Effect of paracetamol on mitochondrial membrane function in rat liver slices.
The effect of paracetamol on mitochondrial function was studied using rat liver slices. Changes in the potential of the mitochondrial and plasma membrane were monitored using [3H]-triphenylmethylphosphonium (TPMP+) and [14C]thiocyanate (SCN-) probes, respectively. Liver slices were exposed to 10 mM paracetamol for various time periods (0-360 min) after loading with TPMP+. The release of TPMP+ which correlates with a decrease in the mitochondrial membrane potential became significant after 30 min incubation with 10 mM paracetamol. The change in the mitochondrial membrane potential was shown to be independent of cytochrome P450 activity. No significant change in plasma membrane potential was observed, until the release of lactate dehydrogenase (LDH) had begun, 4 hr after exposure, reflecting the ultimate stages of cell injury by paracetamol. These results suggest that paracetamol elicits a direct effect on the mitochondrial function before cell injury develops and adds further evidence to the role of mitochondria in paracetamol toxicity.
Nazareth
W M
WM
Department of Clinical Pharmacology, University College London, U.K.
Sethi
J K
JK
McLean
A E
AE
D000082:Acetaminophen / Q000633:toxicity*; D000818:Animals; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone / Q000494:pharmacology; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D003545:Cysteine / Q000494:pharmacology; D007424:Intracellular Fluid / Q000378:metabolism; D007425:Intracellular Membranes / Q000187:drug effects* / Q000502:physiology; D008099:Liver / Q000033:anatomy & histology / Q000502:physiology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000502:physiology; D009861:Onium Compounds / Q000493:pharmacokinetics; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013861:Thiocyanates / Q000493:pharmacokinetics; D014320:Triphenylmethyl Compounds / Q000493:pharmacokinetics
D009861:Onium Compounds; D011725:Pyridines; D013861:Thiocyanates; D014320:Triphenylmethyl Compounds; C011561:triphenylmethylphosphonium; C013109:metapyrone; D000082:Acetaminophen; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone; D003545:Cysteine