Function and mode of action of nuclear receptors: Estrogen, progesterone,
and vitamin D
E. A. Kimbrel and D. P. McDonnell
Duke University Medical Center, Durham, NC 27710,
USA
Abstract: Estrogens and progestins play important roles in regulating
growth and differentiation of a wide range of cell types, in both reproductive
and nonreproductive tissues. Not surprisingly, therefore, endocrine
active substances that mimic the actions of these steroid hormones have
been demonstrated to have untoward effects on the reproductive function
of a variety of animals. Although direct links between exposure to endocrine
active substances of this class and reproductive abnormalities in humans
have been difficult to establish, the potential for harm by this class
of chemicals warrants further investigation. This chapter summarizes
our current understanding of the molecular pharmacology of the estrogen
and progesterone receptors, ER and PR, beginning with a historical perspective
of ER pharmacology and ending with a comparison of these receptors to
the vitamin D receptor (VDR), a nonsteroid hormone nuclear receptor
involved in regulating growth and development in nonreproductive tissues.
Major topics discussed include receptor subtypes (or isoforms), receptor
functional domains, ligand-binding characteristics, receptor structure,
cofactor binding, effects of phosphorylation, and nonclassical modes
of action. This discussion will demonstrate the need for developing
novel screens for potential endocrine disruptors that incorporate our
current understanding of nuclear receptor pharmacology.
*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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