Evidence that Ciclosporin Is Hepatotoxic and Hepatotrophic in 70% Hepatectomized Rats and Mice

Abstract

The influence of ciclosporin (Cs) on liver regeneration was studied in rats and mice with or without thymus after two-third hepatectomy. Rats were treated at –24, 0, and +24 h posthepatectomy with oral Cs, 5, 10, or 20 mg/kg. Before hepatectomy, mice were given a 4-day course of Cs 10 mg/kg. The peak mitosis (30 h posthepatectomy) of remnant hepatocytes in rats was doubled by the two lower dosages of Cs but was suppressed by the highest dosage compared with control. In addition, the rise in serum transaminase and total bilirubin concentrations was proportionate to the increase in Cs dosage given. Cs increased hepatocyte division in thymic mice but was hepatotoxic in athymic nude mice. These data present evidence that Cs is both hepatotrophic and hepatotoxic in regenerating liver.

Augmentative Effect of Cyclosporin A on Rat Liver Regeneration: Influence on Hepatocyte Growth Factor and Transforming Growth Factor-β₁

“…Our previous work demonstrated that oral administration of 20 mg/kg CsA tended to suppress rather than augment peak mitotic activity and to increase serum levels of ALT and total bilirubin as an index of hepatotoxicity [17]. Kahn et al [14] demonstrated that CsA pretreatment significantly increased hepatic levels of metabolic enzymes including thymidine kinase and ornithine decarboxylase.…”

Effect of cyclosporine on liver regeneration in partial hepatectomized rats

“…However, other authors didn't achieve the same results 12,13 . In this study, the authors used oral cyclosporine in a 10mg/Kg/day with rigid plastic orogastric tube as described by other researchers [9][10][11][15][16][17][18] . All groups lost body weight in the moment of death with statistical significance.…”

“…Some studies have shown the influence of pretherapy with cyclosporine in liver regeneration after a 70% hepatectomy [8][9][10][11] , although some papers don't confirm the same results 12,13 .…”

Invited commentary

“…Perhaps no less plausible is the paradox of pharmacologic enhancement of recovery of the native liver by the very same immunosuppressive agents given to protect the graft. Several groups have now documented that cyclosporine [2][3][4][5][6][7] and FK 506 [5,8] enhance liver regeneration. Starzl, Schreiber and coworkers suggest that these drugs may do so through interactions with immunophilins (their specific cytosolic receptors).…”