Effect of Cyclosporine A on Hepatic Compensatory Growth: Role of Calcium Status

Abstract

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 2ϩ 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 2ϩ and an increase in inositol-1,4,5-trisphosphate-sensitive Ca 2ϩ pool, which was dependent on the presence of normal extracellular Ca 2ϩ during CsA exposure. CsA also mediated a significant increase in cellular Ca 2ϩ mobilization by phenylephrine, vasopressin, and epidermal growth factor (EGF) in the presence of extracellular Ca 2ϩ concentration. Our data, therefore, demonstrate that CsA accelerates HCG after PHx by, in part, increasing the cellular Ca 2ϩ pools and the response to EGF and Ca 2ϩ -mobilizing hormones known to be comitogens for hepatocytes.

Cyclosporine A Downregulates Selenoprotein P Expression via a Signal Transducer and Activator of Transcription 3–Forkhead Box Protein O1 Pathway in Hepatocytes In Vitro

“…Although CsA is available for oral administration in clinical treatment, a review concludes that intraperitoneal injection is a sufficient route to examine the effect of a compound in the pharmacological and proof-of-concept animal studies because it maintains the therapeutic bioavailability whereas the oral route has the potential possibility of degradation or modification of compound conformation (Al Shoyaib et al, 2020). Indeed, CsA is often intraperitoneally administrated in animal studies in previous reports (Provencher and Gascon-Barré, 2002;Ciechomska et al, 2005;Colgan et al, 2005). Vehicle or 50 mg/kg/day of CsA was administrated intraperitoneally for 3 days.…”