Effects of two newly synthesized 4-hydroxycoumarin derivatives (4-OHC) on isolated rat hepatocytes.
To clarify the hepatotoxicity of two newly synthesized derivatives of 4-hydroxycoumarin (OX and AC) with proven anticoagulant activity in comparison with warfarin, we investigated freshly isolated rat hepatocytes. Hepatocyte damage after incubation with OX, AC and warfarin at a final concentration of 1 x 10(-8) M to 1 x 10(-3) M was assessed by measuring cell viability, lactatdehydrogenase (LDH) activity and glutathione (GSH) levels. The results of cell viability assessment showed that warfarin had the highest toxicity, followed by OX and AC. LDH activity of the tested compounds was mostly increased by warfarin. According to the average effective concentration of the compounds on this parameter, warfarin possessed the most significant toxic effect (EC50 = 1 x 10(-7) M), followed by AC (EC50 = 9.7 x 10(-5) M) and OX (EC50 = 5.0 x 10(-4) M). The observed cytotoxic effects were most pronounced in the highest concentration 1 x 10(-3) M as follows: warfarin, AC and OX. The differences in the effects of OX and AC may be explained by the differences in the electronic structure of the novel compounds, as assessed by molecular modeling.
Mitcheva
M
M
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Medical University, Sofia, Bulgaria.
Vitcheva
V
V
Manolov
I
I
Valkova
I
I
D015110:4-Hydroxycoumarins / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D000925:Anticoagulants / Q000378:metabolism / Q000633:toxicity*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005982:Glutathione Transferase / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D014859:Warfarin / Q000378:metabolism / Q000633:toxicity
D015110:4-Hydroxycoumarins; D000925:Anticoagulants; D014859:Warfarin; D007770:L-Lactate Dehydrogenase; D005982:Glutathione Transferase