Biochemical origins of the non-monotonic receptor-mediated dose-response

Abstract

A mathematical model was created to examine how xenobiotic ligands that bind to nuclear receptor proteins may affect transcriptional activation of hormone-regulated genes. The model included binding of the natural ligand (e.g. hormone) and xenobiotic ligands to the receptor, binding of the liganded receptor to receptor-specific DNA response sequences, binding of co-activator or co-repressor proteins (Rp) to the resulting complex, and the consequent transcriptional rate relative to that in the absence of the xenobiotic agent. The model predicted that the xenobiotic could act as a pure agonist, a pure antagonist, or a mixed agonist whose dose-response curve exhibits a local maximum. The response to the agent depends on the affinity of the liganded receptor-DNA complex for binding additional transcription factors (e.g. co-activator proteins). An inverted U-shaped dose-response occurred when basal levels of the natural ligand did not saturate receptor binding sites and the affinity for co-activator is weaker when the xenobiotic ligand is bound to the receptor than when the endogenous ligand is bound. The dose-response curve shape was not dependent on the affinity of the receptor for the xenobiotic agent; alteration of this value merely shifted the curve along the concentration axis. The amount of receptor, the density of DNA response sequences, and the affinity of the DNA-bound receptor for Rp determine the amplitude of the computed response with little overall change in curve shape. This model indicates that a non-monotonic dose-response is a plausible outcome for xenobiotic agents that activate nuclear receptors in the same manner as natural ligands.

Perichondrial-mediated TGF-beta regulation of cartilage growth in avian long bone development

“…This type of non-monotonic dose response has been observed in other studies, including the effect of TGF-β on the metastatic potential of mammary adenocarinoma cells (Welch et al, 1990). Although the mechanism(s) responsible for this type of dose response is still speculative, it has been proposed (Kohn and Melnick, 2002) that this may reflect a lack of receptor saturation or an alteration in the affinity of coreceptors/activators for the ligand. In reality, however, we currently have no explanation for this response in the TGF-β-mediated regulation of cartilage growth, as observed here.…”

Non-monotonic dose–response relationship in steroid hormone receptor-mediated gene expression

“…With respect to SHR-mediated action, a variety of mechanisms have been proposed to explain the non-monotonic effects of certain EACs and the bidirectional effects of SRMs in different target tissues (Smith et al 1997, McInerney et al 1998, Kohn & Melnick 2002, Conolly & Lutz 2004, Smith & O'Malley 2004. Using numerical simulation of a relatively standard model of steroid hormone action, the present study demonstrated that non-monotonic steady-state response may be a property intrinsic to SHR-mediated gene expression under a variety of conditions.…”

“…But apparently, if they cannot be formed at all, cells would have a tendency to exhibit U-shaped responses when the exogenous ligand is an agonist. Non-monotonic dose-responses in steroid or nuclear receptor signaling have been previously investigated through numerical simulations (Kohn & Portier 1993, Kohn & Melnick 2002, Conolly & Lutz 2004). Kohn and Portier had proposed that positive cooperative binding between liganded receptor and DNA may result in a U-shaped dose-response curve (Kohn & Portier 1993).…”

“…5A). With respect to inverted U-shape, Kohn & Melnick (2002) suggested that one condition for this to occur is when there are excessive unoccupied receptors and recruitment of CoA by xenobiotic ligands is weaker than by endogenous ligands. However, in their model, receptor dimerization was not considered.…”

“…Alternatively, the opposing effect of SRMs in different tissues may result from the involvement of different SHR subtypes (McInerney et al 1998, Zhou & Cidlowski 2005. Kohn and Melnick found that an inverted U-shaped dose-response can arise from conditions where there are unoccupied receptors by endogenous hormones and recruitment of CoA by xenobiotic ligands is relatively weak (Kohn & Melnick 2002). Conolly and Lutz hypothesized that a U-shaped dose-response curve can result from transcriptionally inactive mixed-ligand receptor dimers (Conolly & Lutz 2004).…”