Paracetamol potentiates isaxonine toxicity in vitro.
The toxicity of isaxonine alone and in combination with the known glutathione depletor, paracetamol, was evaluated using rat hepatocyte primary cultures in vitro by measuring morphometric parameters and the leakage of intracellular lactate dehydrogenase into the culture medium. No cytotoxicity was observed with isaxonine at concentrations up to 10(-3) M, whereas paracetamol was cytotoxic at concentrations above 0.6 x 10(-3) M in the culture medium. Paracetamol cytotoxicity (0.6-3.3 x 10(-3) M) was enhanced in the presence of a non-cytotoxic concentration of isaxonine (10(-7) M). Furthermore cytotoxicity was observed when cells were exposed to a combination of non-cytotoxic concentrations of the paracetamol (0.3 x 10(-3) M) and isaxonine (10(-7) M). These findings demonstrate that isaxonine has no direct cytotoxic effect even at high concentrations. However co-administration of isaxonine with paracetamol greatly potentiates cytotoxicity. We suggest that this effect may be related to glutathione depletion within the cell but additional studies are required to verify this hypothesis.
Shrivastava
R
R
RL-CERM, Riom, France.
John
G
G
Chevalier
A
A
Beaughard
M
M
Rispat
G
G
Slaoui
M
M
Massingham
R
R
D000082:Acetaminophen / Q000633:toxicity*; D000818:Animals; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005978:Glutathione / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000187:drug effects; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008297:Male; D011743:Pyrimidines / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley
D011743:Pyrimidines; D000082:Acetaminophen; C020375:isaxonine; D007770:L-Lactate Dehydrogenase; D005978:Glutathione