HEPATOCYTE PROLIFERATION AND GENE-EXPRESSION INDUCED BY TRIIODOTHYRONINE IN-VIVO AND IN-VITRO

Subcutaneous injections of hormone triiodothyronine in rats resulted i n peak blood levels at 24 hr with return to baseline by 96 hr. The inj ections stimulated a liver regeneration response that resembled in tim ing and in magnitude of DNA synthesis (peak, 24 hr) that induced by 40 % hepatic resection. The principal proliferation was of hepatocytes. A lthough there were some temporal differences from the gene expression of transforming growth factor-alpha, transforming growth factor-beta, and c-Ha-ras that are known to follow partial hepatectomy, the overall profile of these changes was similar to those after partial resection . The effect was liver specific and could be reproduced three times wi th no diminution in response in the same animal with injections at 10- day intervals. No response was detected in kidney or intestine. This e ffect in intact animals contrasted with the minimal ability of triiodo thyronine to stimulate hepatocytes in culture. However, when the cultu re medium was enriched with epidermal growth factor, there was a dose- related response to triiodothyronine. The totality of these experiment s provides a preliminary basis for the creation with pharmacological t echniques of an in vivo hyperplastic hepatic condition permissive of t ransfection of new genes, as an alternative to partial hepatectomy. Al though triiodothyronine was the test agent used, other hepatic growth factors singly or in combination could be candidates for this purpose.