Effect of cyclosporine a on hepatic compensatory growth: role of calcium status.
Cyclosporine A (CsA) has been reported to positively influence hepatic compensatory growth (HCG) in normal animals. The role of calcium in the CsA-mediated influence on HCG was studied in normal and in chronically hypocalcemic rats, a model in which HCG is perturbed. CsA (3.33 mg/kg/day for 10 days) was administered before 2/3 partial hepatectomy (PHx). CsA did not influence serum Ca(2+) but significantly increased concentrations of the vitamin D hormone calcitriol. After PHx in normal animals, CsA accelerated DNA synthesis without influencing liver weight restitution, suggesting that its main effect was to mediate an accelerated progression through the cell cycle G(0) to G(1)/S phase(s). In hypocalcemic rats, CsA did not influence DNA synthesis, but normalization of circulating calcium alone accelerated DNA synthesis but abrogated the stimulatory effect of CsA, indicating that CsA could not superimpose its stimulatory effect on the calcium effect. In vitro investigation on the CsA mechanisms of action revealed a dose-dependent increase in hepatocyte basal resting cytoplasmic Ca(2+) and an increase in inositol-1,4,5-trisphosphate-sensitive Ca(2+) pool, which was dependent on the presence of normal extracellular Ca(2+) during CsA exposure. CsA also mediated a significant increase in cellular Ca(2+) mobilization by phenylephrine, vasopressin, and epidermal growth factor (EGF) in the presence of extracellular Ca(2+) concentration. Our data, therefore, demonstrate that CsA accelerates HCG after PHx by, in part, increasing the cellular Ca(2+) pools and the response to EGF and Ca(2+)-mobilizing hormones known to be comitogens for hepatocytes.
Provencher
Sébastien J
SJ
Centre de Recherche, Centre Hospitalier de l'Université de Montréal, Hôpital Saint-Luc, Montréal, Québec, Canada.
Gascon-Barré
Marielle
M
D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D016572:Cyclosporine / Q000494:pharmacology*; D004261:DNA Replication / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006498:Hepatectomy; D007700:Kinetics; D008099:Liver / Q000033:anatomy & histology* / Q000187:drug effects*; D008115:Liver Regeneration / Q000187:drug effects*; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D013936:Thymidine / Q000378:metabolism; D013997:Time Factors; D014808:Vitamin D Deficiency / Q000503:physiopathology
D004791:Enzyme Inhibitors; D016572:Cyclosporine; D002118:Calcium; D013936:Thymidine