Effects of paraquat, dinoseb and 2,4-D on intracellular calcium and on vasopressin-induced calcium mobilization in isolated hepatocytes

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Abstract
The effects of the herbicides paraquat, dinoseb and 2,4-D on intracellular Ca2+ levels and on vasopressin-induced Ca2+ mobilization were investigated in intact isolated hepatocytes. Incubation of rat hepatocytes with paraquat (5 mM for 60 min) and dinoseb (10 μM) resulted in a time-dependent loss of viability by approximately 25%. Viability of cells treated with 2,4-D decreased significantly, dropping to about 20% at 10 mM and 60 min incubation. Exposure of hepatocytes to paraquat (1–10 mM) for 60 min had no effect on the basal level of [Ca2+]i. Additionally, exposure to paraquat had no effect on the magnitude and on the duration of the [Ca2+]i response to vasopressin. In the presence of 2,4-D (1–10 mM), basal [Ca2+]i increases as a function of herbicide concentration. The magnitude of the Δ[Ca2+]i response decreases from 256± 8nM in control to 220 ± 5nM, at 10mM 2,4-D. Exposure of hepatocytes to dinoseb (1–10 μM) had no effect on the basal level of [Ca2+]i. However, a strong concentration-dependent decrease in the magnitude of Δ[Ca2+]i in response to vasopressin was noticed at 60 min incubation. Dinoseb markedly inhibited the stimulation of the production of inositol phosphates by vasopressin stimulus. The present study demonstrates that paraquat, 2,4-D and dinoseb cause cell death in hepatocytes by mechanisms not related to an early increase in [Ca2+]i. Additionally, it has been shown for the first time that dinoseb disturbs the transduction mechanism promoted by vasopressin by inhibiting the formation of IP3.