2, 4-diamino-6- hydroxy pyrimidine inhibits NSAIDs induced nitrosyl-complex EPR signals and ulcer in rat jejunum.
BACKGROUND
It has been suggested that one aspect of non-steroidal anti-inflammatory drugs induced intestinal damage is due to either uncoupling of mitochondrial oxidative phosphorylation or inhibition of electron transport. We investigated the latter possibility using electron paramagnetic resonance spectroscopy.


RESULTS
Electron paramagnetic studies of NSAIDS on sub-mitochondrial particles revealed that indomethacin, but not with nabumetone, bound to a site near to Complex I and ubiquinone to generate a radical species. Normal rats exhibited prominent [3Fe-4S]ox signals (g approximately 2.01) at 20 K. One hour after indomethacin there was a prominent, intense and broad absorption pattern at (g approximately 2.07) suggesting, appearance of radical species overlapping [3Fe-4S]ox and was unaffected by pretreatment with 2,4 diamino -6-hydroxy pyrimidine. At 24 hrs, when macroscopic ulcers were seen, there was a new signal due to a nitric oxide radical (NO*). In contrast, nabumetone and 2,4 diamino-6-hydroxy pyrimidine pre-treated animals receiving indomethacin exhibited electron paramagnetic resonance spectra identical to those of controls at 24 hrs and neither was associated with small intestinal ulcers. Indomethacin and 2,4 diamino hydroxy pyrimidine pre-treated rats, but not nabumetone, had increased intestinal permeability.


CONCLUSIONS
The results suggest that the in vivo effects of indomethacin modulate the mitochondrial respiratory chain directly at 1 h and 24 h through formation of nitric oxide. NO* appears to play an important role in the late pathogenic stages of NSAID enteropathy and may be the site for targeted treatment to reduce their toxicity.
Somasundaram
S
S
Lineberger Comprehensive Cancer Center, CB#7295, University of North Carolina, Chapel Hill, NC 27599, USA. sivasoma@med.unc.edu
Simpson
R
R
Rafi
S
S
Shergill
J K
JK
Bjarnason
I
I
Wrigglesworth
J
J
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000037:antagonists & inhibitors*; D002074:Butanones / Q000494:pharmacology; D002463:Cell Membrane Permeability / Q000187:drug effects; D004578:Electron Spin Resonance Spectroscopy; D004579:Electron Transport / Q000187:drug effects*; D007042:Hypoxanthines / Q000494:pharmacology*; D007579:Jejunal Diseases / Q000139:chemically induced* / Q000378:metabolism; D000077430:Nabumetone; D009569:Nitric Oxide / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013367:Submitochondrial Particles / Q000187:drug effects; D014456:Ulcer / Q000139:chemically induced* / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D002074:Butanones; D007042:Hypoxanthines; D009569:Nitric Oxide; C017202:2,4-diaminohypoxanthine; D000077430:Nabumetone