An early mitosis-determining event in regenerating rat liver and its possible mediation by prostaglandins or...

Inhibitors of prostaglandin and thromboxane production such as mefenamic acid, hydrocortisone, and dexamethasone prevented a large proportion of the parenchymal cells of rat liver, proliferatively activated by a two-thirds partial hepatectomy, from entering mitosis without preventing them from initiating or completing DNA synthesis. This specific mitosis-inhibiting action was maximum when the drugs were present during the first few hours after partial hepatectomy. In contrast, indomethacin, another inhibitor of prostaglandin and thromboxane production, maximally inhibited both DNA synthetic and mitotic activities when present during the same early period of prereplicative development, which showed that it had an action not shared by the other inhibitors. Arachidonic acid completely reversed the hydrocortisone- or dexamethasone-induced inhibition of mitotic activity, but it did so only when it was injected between 2 and 3 hours after partial hepatectomy and glucocorticoid injection. Arachidonate's reversal of the hydrocortisone-induced inhibition did not occur in the presence of mefenamic acid. These observations indicate that there is an early, prostaglandin- or thromboxane-mediated, prereplicative process in proliferatively activated hepatocytes which determines their later entry into mitosis and which is separate from the early events leading to DNA synthesis.