ACTH precursors: biological significance and clinical relevance.

Abstract

ACTH is synthesized as part of the precursor proopiomelanocortin or POMC (Fig. 1). In the human pituitary POMC is enzymatically processed to pro-ACTH, which is then cleaved to give ACTH. Processing of POMC in the pituitary takes place within the regulated secretory pathway and is accomplished by the protease PC1 located within mature dense core granules (Benjannet et al., 1991; Smeekens et al., 1991). The presence of ACTH precursors in plasma was first demonstrated in normal subjects after stimulation with metyrapone (Yalow & Berson, 1971) and was later observed after insulin-induced hypoglycaemia (Hale et al., 1986). However, complex chromatographic techniques were required to separate ACTH precursors from ACTH. Clearly, this approach could not be used for large numbers of patient samples and would not provide a quantitative assessment of the concentrations of the ACTH precursors in plasma. We have subsequently quantified the concentrations of ACTH precursors in the human circulation under basal conditions. Direct measurement of these peptides was made possible by the development of a two-site immunoradiometric assay for the ACTH precursors, POMC and pro-ACTH (Crosby et al., 1988). The assay is based on a labelled monoclonal antibody which binds within the ACTH region of POMC and a solid phase antibody which recognizes N-terminal POMC (N-POC, Fig. 1). As binding of both antibodies is required to generate a signal, the assay does not detect ACTH. Using this assay, the concentrations of ACTH precursors in normal subjects were found to be 5-40 pmol/l which is equivalent to or greater than those of ACTH, N-POC, b-lipotrophin (b-LPH) and b-endorphin (Gibson et al., 1994). The levels of ACTH precursors and ACTH in the circulation at any given time are dependent on regulatory mechanisms influencing expression of the POMC gene. However, the relative concentrations of ACTH precursors and ACTH will depend on precursor processing and mechanisms of secretion from the corticotroph cells. Evidence from studies with the mouse corticotroph adenoma cell line, AtT20, suggests that in the absence of stimulation, corticotroph cells ‘leak’ newly synthesized POMC (Kelly, 1985). Furthermore, results we have obtained in normal subjects and from clinical studies indicate that acute regulation of secretion of ACTH and ACTH precursors differs (see below).