Restoration of sensitivity of cultured hepatoma cells to cyclic nucleotides shows permissive effect of dexamethasone.

Abstract

CULTURED rat hepatoma cell lines H-35, HTC and RLC respond to glucocorticoid hormones and have revealed details of how these steroids regulate the activity of tyrosine aminotransferase (TAT) that could not have been learned using intact liver1–4. Unfortunately, the apparent lack of other regulatory mechanisms normally present in liver often limits the usefulness of these lines. For. example, although cyclic AMP or its dibutyryl derivative reproducibly cause a several-fold induction of TAT in adult5 and foetal rat liver6 and in the H-35 (refs 7 and 8) and RLC9 hepatoma cell lines, these compounds have generally been found to be ineffective inducers of HTC cell tyrosine aminotransferase8–10. Taken with the demonstration that HTC cells have marginally detectable levels of adenylate cyclase and cyclic AMP, this insensitivity to cyclic nucleotides led to the suggestion that glucocorticoid induction does not depend on cyclic AMP10. The following evidence suggests that the converse may not be true: TAT induction by dibutyryl cyclic AMP (db cyclic AMP) in adult rat liver is reduced by adrenalectomy11; combinations of db cyclic AMP and steroids result in synergistic induction in rat liver and liver organ culture5; and cortisol increases the absolute degree of induction of TAT by db cyclic AMP in some responsive hepatoma cell lines8–12. This putative interrelationship could be clarified if a cell line, otherwise unresponsive to cyclic nucleotides, could be made to respond to these agents by adrenal steroid hormones. This report describes such an accomplishment and suggests that HTC cells are a model system for studies of the permissive effects of glucocorticoid hormones.