Effect of metyrapone on tryptophan binding to rat hepatic nuclei

Abstract

This study evaluated whether metyrapone (2-methyl-1,2-di-3-pyridyl-1-propanone), an inhibitor of endogenous adrenal corticosteroid synthesis via inhibition of cytochrome P-450-mediated steroid hydroxylation, would influence the binding of l-tryptophan to rat hepatic nuclei or nuclear envelopes. Previous publications have indicated that binding of l-tryptophan to hepatic nuclear envelope proteins was saturable, stereospecific, and of high affinity. In this study, we investigated whether metyrapone would influence l-tryptophan binding to rat hepatic nuclei or nuclear envelopes as assayed by in vitro l-(5- 3H)tryptophan binding. Our results indicate that the addition of metyrapone in vitro has little influence on l-(5- 3H)tryptophan binding to hepatic nuclei or nuclear envelopes. On the other hand, when metyrapone ( 1 mg 100 g body weight ) is tube-fed 30 minutes before killing, the isolated hepatic nuclei show decreased specific l-tryptophan binding (total binding minus nonspecific binding [using 2,000-fold excess of unlabeled l-tryptophan]) compared with controls. Also, addition of metyrapone in vitro to rat liver before homogenization and preparation of nuclei caused the nuclei to show decreased specific tryptophan binding compared with controls. Under these in vitro conditions, SKF 525A, another inhibitor of hydroxylation, showed inhibitory effects similar to those of metyrapone. Thus, metyrapone can interfere with rat liver nuclear envelope receptor binding to l-tryptophan, and possibly acts via its effects on hydroxylation. At high doses, metyrapone ( 20 mg 100 g body weight ) appears to inhibit tryptophan-induced stimulation of hepatic protein synthesis.