A study of the effects of indometacin on liver mitochondria from rats, mice and humans.
BACKGROUND
A part of the mechanism of the gastrointestinal toxicity exhibited by non-steroidal anti-inflammatory drugs is believed to involve the uncoupling of mitochondrial oxidative phosphorylation. Most previous uncoupling studies have used rat liver mitochondria. There is little information on the effects of the drugs on mitochondria from other species.


OBJECTIVE
To study the effect of indometacin on isolated liver mitochondria from rats, mice and humans.


METHODS
We studied the effects of indometacin on respiration and adenosine triphosphate synthesis by isolated liver mitochondria from rats, mice and humans. Its effects were compared with those of dinitrophenol, a classical uncoupler.


RESULTS
Indometacin uncoupled oxidative phosphorylation at low concentrations (P < 0.05) and inhibited respiration at high concentrations (P < 0.01) in all three species. Adenosine triphosphate synthesis was, however, more sensitive to dinitrophenol or indometacin at lower concentrations in mouse and human compared to rat liver mitochondria (P < 0.05).


CONCLUSIONS
The current study shows that indometacin acts as an inhibitory uncoupler in human mitochondria. It also demonstrates that the responses of rat, mouse and human mitochondria to indometacin are broadly similar.
Jacob
M
M
Department of Biochemistry, Christian Medical College, Vellore, India.
Bjarnason
I
I
Rafi
S
S
Wrigglesworth
J
J
Simpson
R J
RJ
D000255:Adenosine Triphosphate / Q000096:biosynthesis*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects*; D046508:Culture Techniques; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007213:Indomethacin / Q000009:adverse effects*; D008297:Male; D051379:Mice; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000473:pathology* / Q000502:physiology; D010101:Oxygen Consumption / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000255:Adenosine Triphosphate; D007213:Indomethacin