouse MW. Anti-inflammatory antipyretic salicylic esters, with low gastric ulcerogenic activity. Agents Actions. 1980;10:451–6.
Wallace JL, Reuter B, Cicala C, McKnight W, Grisham MB, Cirino G. Novel nonsteroidal anti-inflammatory drug derivatives with markedly reduced ulcerogenic properties in the rat. Gastroenterology. 1994;107:173–90.
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© 1997 Springer Science+Business Media Dordrecht
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Mahmud, T., Wrigglesworth, J.M., Scott, D.L., Bjarnason, I. (1997). Mitochondrial Function and Modification of Nsaid Carboxyl Moiety. In: Rainsford, K.D. (eds) Side Effects of Anti-Inflammatory Drugs IV. Springer, Dordrecht. https://doi.org/10.1007/978-94-011-5394-2_26
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DOI: https://doi.org/10.1007/978-94-011-5394-2_26
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