Regulation of a xenobiotic sulfonation cascade by nuclear pregnane X receptor (PXR)
Open Access
- 7 October 2002
- journal article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 99 (21), 13801-13806
- https://doi.org/10.1073/pnas.212494599
Abstract
The nuclear receptor PXR (pregnane X receptor) protects the body from hepatotoxicity of secondary bile acids such as lithocholic acid (LCA) by inducing expression of the hydroxylating cytochrome P450 enzyme CYP3A and promoting detoxification. We found that activation of PXR also increases the activity and gene expression of the phase II conjugating enzyme dehydroepiandrosterone sulfotransferase (STD) known to sulfate LCA to facilitate its elimination. This activation is direct and appears to extend to other xenobiotic sulfotransferases as well as to 3′-phosphoadenosine 5′-phosphosulfate synthetase 2 (PAPSS2), an enzyme that generates the donor cofactor for the reaction. Because sulfation plays an important role in the metabolism of many xenobiotics, prescription drugs, and toxins, we propose that PXR serves as a master regulator of the phase I and II responses to facilitate rapid and efficient detoxification and elimination of foreign chemicals.Keywords
This publication has 64 references indexed in Scilit:
- SXR, a novel steroid and xenobioticsensing nuclear receptorGenes & Development, 1998
- Molecular Cloning, Expression, and Functional Characterization of Novel Mouse SulfotransferasesBiochemical and Biophysical Research Communications, 1998
- Regulation of sulfotransferase mRNA expression in male and female rats of various agesChemico-Biological Interactions, 1998
- Different Mechanism of Saturation of Acetaminophen Sulfate Conjugation in Mice and RatsToxicology and Applied Pharmacology, 1996
- Hepatic levels of bile acids in end-stage chronic cholestatic liver diseaseClinica Chimica Acta; International Journal of Clinical Chemistry, 1996
- Rat Chondrosarcoma ATP Sulfurylase and Adenosine 5'-Phosphosulfate Kinase Reside on a Single Bifunctional ProteinBiochemistry, 1994
- Effect of the progestagen R5020 (promegestone) and of progesterone on the uptake and on the transformation of estrone sulfate in the MCF-7 and T-47d human mammary cancer cells: correlation with progesterone receptor levelsCancer Letters, 1992
- Drug metabolism in end-stage liver diseaseJournal of Hepatology, 1990
- COMPARISON OF RIFAMPICIN WITH PHENOBARBITONE FOR TREATMENT OF PRURITUS IN BILIARY CIRRHOSISThe Lancet, 1989
- Fecal steroids and colorectal cancerNutrition and Cancer, 1987