The thyromimetic KB2115 (Eprotirome) induces rat hepatocyte proliferation

Although the hepatomitogenic activity of T3 is well established, the wide range of harmful effects exerted by this hormone precludes its use in regenerative therapy. The aim of this study was to investigate whether an agonist of TR, KB2115 (Eprotirome) could exert a mitogenic effect in the liver, without most of the adverse T3/TR-dependent side effects. F-344 rats treated with KB2115 for one week displayed a massive increase in bromodeoxyuridine incorporation (from 20 to 40% vs. 5% of controls), which was associated with increased mitotic activity in the absence of significant signs of liver toxicity. Noteworthy, while cardiac hypertrophy typical of T3 was not observed, beneficial effects, such as lowering blood cholesterol levels, were associated to KB2115 administration. Following a single dose of KB2115, hepatocyte proliferation was evident as early as 18 hours demonstrating its direct mitogenic effect. No increase of serum transaminase levels or apoptosis was observed prior to- or concomitantly with S phase. While KB2115-induced mitogenesis was not associated to enhanced expression of c-fos, c-jun and c-myc, cyclin D1 levels rapidly increased. In conclusion, KB2115 induces hepatocyte proliferation without overt toxicity. Hence this agent may be useful for regenerative therapies in liver transplantation or other surgical settings.