Toxicol Lett 2003 Feb 03;1373:185-92. doi: 10.1016/s0378-4274(02)00402-2.

Involvement of calcium channels in the sexual dimorphism of cadmium-induced hepatotoxicity.

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Cadmium toxicity has been evaluated in a number of in vivo and in vitro toxicological studies. In vivo Cd toxicity exhibits sexual dimorphism with females being more susceptible to Cd uptake, accumulation, and toxicity in the liver. Research to date does not explain why females are more sensitive to Cd-induced hepatotoxicity. Recent studies demonstrate that progesterone sensitizes female F(344) rats and TRL-1215 cells to Cd toxicity, however the mode of action is still unclear. Approximately one half of the Cd entering the cytoplasm does so through receptor operated Ca(2+) channels. Progesterone treatment of human spermatozoa and Xenopus laevis oocytes causes a rapid influx of Ca(2+) suggesting a possible mechanism. Since hepatocytes have progesterone receptors on their cellular membrane and Ca(2+) influx into the cytoplasm occurs following progesterone treatment we evaluated the hypothesis that progesterone facilitates the uptake and accumulation of Cd via Ca(2+) channels, leading to enhanced toxicity. Primary isolated rat hepatocytes were treated with Cd, progesterone, and/or verapamil for 4 h and cytolethality was measured. Pretreatment with the Ca(2+) channel blocker verapamil increased the Cd concentration producing 50% lethality (LC(50)) by 2-fold, thus decreasing Cd cytolethality. In contrast, pretreatment with progesterone decreased the Cd LC(50) by 2-fold resulting in enhanced Cd cytolethality. Verapamil treatment reversed the progesterone enhanced Cd cytolethality. Verapamil and/or progesterone in the absence of Cd did not affect hepatocyte viability. Overall, the results of this study demonstrate that inhibition of progesterone-induced Ca(2+) influx with the Ca(2+) channel blocker verapamil, decreases Cd cytolethality in primary isolated rat hepatocytes. These findings indicate that progesterone activation of receptor-mediated Ca(2+) channels is involved in the sexually dimorphic hepatotoxicity seen following acute Cd exposure.

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