Chemical structure and toxicity of diuretics in isolated hepatocytes.
The effects of several diuretics, including tienilic acid and indacrinone, on isolated rat heaptocytes were examined. Addition of tienilic acid and indacrinone at 1 mM to a suspension of freshly isolated cells caused dose-dependent loss of cell viability as judged by the LDH-latency test. Survey of 19 structurally related compounds revealed that the extent of cell injury and chemical structure were correlated, and an intense adverse effect was attributed to the 2-thienylcarbonyl moiety. Several other factors influencing cell viability are also disclosed. Further study revealed that tienilic acid and indacrinone were toxic to the primary culture of hepatocytes at a lower dose than that a freshly isolated hepatocytes. Thus, an isolated hepatocyte system can be used to select compounds displaying low hepatotoxicity, as for example is needed when screening diuretics.
Higaki
J
J
Shionogi Research Laboratories, Shionogi & Co., Ltd., Osaka, Japan.
Harada
H
H
Tonda
K
K
Hirata
M
M
D000818:Animals; D002478:Cells, Cultured; D004232:Diuretics / Q000633:toxicity*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008099:Liver / Q000166:cytology* / Q000378:metabolism; D008297:Male; D015394:Molecular Structure; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship; D014528:Uricosuric Agents / Q000633:toxicity
D004232:Diuretics; D014528:Uricosuric Agents; D007770:L-Lactate Dehydrogenase