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 abrogating receptor-mediated elevation of cytosolic free calcium ([Ca2+]i). In rats fed for 16 weeks with ethanol, hepatocellular proliferation induced by partial hepatectomy was greatly impaired. Similarly, EGF-induced DNA synthesis was reduced in cultured hepatocytes from ethanol-fed rats. There was no change in the number or affinity of EGF receptors on hepatocytes from ethanol-fed rats. Despite this, EGF-mediated production of inositol 1,4,5-trisphosphate (Ins[1,4,5]P3) was lower in hepatocytes from ethanol-fed rats, and the EGF-induced [Ca2+]i transient appeared to be abrogated. When vasopressin or phenylephrine were used as cell surface receptor ligands, hepatocytes cultured from ethanol-fed rats exhibited major reductions in Ins(1,4,5)P3 synthesis. This was associated with greatly truncated [Ca2+]i transients. These changes were not due to an effect on the Ins(1,4,5)P3 receptor on the endoplasmic reticulum or to a decrease in the size of the Ins(1,4,5)P3-mobilizable intracellular Ca+2 store. Further, mobilization of the same Ca2+ store by 2,5-di-tert-butylhydroquinone or thapsigargin restored the ability of hepatocytes from ethanol-fed rats to proliferate when exposed to EGF. It is concluded that chronic ethanol consumption inhibits liver regeneration by a mechanism that is, at least partly, the result of impaired receptor-operated [Ca2+]i signaling due to reduced generation of Ins(1,4,5)P3.
Zhang
B H
BH
Department of Medicine, University of Sydney at Westmead Hospital, NSW, Australia.
Hornsfield
B P
BP
Farrell
G C
GC
D000437:Alcoholism / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D002463:Cell Membrane Permeability; D002478:Cells, Cultured; D004815:Epidermal Growth Factor / Q000378:metabolism / Q000494:pharmacology; D006498:Hepatectomy; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism*; D008099:Liver / Q000166:cytology / Q000254:growth & development / Q000378:metabolism*; D008115:Liver Regeneration / Q000187:drug effects*; D008297:Male; D010656:Phenylephrine / Q000494:pharmacology; D011485:Protein Binding; D051381:Rats; D017208:Rats, Wistar; D011956:Receptors, Cell Surface / Q000378:metabolism*; D014667:Vasopressins / Q000494:pharmacology
D011956:Receptors, Cell Surface; D014667:Vasopressins; D010656:Phenylephrine; D004815:Epidermal Growth Factor; D015544:Inositol 1,4,5-Trisphosphate; D002118:Calcium