Page 265 - The Toxicology of Fishes

Receptor-Mediated Mechanisms of Toxicity 245

the ligand bound, which produces differences in the activity of the receptor. The relative ability of the
ligand–receptor complex to produce a downstream response is termed efficacy.
Measurement of efficacy is complicated by the fact that it depends not only on the ligand and receptor
but also on the presence of other factors in the cell; for example, the same ligand for a G-protein-coupled
receptor may produce varying responses in different tissues depending on the identity and concentration
of G proteins present. Even within a single tissue type, efficacy varies among responses. Perhaps the
best-studied example of differential efficacy among tissues and responses is the effects of the hormone
estrogen and synthetic estrogen receptor ligands, termed selective estrogen receptor modulators
(SERMs), which recapitulate different subsets of estrogenic responses (MacGregor and Jordan, 1998).
The mechanism of differential efficacy has been established for the SERM tamoxifen, which induces a
receptor conformation that does not facilitate interaction with transcriptional coactivator proteins (Shiau
et al., 1998).
The response produced by the ligand also varies among cell types due to differences in receptor
concentration. Some cells may possess receptor reserve (i.e., “spare” receptors), such that only a fraction
of the receptors must be occupied to produce a maximal response, while other cells contain just sufficient
receptors to produce a maximal response, and others so few that a maximal response is never produced,
regardless of ligand concentration.
All of these factors contribute to the observed efficacy of a ligand, which is determined by dose–
response studies. Ligands can be classified based on the responses they produce as full agonists (which
produce the maximal response possible), partial agonists (which produce a less-than-maximal response,
even at high ligand concentrations), and antagonists (which interact with the receptor but produce no
response). Because of tissue-specific differences in the concentration of receptors and other necessary
factors, the same ligand could be a full agonist in one tissue, a partial agonist in another, and an antagonist
in a third. Also, partial agonists can vary widely in the amount of response they produce. For these
reasons, it can be useful to compare a set of ligands in terms of their relative efficacies rather than
applying conditional (i.e., tissue-dependent) labels such as “full agonist” or “partial agonist.”
Several models have been advanced to describe the contribution of efficacy to response. The operational
model of Black and Leff (1983) has the advantage of representing efficacy in a single term, K , analogous
E
to the representation of affinity with K . The operational model assumes a hyperbolic relationship
D
between the amount of ligand-occupied receptor and response:
E [ LR]
= (5.7)
E max [ LR]+ K E
where E and E max are the response produced and maximal response. Substituting Equation 5.3 into
Equation 5.7 produces:
LR T]
[][
E
= KK E + [ ( R T] + ) (5.8)
L
E max D K E []
If the binding affinity of the ligand and the concentration of receptors is known for the system, K can
E
be determined by fitting dose–response data to Equation 5.8. Equation 5.8 can be solved for the conditions
when response is half maximal (i.e., the EC for the system and ligand):
50
EC 50 = 1+ [ ( R T] K E) (5.9)
K D

It is important to note that K depends both on the properties of the ligand–receptor complex and on
E
properties of the tissue; however, if response is measured for a series of compounds in a single cell type,
then differences among K values are due solely to the interaction of the ligand and receptor (Hestermann
E
et al., 2000). Also, K is a useful value because it carries the same units as [R ], so K /[R ] is the fraction
T
E
T
E
of receptors that must be occupied for a half-maximal response, giving a ready estimate of receptor reserve.