Steroid hormone antagonism and a cyclic model of receptor kinetics

Abstract

Steady state agonist-antagonist relations have been derived for a general version of a cyclic model of glucocorticoid-receptor kinetics. The model was previously shown to account quantitatively for the transient and steady state distribution of hormone-receptor complexes formed in thymus cells by several glucocorticoids. Agonist-antagonist properties of a steroid in the model are expressed quantitatively by its “agonist activity” A, the steady state ratio of nuclear-bound to total complexes it forms. For a pure agonist A = 1, for a pure antagonist A = 0. This ratio is found to be independent of steroid concentration and a function only of the rate constants of reactions involving complexes formed by the steroid. Analysis of the dependence of A on each rate constant reveals how each reaction in the cyclic model—activation, nuclear binding, dissociation of activated and nuclear-bound complexes—influences antagonist properties. The steady state interaction of an antagonist with an agonist is shown to be governed by relations that are indistinguishable from competition relations for the simplest equilibrium system, and to yield dose-response curves that are very similar to those produced by two-state allosteric models of steroid hormone antagonism, despite the fact that the cyclic model includes no allosteric mechanisms. With steroids for which relevant rate constants can be measured, the model is directly testable. Limitations of the model arise from lack of information about the nuclear events that lead to biological activity following binding of activated complexes to the nucleus.