CHRONIC ETHANOL ADMINISTRATION TO RATS DECREASES RECEPTOR-OPERATED MOBILIZATION OF INTRACELLULAR IONIC CALCIUM IN CULTURED-HEPATOCYTES AND INHIBITS 1,4,5-INOSITOL TRISPHOSPHATE PRODUCTION - RELEVANCE TO IMPAIRED LIVER-REGENERATION

We tested the hypothesis that ethanol impairs liver regeneration by ab rogating receptor-mediated elevation of cytosolic free calcium {[Ca2+] (i)}. In rats fed for 16 weeks with ethanol, hepatocellular proliferat ion induced by partial hepatectomy was greatly impaired. Similarly, EG F-induced DNA synthesis was reduced in cultured hepatocytes from ethan ol-fed rats. There was no change in the number or affinity of EGF rece ptors on hepatocytes from ethanol-fed rats. Despite this, EGF-mediated production of inositol 1,4,5-trisphosphate (Ins[1,4,5]P-3) was lower in hepatocytes from ethanol-fed rats, and the EGF-induced [Ca2+](i) tr ansient appeared to be abrogated. When vasopressin or phenylephrine we re used as cell surface receptor ligands, hepatocytes cultured from et hanol-fed rats exhibited major reductions in Ins(1,4,5)P-3 synthesis. This was associated with greatly truncated [Ca2+](i) transients. These changes were not due to an effect on the Ins(1,4,5)P-3 receptor on th e endoplasmic reticulum or to a decrease in the size of the Ins(1,4,5) P-3-mobilizable intracellular Ca2+ store. Further, mobilization of the same Ca2+ store by 2,5-di-tert-butylhydroquinone or thapsigargin rest ored the ability of hepatocytes from ethanol-fed rats to proliferate w hen exposed to EGF. It is concluded that chronic ethanol consumption i nhibits liver regeneration by a mechanism that is, at least partly, th e result of impaired receptor-operated [Ca2+](i) signaling due to redu ced generation of Ins(1,4,5)P-3.