Calmodulin antagonist trifluoperazine inhibits polyamine biosynthesis and liver regeneration

Polyamines are essential for cell growth and differentiation. Trifluoperazine (TFP) is a potent, competitive inhibitor of the calcium-calmodulin complex. TFP, when given to rats after partial hepatectomy, causes a significant decrease in DNA synthesis. The purpose of this study was to examine the effects of TFP on polyamine biosynthesis and on liver regeneration after partial hepatectomy. TFP (60 mg/kg, bodyweight) or saline control was administered to 80 male Sprague-Dawley rats 2 h before, 2 h after, or at the time of hepatectomy. Polyamines (putrescine, spermidine and spermine) were measured at the time of hepatectomy, and at 6, 24, 48, and 72 h after hepatectomy. TFP, when it was administered either 2 h before or at time of hepatectomy, blocked increases in putrescine that are seen normally at 6 h after hepatectomy. When TFP was given at the time of partial hepatectomy, putrescine was increased at 24 h, and then returned to normal levels at 72 h. Spermidine was inhibited at 24 h, but not at 48 and 72 h. Spermine was not significantly altered at any time. The administration of TFP 2 h after hepatectomy did not significantly alter concentrations of polyamines. The weight of regenerating liver was decreased by TFP at 48 h (23 per cent) and 72 h (22 per cent) after hepatectomy. These findings provide evidence that the calcium-calmodulin complex is required for the synthesis of liver polyamines before liver regeneration can proceed.