Interactions of exogenous endocrine active substances with nuclear
receptors
J. A. Katzenellenbogen and R. Muthyala
Department of Chemistry, University of Illinois, Urbana,
IL 61801, USA
Abstract: Nuclear receptors function as ligand-regulated transcription
factors and modulate the expression of sets of genes in response to
varying concentrations of ligands. The ligand modulators can be endogenous
metabolites that function as hormones, or they can be exogenous substances,
such as pharmaceutical agents or environmental substances of natural
or man-made origin, which in some cases can cause endocrine disruption.
Ligands modulate nuclear receptor activity by binding to their ligand-binding
domains and stabilizing conformations that lead either to transcriptional
activation or repression. The ligand-binding pocket is somewhat flexible,
and binding affinities can be measured over a 10-million-fold range
(i.e., with equilibrium dissociation constant values ranging from ca.
0.01 nM to 100 mM). Thus, it is not surprising
that by binding a large variety of structures, some nuclear receptors
can appear to be promiscuous; however, when affinity is considered,
the binding patterns are more restricted. The spectrum of ligands that
bind to the estrogen receptor has been most thoroughly investigated.
Those from natural sources include natural products in food, such as
soy isoflavones and whole grain lignans, as well as microbial products
and components from wood. Aside from pharmaceuticals, man-made estrogen
ligands can be found in industrial products, such as alkyl phenols from
nonionic detergents, bisphenols from plastics, indicator dye impurities,
polymer chemicals, and chlorinated aromatics and pesticides. Exogenous
ligands are also known for the androgen and progesterone receptors.
While it is possible that endocrine disruption can result from exogenous
chemicals acting directly as ligands for the nuclear receptors, endocrine
disruption needs to be considered in the broader context; thus, compounds
also need to be assessed for their effects at other levels, such as
on endogenous hormone production, transport, metabolism, and clearance,
and at points in signal transduction cascades that are beyond the ligand-receptor
interaction.
*Report from a SCOPE/IUPAC project: Implication of
Endocrine Active Substances for Human and Wildlife (J. Miyamoto and
J.Burger, editors). Other reports are published in this issue,
pp. 1617-2615.
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