Biological function and mode of action of nuclear xenobiotic receptors
J. Sonoda and R. M. Evans
Howard Hughes Medical Institute, Gene Expression Laboratory,
The Salk Institute for Biological Studies, 10010 North Torrey Pines
Road, La Jolla, CA 92037, USA
Abstract: Two related nuclear receptors, the pregnane X receptor
(PXR) and the constitutive androstane receptor (CAR), act as xenobiotic
sensors that protect the body from a multitude of foreign chemicals
(xenobiotics) and play a central role in the metabolism and clearance
of steroids and toxic endogenous lipids (endobiotics). A structurally
diverse array of chemicals including pharmaceutical drugs, steroids,
herbal extracts, and pesticides activate PXR or CAR. This activation
results in induction of overlapping, but yet distinct drug clearance
pathways consisting of cytochrome P450 enzymes, conjugating enzymes,
drug transporters, and other related proteins. Similar pathways are
also utilized to protect the body from toxic compounds of endogenous
origin. Thus, the xenobiotic regulatory circuit contributes both to
drug-drug and food-drug interactions as well as endocrine disruption.
Consistent with the notion that xenobiotic receptors regulate drug clearance,
single nucleotide polymorphisms (SNPs) in either the receptors themselves
or receptor-binding sites in the regulatory region of genes encoding
metabolic enzymes appear to contribute to the polymorphic expression
of components of drug clearance pathways. Together, the xenobiotic receptors
PXR and CAR confer metabolic immunity via the ability to control an
integrated array of target genes.
*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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